Ignite Creation Date:
2024-05-05 @ 4:51 PM
Last Modification Date:
2024-10-26 @ 9:25 AM
Study NCT ID:
NCT00329680
Status:
COMPLETED
Last Update Posted:
2009-12-31
First Post:
2006-05-23
Brief Title:
The Effects of Eicosapentaenoic Acid EPA Gamma-Linolenic Acid GLA and Antioxidants in the Treatment of Sepsis
Sponsor:
Fernandes Tavora Hospital
Organization:
Fernandes Tavora Hospital
Study Overview
Official Title:
Investigating Nutritional Therapy With EPA GLA and Antioxidants Role in Sepsis Treatment-INTERSEPT STUDY
Status:
COMPLETED
Status Verified Date:
2009-10
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 scope of this clinical study is to evaluate the possible role of an enteral formulation enriched with EPA GLA and Antioxidants in patients diagnosed in the early stages of sepsis despite mechanical ventilation requirements as well as the impact of this diet upon glycemic control and its capacity to prevent the development of sepsis into severe sepsis and septic shock
Detailed Description:
The effectiveness of nutritional support in modulating the chain of inflammatory response and in reducing demands of the respiratory system through use of nutritional intervention has received a growing attention as a result of its capacity to interfere in a variety of biological processes 1 Nutritional formulations that are low in carbohydrates and rich in lipids may reduce minute-ventilation and ventilatory demand leading to a reduction of respiratory coefficient and CO2 production 2 Gadek et al 3 used a high lipid enteral diet enriched with eicosapentaenoic acid EPA or fish oil gamma-linolenic acid GLA or borage oil and enhanced levels of antioxidant vitamins in patients with ARDS demonstrating a significant improvement not only in the PaO2FiO2 ratio but also in several outcomes such as ventilator-free days ICU-free days and reduced new organ dysfunctions A recent clinical trial demonstrated that the use of this type of diet may produce better outcomes also in patients with acute lung injury ALI 4
Recent pharmaceutical interventions proposed for sepsis have sought to focus on regulating the chain of pro and anti-inflammatory mediators 56 responsible for causing the systemic characteristics of the disease and consequently for leading to multiple organ failure The inflammatory reaction is capable of activate synthesis of lipid mediators such as prostaglandin E2 which are involved in the complex regulation of the inflammatory process 7
Many of these inflammatory mediators are metabolites of omega-6 fatty acids such as linoleic acid and the product of its elongationdesaturation arachidonic acid 8 Substitution of Omega-6 fatty acids by fatty acids rich in Omega-3 such as EPA has proved to be beneficial in modulating the inflammatory processes both in animal models and in humans 9-17
Interest has also grown around the potential metabolic effects of GLA This oil is rapidly lengthened to dihomo-gamma-linolenic acid DGLA and is incorporated into tissue lipids DGLA may amongst other effects suppress bio-synthesis of leukotrienes being rapidly metabolized to monoenoic prostaglandins 18 In addition although EPA allows the elongation of GLA into DGLA it tends to prevent its desaturation into arachidonic acid This mechanism can produce an increase in 1 series prostanoids and a decrease in 2 series eicosanoids
Research using animal models of sepsis-induced ARDS has shown that a diet low in carbohydrates and rich in EPA and GLA may modulate the production of inflammatory mediators improving the functional capacity of the lungs This type of diet is capable of rapidly reducing the phospholipid fatty acid content of arachidonic acid in inflammatory cell membranes 19 even if administered parenterally 20 In animal models of sepsis a diet enriched with omega-3 fatty acids has been associated with reduced mortality 21-24
Moreover a recent study 25 demonstrated the beneficial effects of an enteral diet enriched with EPA GLA and elevated level of antioxidant vitamins in patients with severe sepsis and septic shock requiring mechanical ventilation In this subpopulation of patients the use of an enteral formulation enriched with EPA GLA and Antioxidants is associated with an improvement in oxygenation status reduced mechanical ventilation time fewer days in ICU less new organ dysfunction and also with a 194 absolute risk reduction in mortality NNT5 Since there is evidence in the literature pointing towards the anti-inflammatory roles not only of EPA and GLA 26 but also of antioxidant vitamins alone 27-29 the differences between both groups may be explained not just by the effects of EPA GLA or antioxidants but also by a combination of them Although this and the previously published trials were designed to investigate the effect of this diet in patients with ARDS certain differences prove to be particularly relevant First the former study examines the effects of such a diet in a population of ARDS patients constituted solely by patients with severe sepsis or septic shock Moreover it enrolled patients with a PaO2FiO2 ratio below 200 rather than below 250 as occurred in the latter study The heightened gravity of the patients used may have contributed to the greater number of days requiring mechanical ventilation and lower days outside ICU when compared with previously published results Finally this study allows only 6 hours from the moment at which patients fulfilled all entry requirements to effective onset of diet rather than 24 hours leading to a significant reduction in time necessary to achieve 75 of BEE x 13 Recent studies have shown that time-dependence is a determinant aspect in the treatment of septic patients
For instance the PROWESS study 5 showed a significant reduction in the mortality of severe septic patients with a high APACHE II score and who were treated with recombinant human activated protein C rhAPC in the first 48 hours after fulfillment of study entry criteria Nevertheless the ENHANCE study showed that septic patients who were treated with rhAPC in the first 24 hours after meeting inclusion criteria had lower mortality than those patients who were treated after 24 hours but within the first 48 hours The early use was also associated with a lower consumption of hospital resources including mechanical ventilation and the use of vasopressors 30 Time-dependency was also associated with several other recommendations for the management of septic patients 31
Another important finding from this recent trial is the number of patients who developed new organ failures not observed at the baseline considerably lower in the group that received the study diet This reduction demonstrates a trend towards lower evolution of multiple organ dysfunction in patients fed with EPAGLAAntioxidants If we consider that the development of multiple organ dysfunctions is associated with increasing mortality rates we can hypothesize this may be a determining factor in reducing the mortality rate 32 This also suggested that this diet may develop an important role for patients in the early stages of sepsis by preventing the evolution of the disease to severe sepsis or septic shock
On the other hand hyperglycemia and insulin resistance are common in critically ill patients even when glucose homeostasis has previously been normal Increased gluconeogenesis despite abundantly released is probably central to this disruption of glucoregulation 3334 Strict maintenance of normoglycemia with intensive insulin therapy has been shown to reduce intensive care and hospital mortality and morbidity of critically ill adult patients 35
Supplements or tube feeding using standard nutritional formulations can significantly compromise glycemic control 36-39 very probably due to the rapid and efficient absorption of these liquids This is specially relevant in those individuals with overt diabetes or stress-related glucose intolerance such as occurred in septic patients In such individuals the use of standard nutritional formulations may complicate attempts to achieve and maintain normoglycemia The answer for this matter may remain in the use of enteral diets high in lipids and low in carbohydrates
The scope of this clinical study is to evaluate the possible role of an enteral formulation enriched with EPA GLA and Antioxidants in patients diagnosed in the early stages of sepsis despite pulmonary failure as well as the impact of this diet upon glycemic control and its capacity to prevent the development of sepsis into severe sepsis and septic shock
Recent pharmaceutical interventions proposed for sepsis have sought to focus on regulating the chain of pro and anti-inflammatory mediators 56 responsible for causing the systemic characteristics of the disease and consequently for leading to multiple organ failure The inflammatory reaction is capable of activate synthesis of lipid mediators such as prostaglandin E2 which are involved in the complex regulation of the inflammatory process 7
Many of these inflammatory mediators are metabolites of omega-6 fatty acids such as linoleic acid and the product of its elongationdesaturation arachidonic acid 8 Substitution of Omega-6 fatty acids by fatty acids rich in Omega-3 such as EPA has proved to be beneficial in modulating the inflammatory processes both in animal models and in humans 9-17
Interest has also grown around the potential metabolic effects of GLA This oil is rapidly lengthened to dihomo-gamma-linolenic acid DGLA and is incorporated into tissue lipids DGLA may amongst other effects suppress bio-synthesis of leukotrienes being rapidly metabolized to monoenoic prostaglandins 18 In addition although EPA allows the elongation of GLA into DGLA it tends to prevent its desaturation into arachidonic acid This mechanism can produce an increase in 1 series prostanoids and a decrease in 2 series eicosanoids
Research using animal models of sepsis-induced ARDS has shown that a diet low in carbohydrates and rich in EPA and GLA may modulate the production of inflammatory mediators improving the functional capacity of the lungs This type of diet is capable of rapidly reducing the phospholipid fatty acid content of arachidonic acid in inflammatory cell membranes 19 even if administered parenterally 20 In animal models of sepsis a diet enriched with omega-3 fatty acids has been associated with reduced mortality 21-24
Moreover a recent study 25 demonstrated the beneficial effects of an enteral diet enriched with EPA GLA and elevated level of antioxidant vitamins in patients with severe sepsis and septic shock requiring mechanical ventilation In this subpopulation of patients the use of an enteral formulation enriched with EPA GLA and Antioxidants is associated with an improvement in oxygenation status reduced mechanical ventilation time fewer days in ICU less new organ dysfunction and also with a 194 absolute risk reduction in mortality NNT5 Since there is evidence in the literature pointing towards the anti-inflammatory roles not only of EPA and GLA 26 but also of antioxidant vitamins alone 27-29 the differences between both groups may be explained not just by the effects of EPA GLA or antioxidants but also by a combination of them Although this and the previously published trials were designed to investigate the effect of this diet in patients with ARDS certain differences prove to be particularly relevant First the former study examines the effects of such a diet in a population of ARDS patients constituted solely by patients with severe sepsis or septic shock Moreover it enrolled patients with a PaO2FiO2 ratio below 200 rather than below 250 as occurred in the latter study The heightened gravity of the patients used may have contributed to the greater number of days requiring mechanical ventilation and lower days outside ICU when compared with previously published results Finally this study allows only 6 hours from the moment at which patients fulfilled all entry requirements to effective onset of diet rather than 24 hours leading to a significant reduction in time necessary to achieve 75 of BEE x 13 Recent studies have shown that time-dependence is a determinant aspect in the treatment of septic patients
For instance the PROWESS study 5 showed a significant reduction in the mortality of severe septic patients with a high APACHE II score and who were treated with recombinant human activated protein C rhAPC in the first 48 hours after fulfillment of study entry criteria Nevertheless the ENHANCE study showed that septic patients who were treated with rhAPC in the first 24 hours after meeting inclusion criteria had lower mortality than those patients who were treated after 24 hours but within the first 48 hours The early use was also associated with a lower consumption of hospital resources including mechanical ventilation and the use of vasopressors 30 Time-dependency was also associated with several other recommendations for the management of septic patients 31
Another important finding from this recent trial is the number of patients who developed new organ failures not observed at the baseline considerably lower in the group that received the study diet This reduction demonstrates a trend towards lower evolution of multiple organ dysfunction in patients fed with EPAGLAAntioxidants If we consider that the development of multiple organ dysfunctions is associated with increasing mortality rates we can hypothesize this may be a determining factor in reducing the mortality rate 32 This also suggested that this diet may develop an important role for patients in the early stages of sepsis by preventing the evolution of the disease to severe sepsis or septic shock
On the other hand hyperglycemia and insulin resistance are common in critically ill patients even when glucose homeostasis has previously been normal Increased gluconeogenesis despite abundantly released is probably central to this disruption of glucoregulation 3334 Strict maintenance of normoglycemia with intensive insulin therapy has been shown to reduce intensive care and hospital mortality and morbidity of critically ill adult patients 35
Supplements or tube feeding using standard nutritional formulations can significantly compromise glycemic control 36-39 very probably due to the rapid and efficient absorption of these liquids This is specially relevant in those individuals with overt diabetes or stress-related glucose intolerance such as occurred in septic patients In such individuals the use of standard nutritional formulations may complicate attempts to achieve and maintain normoglycemia The answer for this matter may remain in the use of enteral diets high in lipids and low in carbohydrates
The scope of this clinical study is to evaluate the possible role of an enteral formulation enriched with EPA GLA and Antioxidants in patients diagnosed in the early stages of sepsis despite pulmonary failure as well as the impact of this diet upon glycemic control and its capacity to prevent the development of sepsis into severe sepsis and septic shock
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