The Effects of the Anesthetic Drug Propofol on the Way the Heart Recovers Between Beats
Condition: Myocardial Repolarization
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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
    

Intervention name(s): Propofol
Intervention type(s): Drug
Intervention description(s): See Detailed Description.
Intervention MeSH terms: Propofol
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Randomized; double-blind; 3-group clinical interventional study