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PEDIATRIC ANESTHESIOLOGY

The Effect of Propofol Concentration on Dispersion of Myocardial Repolarization in Children

Helen V. Hume-Smith, MBBS, BSc, FRCA^*, Shubhayan Sanatani, MD, BSc, FRCPC, Joanne Lim, MASc^*, Anthony Chau, Bsc (Pharm), ACPR^*, and Simon D. Whyte, MBBS, FRCA^*

From the *Department of Pediatric Anesthesia, British Columbia Children’s Hospital and the Department of Anesthesiology, Pharmacology and Therapeutics, Division of Pediatric Cardiology, British Columbia Children’s Hospital and the Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.

Address correspondence and reprint requests to Dr. S. D. Whyte, Department of Pediatric Anesthesia, Room 1L7, British Columbia Children’s Hospital, 4480 Oak St., Vancouver, BC, V6H 3V4, Canada. Address e-mail to swhyte{at}cw.bc.ca.

Abstract

BACKGROUND: QT interval prolongation on the electrocardiogram (ECG) may be drug-induced and is traditionally associated with torsades des pointes. A better predictor of torsades des pointes is the time interval between the peak and the end of the T-wave (Tp-e). Older studies of propofol’s effect on the corrected interval (QTc) are conflicting and confounded by polypharmacy. It was recently shown that target-controlled infusion of propofol at 3 µg/mL has no effect on QTc or Tp-e. This plasma concentration of propofol is at the extreme lower end of the range for surgical anesthesia. In this randomized, double-blind, clinical study, we investigated the dose–response relationship between propofol, QTc, and Tp-e in a range of doses clinically relevant for surgical anesthesia.

METHODS: Sixty healthy unpremedicated children, aged 3–10 yr, were recruited. Subjects were randomized to receive target-controlled infusions of propofol, to achieve 1 of 3 plasma concentrations: 3, 4.5, and 6 µg/mL. A preoperative 12 lead ECG was performed and repeated 5 min after induction. Two investigators, blinded to group allocation and to the timing of the ECG traces, independently measured QTc and Tp-e within and between each group. Paired t-tests were used to compare QTc and Tp-e within groups. One-way analysis of variance was used for intergroup analysis. The primary outcome measure was a change of >25 ms in Tp-e both within and between groups.

RESULTS: ECG recordings were obtained in 51 children. There were no demographic or ECG differences at baseline, at which time QTc and Tp-e values were within normal limits. There were no differences in QTc or Tp-e after induction within or between the three different groups.

DISCUSSION: Propofol has no effect on myocardial repolarization in healthy children at clinically relevant doses. This suggests that propofol would be a rational choice for children with a preexisting repolarization abnormality.

Torsades des pointes (TdP) is a polymorphic ventricular tachycardia that may lead to cardiac arrest in patients with prolongation of myocardial repolarization.

Prolongation of myocardial repolarization is typically associated with long QT syndromes (LQTS). Familial LQTS are caused by inherited defects of myocardial membrane K⁺ and Na⁺ channels. Acquired LQTS are most commonly caused by drugs that block iKr channels, which are partly responsible for conducting the potassium efflux that effects repolarization.

Drug-induced QTc prolongation is not synonymous with drug torsadogenicity (i.e., the risk of causing TdP) (www.torsades.org). A more reliable measure of torsadogenicity is the interval between the peak and the end of the electrocardiogram (ECG) T-wave (Tp-e), which is a surface ECG marker of transmural dispersion of repolarization (TDR) across the myocardial wall. TDR is a physiological phenomenon that results from inhomogeneity of repolarization rates across the myocardial wall, and accounts for the morphology of the T-wave.1,2 Epicardial cells repolarize most rapidly, followed by endocardial cells. Epicardial recovery corresponds to the T-wave peak. Midmyocardial (M) cells have a lower density of K⁺ channels and a higher density of Na⁺ channels compared with adjacent regions.3,4 As a result, these cells repolarize more slowly than either the epicardium or endocardium. Their recovery determines the overall duration of repolarization and corresponds to the end of the T-wave.3,4 It follows that the Tp-e interval is a measure of TDR. Exaggeration of TDR occurs when M cell repolarization is preferentially prolonged. This exacerbates differential refractoriness across the myocardial wall, which allows early after-depolarizations (the R-on-T phenomenon) to initiate and maintain intramyocardial re-entrant circuits.5 A substantial body of research now supports the concept of exaggerated TDR as the substrate for TdP.6–10

The effect of various anesthetics on QTc has been investigated, but few studies have investigated their effect on Tp-e, which is likely a better indicator of drug torsadogenicity. With respect to QT prolongation (and the assumed attendant increased risk of TdP), volatile anesthetics consistently prolong QTc, but studies into the effect of propofol have produced conflicting results, describing no effect,11–13 or prolongation14 of the QTc interval. A preliminary study by our group demonstrated that propofol had no effect on QTc or Tp-e at a target plasma concentration of 3 µg/mL.15,28 This dose of propofol, however, is at the extreme lower end of the range for surgical anesthesia. Furthermore, some drugs show dose-dependent toxicity. The aims of this study were to examine in greater depth the effects of propofol on repolarization dynamics in a pediatric population by investigating the concentration–response relationship between propofol and indices of myocardial repolarization (Tp-e and QTc).

METHODS

With the approval of the institutional and university research and ethics boards, we recruited 60 unpremedicated ASA I–II children, aged between 3 and 10 yr, undergoing elective surgery under general anesthesia. We excluded patients receiving medications known to prolong the QT interval or with a family history of LQTS. After obtaining written informed consent from parents, and the written assent of older children where appropriate, we randomized enrolled patients to receive one of three different target effect–site concentrations of propofol. Block randomization was prepared using computer-generated random numbers with allocation concealed in sequentially numbered opaque envelopes. Before induction of anesthesia, we placed ECG electrodes at standardized locations for acquisition of a preoperative 12 lead ECG. An intraoperative ECG, using the same electrode positions, was taken 5 min after induction of anesthesia when the appropriate target effect–site concentration of propofol had been reached. The subject’s involvement in the study was then complete and conduct of anesthesia continued at the discretion of the supervising anesthesiologist.

All ECGs were recorded in duplicate on a Hewlett Packard Pagewriter Xli Model 1700A (Philips Medical Systems, Bothell, WA) at a paper speed of 50 mm/s. No identifying data or automated analysis were printed on the recorded traces. Each ECG was given a random number three-figure code to allow identification of paired pre- and intraoperative traces after analysis.

Immediately before induction, a peripheral IV cannula was inserted at the site of previously applied topical local anesthetic cream, as is standard practice in our institution. No inhaled anesthetic or nitrous oxide supplementation was used. Children in whom IV access could not be established, for whatever reason, were excluded from the rest of the study. Anesthesia was induced and maintained with a target-controlled infusion (TCI) of propofol, calculated to achieve, after 5 min, a steady-state effect–site concentration value of 3 µg/mL (Group 1), 4.5 µg/mL (Group 2), or 6 µg/mL (Group 3). We used TIVATrainer® (v8.0) with its in-built pediatric pharmacokinetic dataset16 to simulate propofol infusions that would achieve these three target effect–site concentrations in children weighing 10, 15, 20, 25, 30, 35, and 40 kg. Because TCI pumps are not available for clinical use in North America, we took the infusion rates, in milliliter per hour, that the TIVATrainer program would use to drive a TCI pump, and generated infusion regimens to follow during the study period. We grouped the infusion regimens by weight at 5 kg intervals; thus, any child weighing, for example, 17.6–22.5 kg received the 20 kg infusion regimen for the effect–site target to which he or she was randomized.

We maintained the airway by facemask or laryngeal mask airway. Laryngoscopy was not permitted and no other anesthetic drugs were administered during the study period, in an attempt to minimize sympathetic stimulation. Throughout the study period, all children received routine monitoring.

Two authors (SS and SW) independently analyzed all the ECG traces. Both were blinded to the concentration of anesthetic used and to the status of the ECG recording (pre- or intraoperative). Neither was involved in recruitment or randomization of patients, in conduct of anesthesia, nor acquisition of ECG recordings, all of which were performed by HHS and AC.

We measured the QT, RR, and Tp-e intervals in leads II and V5. The QT interval was measured from the start of the QRS complex to the end of the T-wave and the Tp-e interval from the peak of the T-wave to the end of the T-wave. The T-wave end was defined as the point of intersection with the baseline of a line extrapolated from the maximum rate of descent of the T-wave.17 If U waves were present, we defined the end of the T-wave as the nadir of the curve between the T and U-waves. We calculated QTc and Tp-e intervals for three consecutive complete P-QRS-T cycles in each lead and averaged them to give a mean QTc interval and Tp-e interval for that lead. QT intervals were corrected according to the formula of Bazett, where QTc = QT/RR.18

Thus, for leads II and V5 in each trace, we eventually obtained two values for the mean RR interval, the mean QTc interval and the mean Tp-e interval, one from each independent reviewer. On the basis of excellent agreement between the same two reviewers in our previous studies, we did not formally assess interobserver variability of ECG measurements in this study. Instead, we undertook the statistical analysis described below for each individual reviewer’s data, with the intention of returning to formal interobserver variability analysis if significant differences were apparent between the results generated from SS’s and SDW’s data. This did not occur and we therefore proceeded to combine the raw data. Each pair of RR, QTc, and Tp-e values, from leads II and V5 in each ECG trace, one from each reviewer, was averaged to give an overall mean value for use in statistical analysis.

We performed within-group and between-group comparisons of pre- and intraoperative ECG indices using two-way analysis of variance with a priori Bonferroni correction for multiple pairwise testing. Statistical analysis was conducted with Analyze-It® software (Analyze-It Software Ltd., Leeds, England). Using previously published data,15 interpretation of an effect in either direction, and the criterion for significance, , set at <0.003 (<0.01 before a priori Bonferroni correction), we had calculated that a sample size of 14 per group would detect a difference of 25 ms in Tp-e among the three groups with a power of >99%.

RESULTS

Sixty patients were recruited to the study. Lack of cooperation prevented preoperative ECG acquisition in two subjects. Obtaining preinduction IV access was unsuccessful in six subjects. One subject in Group 1 required a further bolus of propofol prior to acquisition of the 5 min ECG. These exclusions left 51 patients with complete data.

There were no significant demographic differences among the three groups generated by randomization (Table 1).

Table 2 shows the results of the within-group analyses of pre- and intraoperative QTc measurements. The QTc interval was normal preoperatively in all three groups, with no significant differences among groups (ANOVA, P = 0.75 and 0.55 for leads II and V5, respectively). Propofol had a tendency to prolong the QTc in a dose-dependent manner in lead II and V5. This did not achieve statistical significance and the QTc never exceeded the upper limit of normal in any group. Between-group analysis of the QTc values at different TCI concentrations of propofol confirmed the absence of a statistically significant dose–response relationship (ANOVA, P = 0.26 and 0.81 for leads II and V5, respectively).

Table 3 shows the results of the within-group analysis of pre- and intraoperative Tp-e measurements. The Tp-e interval was normal preoperatively in all three groups, with no significant differences among the groups (ANOVA, P = 0.97 and 0.68 for leads II and V5, respectively). There were no significant changes in Tp-e in either lead II or V5 after propofol exposure and no dose–response relationship between propofol and Tp-e was demonstrated (ANOVA, P = 0.96 and 0.09 for leads II and V5, respectively).

DISCUSSION

The association of a prolonged QT interval and TdP is deeply entrenched in medical learning. However, QTc prolongation is a poor predictor of the risk of TdP actually occurring: up to 40% of patients with congenital QT prolongation are asymptomatic at the time of diagnosis19; not all drugs that are capable of prolonging the QT interval are torsadogenic (www.torsades.org); 5%–10% of patients with symptomatic LQTS (i.e., syncopal episodes due to TdP) have a baseline QTc that is not absolutely prolonged.20 In arterially perfused canine heart wedge models, it has been demonstrated that QTc prolongation per se does not predispose to TdP, but exaggeration of physiological TDR does.1,21,22 Preclinical drug testing for torsadogenicity includes assessment of the effect of drugs on TDR, although considerable debate continues about the best indices for measuring it.23

The observation, in the arterially perfused wedge model, that conclusion of epicardial repolarization coincides with the peak of the T-wave and completion of M cell repolarization coincides with the end of the T-wave, led to the proposition of the Tp-e interval as a surface ECG marker of TDR.2 Evidence for the validity of this variable in clinical practice continues to accumulate. In patients with acquired LQTS, Tp-e was found by logistic regression analysis to be the best predictor of which patients developed TdP.8 Tp-e is prolonged in symptomatic LQTS patients.9 In assessing the risk of arrhythmia in LQT1 and LQT2, Tp-e appears to be a useful index of TDR.9,10 Tp-e is prolonged in premature neonates receiving the torsadogenic drug cisapride.6

Congenital LQTS are a complex family of channelopathies. Currently three phenotypes with cardiac involvement are recognized, which arise from six genotypes. Many mutations in the long QT genes have been described, not all of which result in phenotypic LQTS. Furthermore, about half of all patients with a LQTS phenotype do not have a recognized mutation, indicating that many causative mutations remain to be elucidated.

Several points of clinical relevance arise from this. The first is that patients with known LQTS may present for incidental surgery, or may require anesthesia for pacemaker or defibrillator insertion. An evidence base for how to most safely anesthetize these patients is lacking. Next, there is a cohort of apparently healthy, normal patients who, in fact, have genotypic LQTS due to a mutation with low or no penetrance. These patients, with so-called latent LQTS, may have reduced repolarization reserve that is insufficient to render them symptomatic, but which may predispose them to do so if other challenges to their repolarization mechanism are mounted. Drugs that influence myocardial repolarization dynamics represent such a challenge and there is evidence that some patients who develop TdP on exposure to torsadogenic drugs do indeed have a preexisting repolarization deficit, courtesy of a silent LQTS genotype.24–27

As previously mentioned, there have been conflicting reports on the effect of propofol on QTc. Moreover, because of the poor ability of QTc to predict TdP, the clinical relevance of anesthetic-induced QTc changes is unclear. Our group has been investigating the effect of anesthetics on Tp-e. In a pilot study, we demonstrated that propofol had no effect on QTc or Tp-e at a target plasma concentration of 3 µg/mL.15 This dose of propofol is insufficient for surgical anesthesia. In the present study, we investigated clinically relevant effect–site concentrations of propofol for their effects on QTc and Tp-e intervals. We found propofol had a dose-dependent tendency to prolong the QTc, which was statistically insignificant, clinically unimportant, and certainly far less than that caused by sevoflurane.16,29 This is consistent with work demonstrating that QT prolongation under inhaled anesthesia can be reversed by conversion to propofol anesthesia.30 Our finding that propofol has no significant effect on Tp-e at clinically relevant doses suggests that propofol is not torsadogenic.

QTc is conventionally measured in lead II. It has been suggested that left precordial lead values may best reflect true TDR.31 We therefore elected to measure QTc and Tp-e in leads II and V5, where we have previously found interobserver agreement to be excellent.

In this study, we based our power calculations on results from our pilot study, in which we found a mean (sd) Tp-e of 72.2 (10.9) ms in 49 preoperative ECG traces from healthy children. We now have preoperative Tp-e data on more than 150 healthy children. Their pooled mean (sd) Tp-e intervals are 69 (11) ms and 72 (13) ms in leads II and V5, respectively, validating our pilot data as a basis for our calculations. In neonates receiving cisapride, Tp-e increased by a mean of 35 ms. Lubinski et al.7 reported a mean increase in Tp-e of 17.2 ms in known LQTS adult patients. These reports led us to select 25 ms as a likely clinically relevant increase in Tp-e. We found Tp-e to be essentially unchanged from the preoperative value after the administration of propofol.

We did not study children with known LQTS, which inevitably makes speculative our conclusions regarding the effects of propofol on dispersion of repolarization in such patients. For this reason, we must emphasize caution in the extrapolation of our findings to these patients. We also did not study the effect of prolonged anesthesia with propofol, although target effect-site concentrations are likely to be <6 µg/mL with prolonged anesthesia.

We used infusion regimens designed to produce predicted effect-site concentrations. We undertook no measurements of actual plasma propofol concentrations or of specific pharmacodynamic end-points that would have allowed us to model the precision or bias of the model, as this was not an objective of the study. We recognize that there will have been inter-patient variability in actual plasma and effect–site concentrations, and that this will have been exacerbated somewhat by rounding our infusion regimens to the nearest 5 kg. This is, however, what happens in routine practice when TCI is used; one accepts that the predicted target is subject to imprecision and bias, but one trusts the model to generate clinically acceptable pharmacodynamic end-points.

With respect to the clinical applicability of our results, we acknowledge that perioperative polypharmacy is the norm, although the use of propofol alone, to provide anesthesia for diagnostic imaging and minor surgical procedures such as lumbar puncture, in pediatric patients is well documented. The aim of this study was to establish the effect of one anesthetic drug, at clinically relevant concentrations, on indices of myocardial repolarization. Having established a baseline anesthetic that appears to have no clinically relevant impact on these variables, we now have, in effect, an in vivo, human, perioperative model into which we can introduce additional drugs of clinical relevance, to assess their effects on myocardial repolarization dynamics.

In conclusion, at clinically relevant doses, propofol has no effect on dispersion of myocardial repolarization, as measured by Tp-e and QTc. We believe it is a rational choice of anesthetic in patients predisposed to a repolarization abnormality.

Footnotes

Accepted for publication April 29, 2008.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hume-Smith, H. V. Articles by Whyte, S. D. Search for Related Content PubMed PubMed Citation Articles by Hume-Smith, H. V. Articles by Whyte, S. D. Related Collections Cardiovascular Heart Clinical Pharmacology Pediatrics Pharmacology