Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00624208 |
| Other study ID # |
H07-00615 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
February 18, 2008 |
| Last updated |
November 7, 2017 |
| Start date |
February 2008 |
| Est. completion date |
August 2009 |
Study information
| Verified date |
November 2017 |
| Source |
University of British Columbia |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
