Aanesthetic Agents for Day Surgery - NIHR Health Technology ...

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Discussion
Interpretation of the CESA
RCT findings
Prospective data collection using a pragmatic
RCT design was chosen to evaluate the relative
effectiveness, costs and cost-effectiveness of
alternative anaesthetic agents. The robustness
of the findings, the reliability of the data and the
analysis of the CESA RCT need to be considered
in the context of the clinical-trial setting and
population (internal validity) and application
to alternative settings and populations
(external validity).
Internal validity
Although a RCT design was used to prospectively
collect and analyse data, a number of factors may
have affected the reliability of the results of the
evaluation in the trial population and setting.
Bias
Patients were randomly allocated to treatment
groups, using a computer-generated randomisation
schedule. The randomisation sequence was concealed
from the research nurses responsible for
recruitment. The person responsible for generating
the randomisation sequence was not involved
in the recruitment of patients. There were no
differences in the baseline demographic or clinical
characteristics of the patients in the allocation
groups, indicating that randomisation was successful
in minimising selection and allocation bias.
It was not feasible to mask the anaesthetists, the
research nurses responsible for data collection or
the patients to the anaesthetic regimen to which
the patient had been allocated. This may have
affected the treatment given by the anaesthetists,
the researcher’s assessment of outcomes and the
resource use or the patient’s response to the
anaesthetic regimen, leading to bias in the results.
Available evidence suggests that such bias leads
to an overestimation of the treatment effect. 262
To reduce the impact of bias in treatment a clear
treatment protocol was defined, and deviations
from that protocol were monitored. Overall there
were few major protocol violations that could have
biased the results.
The primary outcome of PONV was recorded
by recovery room or ward staff, rather than the
research nurses. These staff were not blinded to
treatment allocation because, to ensure continuity
of care, normal practice is for recovery staff to be
present during induction of anaesthesia. The
measure of PONV combines a subjective
assessment of the incidence of nausea with an
objective assessment of vomiting. It was not
possible to measure whether the patients’
response to anaesthesia or their assessment of
nausea was influenced by knowledge of the
treatment group to which they were allocated.
However, the direction of the treatment effect in
favour of propofol is supported by the literature
review. In addition, the overall incidence of PONV
in the CESA RCT is at the low end of the range
reported in the clinical trial literature. 53,68,69,74,104,108
Precision of measures
The use of unvalidated or unpublished measures
can reduce the precision of measurement and
introduce bias into the results. To minimise this
problem, the CESA RCT used PONV as the
primary outcome. This is a widely used measure
of the short-term effectiveness of alternative
anaesthetic regimens. A widely used method
to measure PONV was used in the CESA RCT.
The cost measures and assessment of patient
preferences and CV were developed specifically
for the study. Both were developed according
to published methods.
The patient preference and CV measures were
based on a previously published study and were
piloted extensively for the CESA RCT. The pilot
and trial analyses of patients’ preferences and
the CV indicated that the majority of patients
understood and were able to complete the task.
However, in the adult study there was a scale effect
that operated for intravenous but not inhalational
induction. This means that the CV for intravenous
induction may be underestimated, which would
bias the analysis in favour of inhalational induction
for adults. The difference in effectiveness and
the net benefit in favour of intravenous induction
with propofol may be higher for adults than
was estimated in this study.
Two substudies of resource use were carried
out as part of the CESA project to improve
the precision of the cost estimates. These were
a volatile anaesthetic validation study (see
appendix 18) and a staff resource use timeand-motion
study (see appendix 19).
The CESA RCT required accurate and detailed
information on the quantities of anaesthetic used.
This is more problematic with volatile anaesthetic
agents because a simple measurement of volume is
not possible, and vaporisers do not record this type
of information. A substudy was designed to validate
the Dion algebraic approximation used in most
studies, 24 by obtaining the actual weight of volatile