Ignite Creation Date:
2024-05-05 @ 4:59 PM
Last Modification Date:
2024-10-26 @ 9:26 AM
Study NCT ID:
NCT00361751
Status:
COMPLETED
Last Update Posted:
2010-02-15
First Post:
2006-08-07
Brief Title:
Substrate Cycling in Energy Metabolism
Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases NIDDK
Organization:
National Institute of Diabetes and Digestive and Kidney Diseases NIDDK
Study Overview
Official Title:
Phase 2 Trial to Examine the Metabolic Effects of Fenofibrate in Burned Patients
Status:
COMPLETED
Status Verified Date:
2010-02
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:
Insulin resistance and hyperglycemia contribute to negative outcomes in burned patients We will assess insulin sensitivity in traditional terms of glucose metabolism and with regard to the responsiveness of both muscle and liver protein metabolism in severely burned patients Plasma free fatty acid FFA and tissue TG levels will be manipulated via inhibition of peripheral lipolysis with nicotinic acid or activation of plasma lipoprotein lipase activity with heparin stimulation of tissue fatty acid oxidation and thus reduction of tissue TG with the peroxisome proliferate-activated receptor PPAR alpha agonist fenofibrate Methodological approaches will include stable isotope tracer techniques to quantify kinetic responses of protein glucose and lipid metabolism in vivo quantification of intracellular stores of TG and glycogen by means of magnetic resonance spectroscopy MRS as well as quantitative analysis of tissue levels of active products of fatty acids key intermediates of the insulin signaling pathway glycogen the enzyme activities of citrate synthase and glycogen synthase and the activity of the muscle mitochondria These studies will clarify the physiological and clinical significance of the alterations of tissue lipid metabolism that occur after burn injury thereby forming the basis for new therapeutic approaches not only in this specific clinical condition but in other clinical circumstances in which hepatic andor muscle TG is elevated
We will investigate the general hypothesis that the accumulation of intracellular TG in liver and muscle either directly causes insulin resistance in those tissues or serves as an indictor of the intracellular accumulation of active fatty acid products such as fatty acyl CoA and diacylglycerol which in turn disrupt insulin action
The following specific hypotheses will be investigated
1 Intracellular TG is elevated in both muscle and liver in severely burned patients The reduction of the fat in the liver and the insulin resistance will improve clinical outcomes glucose and protein metabolism
2 The insulin signaling pathway as reflected by phosphoinositol-3-kinase PI3K and PKC activity is impaired in tissues with elevated TG
3 Fatty acids or their active intracellular products are the direct inhibitors of insulin action rather than the tissue TG itself
We will investigate the general hypothesis that the accumulation of intracellular TG in liver and muscle either directly causes insulin resistance in those tissues or serves as an indictor of the intracellular accumulation of active fatty acid products such as fatty acyl CoA and diacylglycerol which in turn disrupt insulin action
The following specific hypotheses will be investigated
1 Intracellular TG is elevated in both muscle and liver in severely burned patients The reduction of the fat in the liver and the insulin resistance will improve clinical outcomes glucose and protein metabolism
2 The insulin signaling pathway as reflected by phosphoinositol-3-kinase PI3K and PKC activity is impaired in tissues with elevated TG
3 Fatty acids or their active intracellular products are the direct inhibitors of insulin action rather than the tissue TG itself
Detailed Description:
We will study patients with severe burns defined as 2nd or 3rd degree burn covering 40 of total body surface area TBSA We propose to study burned children from Shriners Burns Hospital The Shriners census is such that approximately 50 children with severe burns are treated every year We will study patients immediately prior to their third surgical procedure approximately 12-15 days after injury One half of the patients will be given fenofibrate 5 mgkgday daily delivered through feeding tube from the time of consent following admission until 12-14 days post-burn This length of time after injury will ensure that untreated patients will have a large accumulation of hepatic TG Because the control group of patients will have elevated liver TGs the experimental group will have their hepatic TGs lowered by fenofibrate By studying the patients the day before the operations it will be possible to remove the staples used in skin grafting without risk of loss of adhesion of the graph thereby ensuring safety in the MRS Femoral line inserted for the surgery can also be utilized and all patient generally receive a full transfusion during surgeries minimizing any study related blood loss In addition to the liver we will study the muscle in burn patients Patients will be studied during brief fasted state The will be fasted four hours prior to the study and then through out the study Their TPN will be immediately reconnected following the study The surgical team at the Shrine places 3Fr 8 cm polyethylene catheters Cook Inc Bloomington IN into the femoral vein and femoral artery under local anesthesia the day before surgery Both femoral catheters will be used for blood sampling while the femoral arterial catheter will also used for indocyanine green infusion for the determination of leg blood flow Systemic concentration of indocyanine green will be measured from a central vein as standard procedure has a multi-lumen subclavian line in all patients Patency of all catheters is maintained by saline infusion
Patients will be infused with stable non-radioactive isotope tracers of glucose phenylalanine and palmitate for up to 8 hours After 4 hours without interruption of the tracer infusion an infusion of insulin will be started and maintained at the rate of 15 mUkgmin for the final 4 h Blood glucose concentrations will be measured throughout the insulin infusion and glucose infused as necessary to maintain the basal plasma glucose concentration
A biopsy of the quadriceps will be obtained with a Bergstrom needle at the beginning of the study 4 h immediately before the insulin infusion and at the end of the 4 h insulin infusion We will use the A-V balance technique to address the relation between tissue fatty acid and TG metabolism and the insulin responsiveness of glucose uptake and myofibrillar and mitochondrial protein synthesis and net protein balance
b Subjects Patients are admitted to the burn unit within 48 h of injury Fluid resuscitation is provided as previously described 94 Within 48 h of admission the burn wound is excised and subsequently grafted by autograft or cadaveric allograft Patients typically return to the operating room for reharvesting of donor sites every five to seven days The experiments proposed here will be performed the day prior to the third surgery at day 12-15 as femoral catheters are normally inserted at the time for access during surgery Enteral feeding with Vivonex TEN Sandoz Nutrition Corp Minneapolis MN is started within 24h of admission and continued until the patient is capable of food by mouth All patients will be eligible for the study unless one of the exclusion criterion listed below apply
c Procedures From day 1 to day 22 patients will be maintained on enteral feeding of a high carbohydrateamino acid mixture Vivonex Novartis Minneapolis MN Vivonex contains 300 kcalserving in the following caloric breakdown 823 carbohydrate 15 protein 27 fat linoleic acid Patients will be given 25 kcalkg of Vivonex plus an additional 45 kcalkg for each percentage point of total body surface area burned One half of the patients will be given fenofibrate 5 mgkgday - maximum daily dose from the time of the first tracer study until the time of the second tracer study
The tracer study subjects can commence once catheters in the femoral artery and vein have been placed by the surgical team if necessary since the majority of patients wil have pre-existing lines placed for clinical reasons The catheters will be used for sampling and in a peripheral vein for infusing as in our previous studies eg 4 Enteral administration of a mixture of carbohydrate and amino acids Vivonex will be stopped four hours prior to the study and will be started immediately following the study
On the day after the tracer infusion the amount of liver and muscle TG and liver glycogen will be determined by MRS After metal staples are removed patients will be transported to the clinical MRS facilities at UTMB Dept of Radiology where measurements will be performed see below for details After obtaining baseline samples tracer infusions will be started as described in Figure 2 Half the patients with high tissue TG will be given nicotinic acid 500 mg orally at the start of period 2 to lower FFA levels acutely In the group given fenofibrate 200 mgd or propranolol 05mgkg every 6 hours to lower FFA half will be infused with heparin 05 Ukgmin 28 U kg prime IV at a dose sufficient to activate lipoprotein lipase thereby elevating plasma FFA while not affecting blood coagulation After baseline blood samples from the femoral artery femoral vein and peripheral vein are collected an 8 hour continuous infusion of primed-constant infusions of 66-d2-glucose 008 mgkgmin prime 68 mgkg and d5-phenylalanine 020 µmolkgmin prime 80 µmolkg will be given in order to quantify hepatic glucose production and protein synthetic rates respectively In addition 2 hours into the protocol U-13C16-palmitate 016 µmolkg per minute will be started with NaH13CO3 prime 150 µmolkg in order to quantify hepatic fatty acid uptake and oxidation These tracer infusions will also be maintained throughout the 8 hour tracer study Blood samples 2- 12 ml will be taken from the artery femoral vein and peripheral vein simultaneously at 120 180 210 225 and 240 minutes see Appendix 2 for full timeline Muscle tissue biopsies will be obtained at the start of period 1 and at 4 hours of period 1 to measure protein kinetics and also determine biochemical parameters Then period 2 will start At the start of period 2 a primed constant infusion of 15N-phenylalanine will be started and maintained throughout period 2 The different tracer of phenylalanine will be used to quantify the plasma protein synthetic rates using the same tracer protocol as in period 1 We have previously shown that the two phenylalanine tracers yield the same results 70 The tracer technique will enable us to measure the primary endpoints of insulin responsiveness of the liver ie endogenous glucose production and synthetic rates of albumin and fibrinogen At 4 hours hyperinsulinemia will be initiated by the infusion of insulin at the rate of 15 mukgmin which will result in circulating levels of approximately 200 uUml 5 This rate of infusion was based on our previous experience with insulin infusion in burned patients eg 1-5 We anticipate a considerable variation in the baseline insulin concentrations such that if a low rate of infusion were to be used the resulting hyperinsulinemia in some patients would likely be below the baseline concentration in others Consequently we have chosen a rate of infusion that will result in a clear-cut difference between the baseline and hyperinsulinemic values Further although during the insulin infusion we anticipate that insulin concentrations will also be variable our endpoints will be assessed in terms of the magnitude of change from the baseline value in each subject This statistical approach should minimize concern regarding subject variability The dosage was selected because we have previously shown that protein metabolism is responsive to this rate of infusion 5 but that it is below the maximally-effective dose 4 Blood glucose concentration will be monitored throughout the second period and glucose will be infused if necessary to maintain glucose concentrations at the baseline level Since the baseline concentrations of glucose will vary this means that during hyperinsulinemia the glucose concentrations will likely differ between subjects but we have selected this approach because in this way only the insulin concentration will differ between periods 1 and 2 thereby simplifying interpretation of the changes in substrate and protein kinetics from period 1 to 2 The sampling schedule will be the same as in period 1 including the timing of the biopsy ie at 4 h of period 2
Leg blood flow will be measured by indocyanine green infusion ad described previously 14 Whole-body indirect calorimetry will be performed to quantify whole-body carbohydrate and fat oxidation
Patients will be infused with stable non-radioactive isotope tracers of glucose phenylalanine and palmitate for up to 8 hours After 4 hours without interruption of the tracer infusion an infusion of insulin will be started and maintained at the rate of 15 mUkgmin for the final 4 h Blood glucose concentrations will be measured throughout the insulin infusion and glucose infused as necessary to maintain the basal plasma glucose concentration
A biopsy of the quadriceps will be obtained with a Bergstrom needle at the beginning of the study 4 h immediately before the insulin infusion and at the end of the 4 h insulin infusion We will use the A-V balance technique to address the relation between tissue fatty acid and TG metabolism and the insulin responsiveness of glucose uptake and myofibrillar and mitochondrial protein synthesis and net protein balance
b Subjects Patients are admitted to the burn unit within 48 h of injury Fluid resuscitation is provided as previously described 94 Within 48 h of admission the burn wound is excised and subsequently grafted by autograft or cadaveric allograft Patients typically return to the operating room for reharvesting of donor sites every five to seven days The experiments proposed here will be performed the day prior to the third surgery at day 12-15 as femoral catheters are normally inserted at the time for access during surgery Enteral feeding with Vivonex TEN Sandoz Nutrition Corp Minneapolis MN is started within 24h of admission and continued until the patient is capable of food by mouth All patients will be eligible for the study unless one of the exclusion criterion listed below apply
c Procedures From day 1 to day 22 patients will be maintained on enteral feeding of a high carbohydrateamino acid mixture Vivonex Novartis Minneapolis MN Vivonex contains 300 kcalserving in the following caloric breakdown 823 carbohydrate 15 protein 27 fat linoleic acid Patients will be given 25 kcalkg of Vivonex plus an additional 45 kcalkg for each percentage point of total body surface area burned One half of the patients will be given fenofibrate 5 mgkgday - maximum daily dose from the time of the first tracer study until the time of the second tracer study
The tracer study subjects can commence once catheters in the femoral artery and vein have been placed by the surgical team if necessary since the majority of patients wil have pre-existing lines placed for clinical reasons The catheters will be used for sampling and in a peripheral vein for infusing as in our previous studies eg 4 Enteral administration of a mixture of carbohydrate and amino acids Vivonex will be stopped four hours prior to the study and will be started immediately following the study
On the day after the tracer infusion the amount of liver and muscle TG and liver glycogen will be determined by MRS After metal staples are removed patients will be transported to the clinical MRS facilities at UTMB Dept of Radiology where measurements will be performed see below for details After obtaining baseline samples tracer infusions will be started as described in Figure 2 Half the patients with high tissue TG will be given nicotinic acid 500 mg orally at the start of period 2 to lower FFA levels acutely In the group given fenofibrate 200 mgd or propranolol 05mgkg every 6 hours to lower FFA half will be infused with heparin 05 Ukgmin 28 U kg prime IV at a dose sufficient to activate lipoprotein lipase thereby elevating plasma FFA while not affecting blood coagulation After baseline blood samples from the femoral artery femoral vein and peripheral vein are collected an 8 hour continuous infusion of primed-constant infusions of 66-d2-glucose 008 mgkgmin prime 68 mgkg and d5-phenylalanine 020 µmolkgmin prime 80 µmolkg will be given in order to quantify hepatic glucose production and protein synthetic rates respectively In addition 2 hours into the protocol U-13C16-palmitate 016 µmolkg per minute will be started with NaH13CO3 prime 150 µmolkg in order to quantify hepatic fatty acid uptake and oxidation These tracer infusions will also be maintained throughout the 8 hour tracer study Blood samples 2- 12 ml will be taken from the artery femoral vein and peripheral vein simultaneously at 120 180 210 225 and 240 minutes see Appendix 2 for full timeline Muscle tissue biopsies will be obtained at the start of period 1 and at 4 hours of period 1 to measure protein kinetics and also determine biochemical parameters Then period 2 will start At the start of period 2 a primed constant infusion of 15N-phenylalanine will be started and maintained throughout period 2 The different tracer of phenylalanine will be used to quantify the plasma protein synthetic rates using the same tracer protocol as in period 1 We have previously shown that the two phenylalanine tracers yield the same results 70 The tracer technique will enable us to measure the primary endpoints of insulin responsiveness of the liver ie endogenous glucose production and synthetic rates of albumin and fibrinogen At 4 hours hyperinsulinemia will be initiated by the infusion of insulin at the rate of 15 mukgmin which will result in circulating levels of approximately 200 uUml 5 This rate of infusion was based on our previous experience with insulin infusion in burned patients eg 1-5 We anticipate a considerable variation in the baseline insulin concentrations such that if a low rate of infusion were to be used the resulting hyperinsulinemia in some patients would likely be below the baseline concentration in others Consequently we have chosen a rate of infusion that will result in a clear-cut difference between the baseline and hyperinsulinemic values Further although during the insulin infusion we anticipate that insulin concentrations will also be variable our endpoints will be assessed in terms of the magnitude of change from the baseline value in each subject This statistical approach should minimize concern regarding subject variability The dosage was selected because we have previously shown that protein metabolism is responsive to this rate of infusion 5 but that it is below the maximally-effective dose 4 Blood glucose concentration will be monitored throughout the second period and glucose will be infused if necessary to maintain glucose concentrations at the baseline level Since the baseline concentrations of glucose will vary this means that during hyperinsulinemia the glucose concentrations will likely differ between subjects but we have selected this approach because in this way only the insulin concentration will differ between periods 1 and 2 thereby simplifying interpretation of the changes in substrate and protein kinetics from period 1 to 2 The sampling schedule will be the same as in period 1 including the timing of the biopsy ie at 4 h of period 2
Leg blood flow will be measured by indocyanine green infusion ad described previously 14 Whole-body indirect calorimetry will be performed to quantify whole-body carbohydrate and fat oxidation
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