The Effects of the Anesthetic Drug Propofol on the Way the Heart Recovers Between Beats
The Effects of the Anesthetic Drug Propofol on the Way the Heart Recovers Between Beats
We are investigating a new technique for testing the effect of drugs on electrical activity
 in the heart. Disturbances of this electrical activity can cause life-threatening changes to
 heart rhythms. A better way of measuring the risk has recently been developed, and our
 research team leads the world in using this tool to test the safety of drugs used in
 children. Children and their families want to know that the drugs being used are safe, as do
 the doctors that care for them. In this study, we will take heartbeat tracings (ECGs) from 60
 children before and during their operations. The ECGs will then be checked by a children's
 heart specialist. Differences on the ECGs will be related to the presence and amount of drug
 (propofol) given. We expect that the propofol will not cause any changes that show increased
 risk of abnormal heart rhythms. We can then tell patients, parents and regulatory authorities
 of the safety profile of this aspect of the drug; moreover, the study can be used as a model
 for testing many other drugs used in hospitals.
1. Purpose: to examine in detail the effect of propofol on Tp-e (an ECG measure of
 dispersion of repolarization); to search with maximum statistical power for a difference
 in this parameter before and after exposure to this widely used anaesthetic. To
 investigate the nature of any dose-response relationship between propofol and mean QTc
 and Tp-e intervals.

 2. Hypotheses: 1. H0: mean pre-operative Tp-e = mean intra-operative Tp-e within each group
 vs. H1: mean pre-operative Tp-e ≠ mean intra-operative Tp-e within each group. 2. H0:
 mean intra-operative Tp-e group 1 = mean intra-operative Tp-e group 2 = mean
 intra-operative Tp-e group 3 vs. H1: mean intra-operative Tp-e group 1 ≠ mean
 intra-operative Tp-e group 2 ≠ mean intra-operative Tp-e group 3.

 3. Justification: Propofol is an anesthetic agent that is widely used for induction and
 maintenance of anesthesia in children. It has long been thought that prolongation of
 repolarization, however caused, predisposes to a rare malignant ventricular
 tachyarrhythmia called torsades de pointes (TdP). The classic model for this hypothesis
 is a group of hereditary conditions collectively known as long QT syndrome. Although
 rare, this condition usually presents in childhood or early adulthood, with syncope,
 aborted cardiac arrest or sudden death, secondary to episodes of TdP. The genetic
 mutation affects the structure and function of myocardial potassium channels involved in
 repolarization dynamics. Some anaesthetic agents block some of these potassium channels,
 thus prolonging repolarization, producing an acquired long QT syndrome.

 QT interval prolongation per se is associated with, but is not the cause of, TdP. It has
 been shown recently that exaggeration of a physiological phenomenon called dispersion of
 repolarization (TDR) provides the right environment and the trigger for TdP. Normal TDR
 reflects the way that different layers of the myocardial wall repolarize at different
 rates - the outside fastest, then the inside & finally the middle. Physiological TDR
 also determines the morphology of the T wave on the surface ECG. The interval between
 the peak and the end of the T wave is a measure of TDR.

 We therefore now have a new tool for assessing the risk posed by a drug that prolongs
 the QT interval. Evidence is accumulating that, if TDR is not increased, the risk of TdP
 is not increased, even if the QT interval is prolonged. Conversely, if TDR is
 exaggerated, the risk of TdP is raised, even if the absolute QT interval is within
 normal limits.

 In a pilot study, Whyte & colleagues showed that propofol does not increase TDR,
 suggesting that the risk of TdP is not increased with this agent. That study examined
 only one dose at the extreme lower end of the range for surgical anesthesia & had only
 80% power. This study is designed to address those weaknesses and investigate more
 thoroughly the relationship between propofol and TDR, with the aim of being able to
 provide evidence-based recommendations, where none currently exist, on its use in
 patients with or at risk of long QT syndromes.

 4. Objectives: a) to determine whether there is a significant difference between pre and
 post-induction mean QTc interval and mean Tp-e interval for each effect-site target
 concentration of propofol. b) to determine whether there is a relationship between
 propofol dose, and mean QTc and Tp-e intervals. The primary outcome of the study will be
 the presence or absence of differences in Tp-e within and between groups of children
 allocated by randomization to receive one of three therapeutic, clinically relevant,
 effect-site target concentrations of propofol. For each child, the endpoint of the study
 will be 5 minutes after induction of anesthesia.

 5. Research Method: randomised, double-blinded within- and between groups comparative study
 in 60 unpremedicated ASA I-II children, aged between 3 and 10 years, undergoing
 procedural general anaesthesia. After obtaining written informed parental consent, and
 patient assent where appropriate, enrolled patients will be randomized to one of three
 groups, to receive a different steady state effect-site concentration of propofol. Block
 randomization will be prepared using computer generated random numbers. Allocation will
 be concealed using sealed sequentially numbered opaque envelopes. Prior to induction of
 anaesthesia, ECG electrodes will be sited at standardised locations for acquisition of a
 pre-operative 12 lead ECG. An intra-operative ECG, using the same electrode positions,
 will be taken 5 min after induction of anaesthesia, when the appropriate steady state
 effect-site concentration of propofol has been reached. The patient's involvement in the
 study will then be complete and the conduct of anaesthesia continued at the discretion
 of the supervising anaesthetist. All ECGs will be recorded in duplicate, at a paper
 speed of 50 mm/sec and with no identifying data or automated analysis on the recorded
 traces. Each ECG will be given a random number three-figure code, to allow
 identification of paired pre- and intra-operative traces after analysis. IV access will
 be obtained immediately before induction. Anaesthesia will be induced and maintained
 with propofol delivered by a syringe pump. After 5 minutes a steady state will have been
 reached at an effect-site concentration value of 3mcg/ml (group 1), 4.5mcg/ml (group 2)
 or 6mcg/ml (group 3). Throughout the study period, all children will receive routine
 monitoring. In an attempt to minimize sympathetic stimulation, laryngoscopy will not be
 permitted during the study period, and the airway will be maintained either by facemask
 or laryngeal mask. All the ECG traces will be analysed independently by two of the
 authors (SS and SW) in accordance with predetermined criteria. Both will be blinded to
 the study group and to the status of the ECG recording (pre- or intra-operative).
 Neither will be involved in recruitment or randomisation of patients, or in the conduct
 of the anaesthesia or acquisition of ECG recordings, all of which will be performed by
 one of the other investigators.

 Data analysis: the QT and Tp-e intervals will be measured for all complete P-QRS-T cycles in
 leads II and V5 and averaged to give a mean QT interval and Tp-e interval for that lead. The
 QT interval will be measured from the start of the QRS complex to the end of the T-wave,
 defined as the point of return to the T-P baseline. If U waves are present, the end of the
 T-wave will be taken as the nadir of the curve between the T and U waves. The Tp-e interval
 will be measured from the peak of the T-wave to the end of the T-wave. Monophasic T wave
 peaks can be identified visually. For more complex T wave morphologies, the peak will be
 identified according to the criteria of Emori & Antzelevitch.

 Bland -Altman plots will be used to compare the ECG data from the two independent reviewers.
 Where an inter-observer difference of >10 msec in an RR interval or >20 msec in a QT or Tp-e
 interval is found, the recordings, still coded, will be re-analysed and a consensus reached
 if possible. Thus for each lead in each trace, two values for the mean RR interval, the mean
 QTc interval and the mean Tp-e interval, one from each independent reviewer, will be
 obtained. Each pair of values will then be averaged to give an overall value, which will then
 be used for further statistical analysis. Within-group and between-group comparisons of pre-
 and intra-operative ECG indices will be performed using two-way analysis of variance. Data
 analysis will be conducted by AC and SDW using Analyse-It® (Analyse-It software, Leeds, UK).

 Sample size calculation: We have based our power calculations on results from a previous
 study carried out by Whyte et al. They found a mean (SD) Tp-e of 72.2 (10.9) msec in 49
 pre-operative ECG traces from healthy children. The smallest ECG difference we can reliably
 detect is half of one small ECG square. At a paper speed of 50 mm/sec, this equates to 10
 msec. However, the standard deviation Tp-e in pre-operative traces is 11 msec, so 10 ms is
 unlikely to be a clinically significant difference. In neonates on cisapride, Tp-e increased
 by a mean of 35 msec. Lubinski et al reported a mean increase in Tp-e of 17.2 msec in known
 (therefore presumably treated) LQTS adult patients. Searching for a larger difference would
 reduce the likelihood of any true difference being due to inter-observer variability. A
 sample size of 14 per group will detect a difference of 25 msec in Tp-e between the
 intra-operative means of the three groups with a power of 99% and the criterion for
 significance set at 0.003 ( 0.01 before a priori Bonferroni correction). In order to provide
 a small buffer in group sizes, to allow for unplanned exclusions, we plan to recruit 60
 patients in total; 20 in each of the three groups
Inclusion Criteria:

 -  Health children (ASA I-II) undergoing procedures that require general anesthesia
 without pre-medication.

 Exclusion Criteria:

 -  Children with long QT syndrome, a family history of long QT syndrome or taking
 medication that is known to prolong the QT interval.

 -  IV access unobtainable pre-operatively.