The Effects of the Anti Nausea Drugs Droperidol and Ondansetron 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
      (droperidol or ondansetron) given. We expect that the droperidol or ondansetron 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 droperidol and ondansetron 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: Droperidol and ondansetron are anti-emetics. 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.

           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 droperidol or ondansetron or a combination of
           both. 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 80 unpremedicated ASA I-II children, aged between 3 and 10 years, undergoing
           elective, day case strabismus; otoplasty; ear, nose & throat; dental surgery. After
           obtaining written informed parental consent, and patient assent where appropriate,
           enrolled patients will be randomized to one of 4 groups, to receive a droperidol,
           ondansetron, a combination, or saline. 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. 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. 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 led by SDW. Based on a mean (SD) Tp-e of 59.5 (8.7) msec in 55 pre-operative ECG traces
      from healthy children, a sample size of 9 per group will detect a clinically relevant
      difference of 25 msec in Tp-e between the intra-operative means of the four groups with a
      power of >99% and the criterion for significance, set at 0.01 In order to provide a small
      buffer in group sizes, to allow for any unplanned exclusions, and to allow for detection of
      interactions, we plan to recruit a total of 80 patients; 20 in each of the four groups.
    

Intervention name(s): droperidol and saline; ondansetron and saline; droperidol and ondansetron; saline and saline
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): droperidol 20 mcg.kg-1 and saline; ondansetron 0.1 mg.kg-1 and saline; droperidol 20 mcg.kg-1 and ondansetron 0.1 mg.kg-1; saline and saline
Intervention MeSH terms: Droperidol; Ondansetron
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Randomized; double-blind; 4-group clinical interventional study