Ignite Creation Date:
2024-05-05 @ 4:52 PM
Last Modification Date:
2024-10-26 @ 9:25 AM
Study NCT ID:
NCT00334009
Status:
COMPLETED
Last Update Posted:
2008-03-06
First Post:
2006-06-05
Brief Title:
Catecholamine-O-Methyl-TransferaseCOMT-Polymorphism in Cardiac Surgery
Sponsor:
Austin Health
Organization:
Austin Health
Study Overview
Official Title:
Impact of Catecholamine-O-Methyl-Transferase Enzyme Activity on Clinical and Biological Parameters in Patients After Cardiac Surgery
Status:
COMPLETED
Status Verified Date:
2008-03
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:
Although clinical risk factors for postoperative development of vasodilatory shock and acute renal failure have been identified there is a considerable proportion of patients undergoing cardiac surgery where this syndrome cannot be predicted
We sought to investigate the impact of Catecholamine-O-Methyltransferase COMT polymorphism on the duration of vasodilatory shock and other important clinical outcomes in cardiac surgery patients
COMT is a key enzyme in the degradation of catechols eg catecholamines 25 of the population have a low activity LL of this enzyme Sustained low COMT activity is associated with an altered metabolic profile of catecholamines and their degradation products
The process of cardiopulmonary bypass CPBover-activates some of the same mechanisms the body uses to defend itself against severe infection One of the main overactive defence mechanisms is the release of highly toxic compounds derived from oxygen - a process called oxidative-stress Increased reactive oxygen species ROS generation can lead to inactivation of biologic mediators including catecholamines It is well established that some radicals autoxidizes catecholamines including DA NE and epinephrine and contribute significantly to vasoplegia
As part of this study we will take six 27mL samples of blood collected before and after the operation from the arterial catheter routinely inserted in every patient This blood will be used to measure COMT genotype the concentration of plasma-catecholamines as well as marker of oxidative stress
Our plan is to enrol patients undergoing cardiac surgery if the use of the CPB is planned
We sought to investigate the impact of Catecholamine-O-Methyltransferase COMT polymorphism on the duration of vasodilatory shock and other important clinical outcomes in cardiac surgery patients
COMT is a key enzyme in the degradation of catechols eg catecholamines 25 of the population have a low activity LL of this enzyme Sustained low COMT activity is associated with an altered metabolic profile of catecholamines and their degradation products
The process of cardiopulmonary bypass CPBover-activates some of the same mechanisms the body uses to defend itself against severe infection One of the main overactive defence mechanisms is the release of highly toxic compounds derived from oxygen - a process called oxidative-stress Increased reactive oxygen species ROS generation can lead to inactivation of biologic mediators including catecholamines It is well established that some radicals autoxidizes catecholamines including DA NE and epinephrine and contribute significantly to vasoplegia
As part of this study we will take six 27mL samples of blood collected before and after the operation from the arterial catheter routinely inserted in every patient This blood will be used to measure COMT genotype the concentration of plasma-catecholamines as well as marker of oxidative stress
Our plan is to enrol patients undergoing cardiac surgery if the use of the CPB is planned
Detailed Description:
Aim of the study
To explore if there is an impact of LL COMT genotype on clinical and biological outcome variables in patients undergoing cardiac surgery compared to HH genotype
Background
Cardiac surgery has been shown to be an effective method for prolonging life in patients with severe coronary artery disease or valvular disease or a combination thereof
Catechol-O-Methyl-Transferase COMT catalyses the O-methylation of biologically active catechols and is responsible for the degradation of catecholamines and catecholestradiols
COMT is an intracellular enzyme which is widely distributed throughout most of all human tissues Roth Maennistoe Because COMT is expressed ubiquitously it appears that the COMT genotype significantly affects levels of catecholamines throughout the body
25 of Caucasians are homozygous for low COMT activity COMT LLMetMet 25 are homozygous for high activity of COMT COMT HHValVal and about 50 are heterozygous COMT HLValMet Palmatier Spielman Boudikova
Thus COMT polymorphism may play an important role in the outcome of patients after cardiac surgery
So far studies due to this polymorphism exist only for chronic non-cardiac surgery disorders like psychiatric diseases breast cancer and alcoholism
In a prospective observational study we used this model of CPB-induced stress-mediated vasodilatory shock to investigate the impact of COMT polymorphism on relevant postoperative clinical outcomes Within this model we tested the hypothesis that in cardiac surgery patients the LL COMT genotype is associated with alterations in catecholamine metabolism and adverse hospital outcomes such as prolonged vasopressor support and acute renal failure compared to HL and HH COMT genotype
Patients with a LL COMT polymorphism are probably used to higher concentrations of endogenous catecholamines because a low COMT enzyme activity can cause an impaired degradation of catecholamines Patients with a LL COMT polymorphism require presumably higher catecholamines support than other patients to maintain cardiovascular stability in extreme stress-conditions occuring during CPB procedures
Acute renal failure ARF is a common postoperative complication in cardiac surgery patients that is associated with increased morbidity and mortality Catechol-O-methyltransferase COMT shows high activity in proximal tubular epithelial cells - target cell in ARF We hypothesized that the COMT met158 genotype might be associated with increased risk of acute renal failure compared to COMT val158 genotype
CPB activates components of the non-specific immune system which leads to the generation of compounds containing oxygen free radicals A study of 14 patients undergoing cardiac surgery found increased levels of serum lipid peroxidation products thiobarbituric acid reactive substances within 15 minutes of the commencement of CPB which returned to preoperative levels by the following morning The total serum antioxidative capacity was correspondingly decreased intraoperatively and remained decreased at 24 hours postoperatively
Outcomes will be the length of vasopressor support in patients with LL COMT genotype compared to patients with HL and HH COMT genotype We hypothesize that there is a significant increase in the duration of vasopressor support in patients with LL COMT compared to patients with HL and HH COMT genotype
Additional outcome measure and hypotheses
We hypothesize that differences similar to that seen in the duration of vasopressor support will be seen in a higher proportion of postoperative acute renal failure increase in serum creatinine 50 from baseline to peak value longer duration of ICU and hospital stay in LL COMT patients compared to HL and HH patients
COMT genotype will be determined and levels of endogenous catecholamines will be measured before and after cardiac surgery We hypothesize that higher levels of endogenous catecholamines will be measured for patients with LL COMT genotype
Study Design - overview and rationale
COMT genotype and outcome measurements of patients after cardiac surgery will be analyzed in this study Concentrations of plasma catecholamines and important degradation products will be determined before and after the use of CPB The duration and dose of postoperative vasopressor support as well as stay in ICU and stay in hospital will be documented
Data collection
age sex body mass index BMI body surface area BSA insulin IDDM or non-insulin dependent diabetes mellitus NIDDM arterial hypertension hypercholesterolemia preoperative serum creatinine chronic obstructive pulmonary disease COPD smoking status peripheral vascular disease PVD carotid artery disease myocardial infarction MI or stroke within last six months atrial fibrillation AF and grade of left ventricular dysfunction defined by the left ventricular ejection fraction using EuroScore definition Pre-operative medication including platelet inhibitors ACE-inhibitorsangiotensin-II-receptor1-antagonists beta-blocker calcium channel blocker and statins
Intra-operative data on type of cardiac surgery valvular or coronary artery bypass CABG concomitant or complex cardiac surgery involving the ascending aorta Redo operation take back to operating room electronically stored MAP and duration of CPB The intra- and post-operative use of vasopressor norepinephrine epinephrine phenylephrine ephedrine and metaraminol and inotropic medications milrinone dobutaminehourly until discharge from the Intensive Care Unit ICU We will note the lowest MAP and the lowest cardiac index CI every 6 hours Postoperative serum creatinine will be measured daily Finally ICU and hospital length of stay as well as hospital mortality were documented
Withdrawal The treating clinician will have the right to withdraw the patient from the study if he or she believes that continued participation is jeopardising the patients well being
Ethical Issues Given the potential knowledge for the future the balance of benefits and risks we consider it ethical to proceed and seek informed consent This is not a drug trial or an interventional trial
Indemnity This is an investigator-initiated study and is not sponsored by industry The investigator is a member of staff at Austin Hospital the hospital is responsible for indemnifying the investigator in relation to this study Warringal Private Hospital will be responsible for indemnification for patients recruited there
To explore if there is an impact of LL COMT genotype on clinical and biological outcome variables in patients undergoing cardiac surgery compared to HH genotype
Background
Cardiac surgery has been shown to be an effective method for prolonging life in patients with severe coronary artery disease or valvular disease or a combination thereof
Catechol-O-Methyl-Transferase COMT catalyses the O-methylation of biologically active catechols and is responsible for the degradation of catecholamines and catecholestradiols
COMT is an intracellular enzyme which is widely distributed throughout most of all human tissues Roth Maennistoe Because COMT is expressed ubiquitously it appears that the COMT genotype significantly affects levels of catecholamines throughout the body
25 of Caucasians are homozygous for low COMT activity COMT LLMetMet 25 are homozygous for high activity of COMT COMT HHValVal and about 50 are heterozygous COMT HLValMet Palmatier Spielman Boudikova
Thus COMT polymorphism may play an important role in the outcome of patients after cardiac surgery
So far studies due to this polymorphism exist only for chronic non-cardiac surgery disorders like psychiatric diseases breast cancer and alcoholism
In a prospective observational study we used this model of CPB-induced stress-mediated vasodilatory shock to investigate the impact of COMT polymorphism on relevant postoperative clinical outcomes Within this model we tested the hypothesis that in cardiac surgery patients the LL COMT genotype is associated with alterations in catecholamine metabolism and adverse hospital outcomes such as prolonged vasopressor support and acute renal failure compared to HL and HH COMT genotype
Patients with a LL COMT polymorphism are probably used to higher concentrations of endogenous catecholamines because a low COMT enzyme activity can cause an impaired degradation of catecholamines Patients with a LL COMT polymorphism require presumably higher catecholamines support than other patients to maintain cardiovascular stability in extreme stress-conditions occuring during CPB procedures
Acute renal failure ARF is a common postoperative complication in cardiac surgery patients that is associated with increased morbidity and mortality Catechol-O-methyltransferase COMT shows high activity in proximal tubular epithelial cells - target cell in ARF We hypothesized that the COMT met158 genotype might be associated with increased risk of acute renal failure compared to COMT val158 genotype
CPB activates components of the non-specific immune system which leads to the generation of compounds containing oxygen free radicals A study of 14 patients undergoing cardiac surgery found increased levels of serum lipid peroxidation products thiobarbituric acid reactive substances within 15 minutes of the commencement of CPB which returned to preoperative levels by the following morning The total serum antioxidative capacity was correspondingly decreased intraoperatively and remained decreased at 24 hours postoperatively
Outcomes will be the length of vasopressor support in patients with LL COMT genotype compared to patients with HL and HH COMT genotype We hypothesize that there is a significant increase in the duration of vasopressor support in patients with LL COMT compared to patients with HL and HH COMT genotype
Additional outcome measure and hypotheses
We hypothesize that differences similar to that seen in the duration of vasopressor support will be seen in a higher proportion of postoperative acute renal failure increase in serum creatinine 50 from baseline to peak value longer duration of ICU and hospital stay in LL COMT patients compared to HL and HH patients
COMT genotype will be determined and levels of endogenous catecholamines will be measured before and after cardiac surgery We hypothesize that higher levels of endogenous catecholamines will be measured for patients with LL COMT genotype
Study Design - overview and rationale
COMT genotype and outcome measurements of patients after cardiac surgery will be analyzed in this study Concentrations of plasma catecholamines and important degradation products will be determined before and after the use of CPB The duration and dose of postoperative vasopressor support as well as stay in ICU and stay in hospital will be documented
Data collection
age sex body mass index BMI body surface area BSA insulin IDDM or non-insulin dependent diabetes mellitus NIDDM arterial hypertension hypercholesterolemia preoperative serum creatinine chronic obstructive pulmonary disease COPD smoking status peripheral vascular disease PVD carotid artery disease myocardial infarction MI or stroke within last six months atrial fibrillation AF and grade of left ventricular dysfunction defined by the left ventricular ejection fraction using EuroScore definition Pre-operative medication including platelet inhibitors ACE-inhibitorsangiotensin-II-receptor1-antagonists beta-blocker calcium channel blocker and statins
Intra-operative data on type of cardiac surgery valvular or coronary artery bypass CABG concomitant or complex cardiac surgery involving the ascending aorta Redo operation take back to operating room electronically stored MAP and duration of CPB The intra- and post-operative use of vasopressor norepinephrine epinephrine phenylephrine ephedrine and metaraminol and inotropic medications milrinone dobutaminehourly until discharge from the Intensive Care Unit ICU We will note the lowest MAP and the lowest cardiac index CI every 6 hours Postoperative serum creatinine will be measured daily Finally ICU and hospital length of stay as well as hospital mortality were documented
Withdrawal The treating clinician will have the right to withdraw the patient from the study if he or she believes that continued participation is jeopardising the patients well being
Ethical Issues Given the potential knowledge for the future the balance of benefits and risks we consider it ethical to proceed and seek informed consent This is not a drug trial or an interventional trial
Indemnity This is an investigator-initiated study and is not sponsored by industry The investigator is a member of staff at Austin Hospital the hospital is responsible for indemnifying the investigator in relation to this study Warringal Private Hospital will be responsible for indemnification for patients recruited there
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