Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT00144118 |
| Other study ID # |
H2000/01072 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 4
|
| First received |
September 2, 2005 |
| Last updated |
September 2, 2005 |
| Start date |
January 2002 |
| Est. completion date |
August 2005 |
Study information
| Verified date |
August 2005 |
| Source |
Austin Health |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Australia: Department of Health and Ageing Therapeutic Goods Administration |
| Study type |
Interventional
|
Clinical Trial Summary
The purpose of this study is to determine if isoflurane and sevoflurane have similar effects
on the kidneys of people with impaired kidneys when the drugs administered with low gas flow
into anaesthetic machines.
Description:
Study Protocol Post-Operative Creatinine Changes In Patients With Pre-Existing Renal
Impairment After Low-Flow Isoflurane Or Sevoflurane: A Randomised Clinical Trial
Introduction
Sevoflurane is a volatile anaesthetic agent available for clinical use in most countries
including Australia, the United States, the United Kingdom, and Canada. Since the first
clinical use of sevoflurane in Japan during the 1980s, millions of anaesthetics have been
given with sevoflurane. Sevoflurane has a number of advantages over other agents for general
anaesthesia, particularly isoflurane. The benefits to patients and the environment include:
- A lower blood and tissue solubility allows patients to wake up faster after anaesthesia
1, 2.
- The lower blood solubility allows faster titration during surgery.
- Heart rate is more stable during increases in inspired concentration.
- Airway resistance is lower than with other volatile agents.
- A pleasant smell allows gas induction
- There is less nausea and vomiting than with isoflurane
- It is a fluorocarbon rather than a chlorofluorocarbon and does not worsen the
atmospheric ozone hole.
The most important concern about sevoflurane is its effect on renal function due to
breakdown products. When sevoflurane is exposed to the carbon dioxide absorbents soda lime
and baralyme a vinyl breakdown product called Compound-A is formed. High dose exposure to
Compound-A alters kidney histology in rats. Some, but not all, studies have found that
Compound-A produces increases urinary secretion of renal tubule enzymes in humans. The
clinical importance of enzyme secretion is unclear.
The most widely used indicator of renal function that has established clinical importance is
plasma creatinine concentration. No study of sevoflurane has shown that sevoflurane produces
greater increases in plasma creatinine concentration than other anaesthetic drugs. The
Austin Health Department of Anaesthesia has recently completed a study in cardiac
anaesthesia that included sevoflurane. We found that, comparing isoflurane, sevoflurane, and
propofol, there was no difference in creatinine change after surgery between the three
groups. This study will be published in Anesthesiology, the manuscript is attached.
The fresh gas flow into an anaesthetic machine is the amount of oxygen, or oxygen and air,
or oxygen and nitrous oxide that flows into the anaesthetic circuit per minute. Moderate
fresh gas flows are around 3 l/min. Low fresh gas flows are around 1 l/min. Low fresh gas
flows have benefits for patients, the environment, and the hospital:
- Patients lose less heat
- Patients lose less water
- There is less environmental contamination with chlorofluorocarbons and nitrous oxide (a
green house gas).
- Lower anaesthetic costs.
At low fresh gas flows, patients are exposed to higher concentrations of Compound A.
A recent multicentre study looked at creatinine changes after major surgery. This study
found no difference between isoflurane and sevoflurane with low fresh gas flows of 1 l/min.
Patients with pre-existing renal impairment were excluded.
Pre-operative renal impairment increases the risk of clinically important deterioration of
renal function after surgery. Studies of changes in creatinine after sevoflurane have
included only a small number of patients with pre-existing renal impairment 10. None of
these small studies has shown that sevoflurane aggravates pre-existing renal impairment more
than other anaesthetic drugs. This includes a subgroup analysis in our Cardiac Anaesthesia
study. No study, however, has examined creatinine changes in those with pre-existing renal
impairment and with low fresh gas flow. This would expose those with increased risk of
further renal impairment to greater doses of Compound-A. From other research and our own, we
believe that sevoflurane would not affect renal function more than isoflurane in patients
with preexisting renal impairment receiving low flow anesthesia.
Research Question What are the post operative changes in serum creatinine after anaesthesia
with sevoflurane or isoflurane using fresh gas flows of 1 l/min in patients with
pre-operative renal impairment?
Methods The study methods draw heavily on our previous study 7, copy attached. The study
design conforms to the Consolidated Standard of Reporting Trials (CONSORT) 11.
Study type Randomized, clinical trial.
Study Site Austin and Repatriation Medical Centre
Eligible patients
Adult patients for elective surgery who will:
1. need to stay at least one night
2. need general anaesthesia
3. have a pre-operative serum creatinine concentration greater than 130 umol/l.
Exclusions
1. The patient refuses.
2. The patient is less than 18 years of age.
3. The patient is on pre-operative dialysis
4. The anaesthetist plans to use only regional or total intravenous anaesthesia.
5. Specific types of surgery: craniotomy, carotid, and cardiac.
Recruiting One of the investigators will recruit patients as soon as possible after the
patients are booked for surgery. We expect to enroll at least 3 patients per week.
Treatment arms
1. Isoflurane OR 2. Sevoflurane Anaesthesia maintenance will be with fresh gas flows of 1
l/min and inspired oxygen of 30% to 100% in nitrogen (oxygen/air) or nitrous oxide.
Individual anaesthetists will determine all other aspects of the peri-operative care
including fluid therapy.
Random allocation Patients will be randomly allocated to receive isoflurane or sevoflurane.
Before the trial ARMC pharmacy staff will provide the allocation sequence using a table of
random numbers. Allocations will be kept in opaque envelopes by the trial coordinator.
Anaesthetists will be notified of the allocation to isoflurane or sevoflurane on the day of
surgery.
Primary end point The primary end point will be the highest change in serum creatinine from
before operation to the first three days postoperatively. Supporting data will be from the
highest creatinine and urea in the first three postoperative days. Patients leaving hospital
before 3 postoperative days will be included. Good clinical care for patients with renal
impairment includes a creatinine measurement on admission and at least one postoperative
creatinine measurement. The trial coordinator will oversee this. The data for this study
will be from clinically indicated tests. Specific blood tests for this study will not be
needed. Data will be collected from the ARMC clinical chemistry results. Data will be stored
on computer in a secure are of the ARMC Department of Anaesthesia in line with the
Therapeutic Goods Administration Guidelines for Good Clinical Research Practice in
Australia.
Clinically important changes
When analysing the differences between the isoflurane and sevoflurane groups, two criteria
will need to be met for the changes in creatinine to be clinically important:
1. at least one mean increase in creatinine will be greater than 45 umol/l above
pre-operative concentration AND
2. the difference between the means will be greater than 20 umol/l. For example: The group
1 mean rises by 50 umol/l and the group 2 mean rises by 25 umol/l.
Power analysis Using a standard deviation of 50 umol/l from our Cardiac Anaesthesia trial
data, for a power of 0.90, alpha < 0.05, to detect a 20 umol/l difference between 2 groups
we would need 270 patients. We estimate we would need two years to complete this study.
Data Collection and Statistical analysis Data will be collected and analysed by
investigators blinded to the drug allocation. Statistical analysis will be by parametric
tests if data are normally distributed. Otherwise equivalent non-parametric tests will be
used.
The statistics will be the point estimate for the difference between the isoflurane and
sevoflurane increases in creatinine, the 95% confidence interval for the point estimate, and
the p value from an unpaired Student’s t-test.
An additional analysis will be an estimate of the proportions of patients in the isoflurane
and sevoflurane groups who have a postoperative creatinine change greater than 45 umol/l.
The statistics will be the point estimate for the difference in the proportions, the 95%
confidence interval for the point estimate, and the p value from a Chi square test.
Supporting statistics will be from the point estimates for the difference between the peak
creatinine and urea, the 95% confidence interval for the point estimates, and the p values
from unpaired Student’s t-tests.
Adverse events. In addition to usual clinical care, patients in this study will have added
surveillance of their clinical chemistry results. Important changes will be passed on to the
surgical units caring for the patient. The investigators will notify the ARMC Human Research
Ethics Committee of any death or serious morbidity of patients enrolled in this study.
Significance of the project For this large trial, with a simple design, our hypothesis is
that sevoflurane will not produce greater increases in creatinine than isoflurane in
patients with preexisting renal impairment. For this project an unequivocal finding would be
that the 95% confidence intervals for the differences between the isoflurane and sevoflurane
groups did not include clinically important differences and that any differences that were
found had a p value of greater than 0.05. Unequivocal findings would lead us to two
conclusions: (1) that it is highly unlikely that sevoflurane has clinically important
adverse renal effects, and (2) that sevoflurane is safe to use with low fresh gas flows in
patients with preexisting renal impairment.
The benefits of sevoflurane and low fresh gas flows are discussed in the introduction. A
finding of no adverse renal effects would provide high quality evidence supporting the
safety of using sevoflurane and low fresh gas flows in patients with preexisting renal
impairment.
