Ignite Creation Date:
2024-05-05 @ 11:48 AM
Last Modification Date:
2024-10-26 @ 9:14 AM
Study NCT ID:
NCT00144118
Status:
TERMINATED
Last Update Posted:
2005-09-05
First Post:
2005-09-02
Brief Title:
The Effect of Isoflurane or Sevoflurane on Kidney Function
Sponsor:
Austin Health
Organization:
Austin Health
Study Overview
Official Title:
Post-Operative Creatinine Changes In Patients With Pre-Existing Renal Impairment After Low-Flow Isoflurane Or Sevoflurane A Randomised Clinical Trial
Status:
TERMINATED
Status Verified Date:
2005-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
Detailed 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 lmin Low fresh gas flows are around 1 lmin 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 lmin 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 lmin 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 umoll
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 lmin and inspired oxygen of 30 to 100 in nitrogen oxygenair 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 umoll above pre-operative concentration AND
2 the difference between the means will be greater than 20 umoll For example The group 1 mean rises by 50 umoll and the group 2 mean rises by 25 umoll
Power analysis Using a standard deviation of 50 umoll from our Cardiac Anaesthesia trial data for a power of 090 alpha 005 to detect a 20 umoll 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 Students 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 umoll 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 Students 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 005 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
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 lmin Low fresh gas flows are around 1 lmin 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 lmin 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 lmin 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 umoll
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 lmin and inspired oxygen of 30 to 100 in nitrogen oxygenair 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 umoll above pre-operative concentration AND
2 the difference between the means will be greater than 20 umoll For example The group 1 mean rises by 50 umoll and the group 2 mean rises by 25 umoll
Power analysis Using a standard deviation of 50 umoll from our Cardiac Anaesthesia trial data for a power of 090 alpha 005 to detect a 20 umoll 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 Students 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 umoll 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 Students 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 005 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None