The Effects of the Anti Nausea Drugs Droperidol and Ondansetron on the Way the Heart Recovers Between Beats
Information source: University of British Columbia
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Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Myocardial Repolarization
Intervention: droperidol and saline (Drug); ondansetron and saline (Drug); droperidol and ondansetron (Drug); saline and saline (Drug)
Sponsored by: University of British Columbia
Official(s) and/or principal investigator(s):
Simon Whyte, MD, Principal Investigator, Affiliation: University of British Columbia
Mark Ansermino, MD, Study Director, Affiliation: University of British Columbia
Shubhayan Sanatani, MD, Study Director, Affiliation: University of British Columbia
Joanne Lim, Study Director, Affiliation: University of British Columbia
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.
Official title: The Effects of Droperidol and Ondansetron on Dispersion of Myocardial Repolarization in Children
Study design: Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
Primary outcome: Change in Tpeak-end interval before & after intervention & between groups.
Secondary outcome: Change in QT intervals before & after intervention & between groups.
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
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
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
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,
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.
Minimum age: 3 Years.
Maximum age: 10 Years.
- Healthy children (ASA I-II) undergoing procedures that require general anesthesia
- 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.
Locations and Contacts
BC Children's Hospital, Vancouver, British Columbia V6H 3V4, Canada
Starting date: February 2008
Last updated: August 17, 2009