Investigation of the effects of intravenous fluid therapy and Imatinib administration in a human intravenous lipopolysaccharide (LPS) model of sepsis.
Lead Research Organisation:
Queen's University Belfast
Department Name: Sch of Medicine, Dentistry & Biomed Sci
Abstract
The problem:
Sepsis is a common, out-of-control immune response to infection which often causes people to become critically ill and require admission to intensive care. Sepsis is a leading cause of death world-wide. Red blood cells carry oxygen around the body through small blood vessels. Sepsis causes blood flow through the blood vessels to become abnormal, so that some areas may not receive enough blood flow and hence not enough oxygen. Without oxygen, cells in the body stop working and die, causing vital organs, such as the kidneys and heart, to fail. Ultimately, this organ failure leads to critical illness and death. Sepsis also causes damage to special cells, called endothelial cells, which form the inner lining of blood vessels. As a result, the blood vessels become "leaky", allowing fluid to move from the blood vessels into surrounding areas. This leaked fluid causes swelling of the areas surrounding the blood vessels, making it even harder for oxygen to reach the cells where it is needed. A key treatment for sepsis is to give fluids intravenously, that is directly into a vein, in order improve blood flow around the body. However, there is evidence that too much fluid may be harmful, perhaps even making patients with sepsis more likely to die. Giving fluid may cause more damage to the lining of blood vessels, thereby making swelling worse. This additional swelling makes it even more difficult for oxygen to be delivered to where it is required, resulting in the failure of multiple organs. It is clearly very important to establish the effects of intravenous fluid on blood vessels and blood flow in people with sepsis, as it may be either helping or causing harm. It is also important to find out if any drugs can protect the blood vessels from damage in the first place or control the immune response to infection.
The Research Proposal:
We will give healthy volunteers a substance derived from bacteria, known as lipopolysaccharide (LPS), by injection into a vein. LPS has been safely and reliably given to hundreds of people over several decades. It causes a predictable and very mild sepsis-like state for a few hours, similar to a mild flu. Symptoms can be treated with Paracetamol, although this is usually not required. People who are given LPS recover fully within 24 hours or less. This will be carried out in a fully equipped medical research centre with trained intensive care doctors. We will use a specialised camera that will allow us to see the small blood vessels under the tongue. We will measure blood flow and look at blood vessels before and up to 24 hours after giving LPS. We will also take blood samples at intervals to look at the immune response to receiving LPS.
After giving LPS, some volunteers will be given intravenous fluids, and some not. By comparing the two groups, we can see what effect, if any, intravenous fluid has on blood flow, on small blood vessels and on the immune system. As well as intravenous fluids, we also plan to investigate the effect of a drug called imatinib, a very safe drug used for decades to treat a type of leukaemia. A number of studies have shown that imatinib may also help protect endothelial cells from damage. Some of the volunteers will be given imatinib and some will not. Again, by comparing the blood flow, blood vessels and blood markers of the immune response, we will be able to see if imatinib has any beneficial effects.
Applications and Benefits:
Through this study, we hope to establish the effects on small blood vessels and on the immune system by giving LPS to healthy human volunteers in order to produce a mild sepsis-like state. We also aim to understand the effects of intravenous fluid and imatinib treatment in people with this sepsis-like condition. Our findings will help us to design future clinical trials to see if different ways of giving fluid, or imatinib, can help real world patients with sepsis. This project will lead to better treatment of sepsis.
Sepsis is a common, out-of-control immune response to infection which often causes people to become critically ill and require admission to intensive care. Sepsis is a leading cause of death world-wide. Red blood cells carry oxygen around the body through small blood vessels. Sepsis causes blood flow through the blood vessels to become abnormal, so that some areas may not receive enough blood flow and hence not enough oxygen. Without oxygen, cells in the body stop working and die, causing vital organs, such as the kidneys and heart, to fail. Ultimately, this organ failure leads to critical illness and death. Sepsis also causes damage to special cells, called endothelial cells, which form the inner lining of blood vessels. As a result, the blood vessels become "leaky", allowing fluid to move from the blood vessels into surrounding areas. This leaked fluid causes swelling of the areas surrounding the blood vessels, making it even harder for oxygen to reach the cells where it is needed. A key treatment for sepsis is to give fluids intravenously, that is directly into a vein, in order improve blood flow around the body. However, there is evidence that too much fluid may be harmful, perhaps even making patients with sepsis more likely to die. Giving fluid may cause more damage to the lining of blood vessels, thereby making swelling worse. This additional swelling makes it even more difficult for oxygen to be delivered to where it is required, resulting in the failure of multiple organs. It is clearly very important to establish the effects of intravenous fluid on blood vessels and blood flow in people with sepsis, as it may be either helping or causing harm. It is also important to find out if any drugs can protect the blood vessels from damage in the first place or control the immune response to infection.
The Research Proposal:
We will give healthy volunteers a substance derived from bacteria, known as lipopolysaccharide (LPS), by injection into a vein. LPS has been safely and reliably given to hundreds of people over several decades. It causes a predictable and very mild sepsis-like state for a few hours, similar to a mild flu. Symptoms can be treated with Paracetamol, although this is usually not required. People who are given LPS recover fully within 24 hours or less. This will be carried out in a fully equipped medical research centre with trained intensive care doctors. We will use a specialised camera that will allow us to see the small blood vessels under the tongue. We will measure blood flow and look at blood vessels before and up to 24 hours after giving LPS. We will also take blood samples at intervals to look at the immune response to receiving LPS.
After giving LPS, some volunteers will be given intravenous fluids, and some not. By comparing the two groups, we can see what effect, if any, intravenous fluid has on blood flow, on small blood vessels and on the immune system. As well as intravenous fluids, we also plan to investigate the effect of a drug called imatinib, a very safe drug used for decades to treat a type of leukaemia. A number of studies have shown that imatinib may also help protect endothelial cells from damage. Some of the volunteers will be given imatinib and some will not. Again, by comparing the blood flow, blood vessels and blood markers of the immune response, we will be able to see if imatinib has any beneficial effects.
Applications and Benefits:
Through this study, we hope to establish the effects on small blood vessels and on the immune system by giving LPS to healthy human volunteers in order to produce a mild sepsis-like state. We also aim to understand the effects of intravenous fluid and imatinib treatment in people with this sepsis-like condition. Our findings will help us to design future clinical trials to see if different ways of giving fluid, or imatinib, can help real world patients with sepsis. This project will lead to better treatment of sepsis.
Technical Summary
Aim
To investigate the biological effects of intravenous fluid therapy and Imatinib on microcirculatory function and injury and systemic inflammation in a human intravenous lipopolysaccharide (IV LPS) model of sepsis.
Objectives
1. To determine the effects of IV fluid administration on (a) microcirculatory function (b) microcirculatory injury and (c) systemic inflammation in healthy human volunteers receiving an IV LPS challenge.
2. To determine the effects of imatinib administration on (a) microcirculatory function (b) microcirculatory injury and (c) systemic inflammation in healthy human volunteers receiving an IV LPS challenge.
3.To elucidate the mechanistic pathways involved in any effect of IV fluids and/or imatinib on (a) microcirculatory function and injury and systemic inflammation.
Methodology
Healthy human volunteers will receive 2ng/kg IV LPS to induce transient features of systemic inflammation reflecting sepsis. Participants will be randomised to receive IV LPS only, IV LPS and IV fluids, IV LPS and imatinib, or IV LPS and IV fluids and imatinib.
Participants assigned to imatinib pre-treatment will receive a dose of 800mg orally 1 hour prior to IV LPS. Participants in the IV fluid therapy groups will receive 30mL/kg of IV fluid 1 hour following IV LPS.
Microcirculatory function will be assessed by sublingual imaging with video microscopy. Levels of circulating biomarkers of microcirculatory injury, coagulation and systematic inflammation will be measured. Transcriptomic analysis will provide further data on immune response pathways. Comparison between groups will allow determination of the effects of each intervention.
Scientific and Medical Opportunities
This model provides a platform to investigate a range of therapies on the human microcirculation in sepsis. As microcirculatory dysfunction is common to many diseases, including diabetes and chronic kidney disease, this study has important implications for other disciplines.
To investigate the biological effects of intravenous fluid therapy and Imatinib on microcirculatory function and injury and systemic inflammation in a human intravenous lipopolysaccharide (IV LPS) model of sepsis.
Objectives
1. To determine the effects of IV fluid administration on (a) microcirculatory function (b) microcirculatory injury and (c) systemic inflammation in healthy human volunteers receiving an IV LPS challenge.
2. To determine the effects of imatinib administration on (a) microcirculatory function (b) microcirculatory injury and (c) systemic inflammation in healthy human volunteers receiving an IV LPS challenge.
3.To elucidate the mechanistic pathways involved in any effect of IV fluids and/or imatinib on (a) microcirculatory function and injury and systemic inflammation.
Methodology
Healthy human volunteers will receive 2ng/kg IV LPS to induce transient features of systemic inflammation reflecting sepsis. Participants will be randomised to receive IV LPS only, IV LPS and IV fluids, IV LPS and imatinib, or IV LPS and IV fluids and imatinib.
Participants assigned to imatinib pre-treatment will receive a dose of 800mg orally 1 hour prior to IV LPS. Participants in the IV fluid therapy groups will receive 30mL/kg of IV fluid 1 hour following IV LPS.
Microcirculatory function will be assessed by sublingual imaging with video microscopy. Levels of circulating biomarkers of microcirculatory injury, coagulation and systematic inflammation will be measured. Transcriptomic analysis will provide further data on immune response pathways. Comparison between groups will allow determination of the effects of each intervention.
Scientific and Medical Opportunities
This model provides a platform to investigate a range of therapies on the human microcirculation in sepsis. As microcirculatory dysfunction is common to many diseases, including diabetes and chronic kidney disease, this study has important implications for other disciplines.
People |
ORCID iD |
| Ross McMullan (Principal Investigator / Fellow) |