Understanding How Sepsis Causes Kidney Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$471,770.00
Summary
Acute renal failure is a serious condition that affects up to 20% of patients in Intensive Care Units. Sepsis and septic shock remain the most important causes of acute renal failure in critically ill patients. Despite our ability to support vital organs and resuscitate patients, the incidence and mortality of septic acute renal failure remain unacceptably high at up to 55%. There have been no major advances in our understanding of its pathogenesis and in its prevention or treatment over the las ....Acute renal failure is a serious condition that affects up to 20% of patients in Intensive Care Units. Sepsis and septic shock remain the most important causes of acute renal failure in critically ill patients. Despite our ability to support vital organs and resuscitate patients, the incidence and mortality of septic acute renal failure remain unacceptably high at up to 55%. There have been no major advances in our understanding of its pathogenesis and in its prevention or treatment over the last 50 years. The traditional view is that sepsis-induced renal failure results from reduced perfusion of the kidney secondary to the low blood pressure. In a model of sepsis in sheep with renal failure, we demonstrated, however, that renal blood vessels dilated and blood flow increased. Furthermore, renal function improved following treatment with vasoconstrictor drugs that raised blood pressure and renal blood flow. These findings indicate that renal ischaemia is not the cause of the renal dysfunction in sepsis. We hypothesise that sepsis causes renal vasodilatation, which reduces glomerular filtration rate and renal function, and induces a delayed development of apopotosis. We will study in sepsis 1) the effects of a treatment to increase glomerular filtration rate 2) the development of apoptosis and the effect of an anti-apoptotic drug, and 3) whether there is bioenergetic failure in the kidney in sepsis and the effects of treatments on this. Finally, in septic patients we will measure renal blood flow and determine the effects of our novel treatment on this and renal function. These studies will significantly increase our understanding of the factors causing acute renal failure in sepsis. They are likely to lead to the development of new therapies to improve renal function in sepsis and their effectiveness will be examined in septic animals and patients.Read moreRead less
How Does Activated Protein C Create Intact, Non-leaky, Stable Blood Vessels?
Funder
National Health and Medical Research Council
Funding Amount
$564,644.00
Summary
Vascular dysfunction is a common feature of many diseases, including sepsis, diabetes, atherosclerosis, tumours and asthma. These vessels have compromised structural and functional integrity, leading to leakage of blood components and causing inflammation in tissues. Based on our recent findings, this project aims to discover how activated protein C creates normal, healthy non-leaky blood vessels and prevents vascular dysfunction in disease.
A Randomised Controlled Trial Of Normoglycaemia Versus Conventional Glycaemic Control In Intensive Care Unit Patients.
Funder
National Health and Medical Research Council
Funding Amount
$1,773,507.00
Summary
The concentration of sugar in the blood is often increased in patients in intensive care and patients with increased blood sugar levels are more likely to die. A recent study performed in a Belgian intensive care unit found that using high doses of insulin to lower blood sugars levels to normal increased the number of patients who survived. The chance of surviving to leave hospital was increased from 89% to 93%. Whilst the result is very encouraging, Intensive Care Specialists in Australia are u ....The concentration of sugar in the blood is often increased in patients in intensive care and patients with increased blood sugar levels are more likely to die. A recent study performed in a Belgian intensive care unit found that using high doses of insulin to lower blood sugars levels to normal increased the number of patients who survived. The chance of surviving to leave hospital was increased from 89% to 93%. Whilst the result is very encouraging, Intensive Care Specialists in Australia are unsure if the treatment would work in their patients because of differences in the types of patients found in intensive care units in Australia, and because of other treatment given to the patients in the Belgian study. In particular the doctors in the Belgian unit studied only patients who had had operations and gave large amounts of intravenous sugar to their patients. This is not normally done in Australian Intensive Care Units and the safety of giving high dose insulin to patients not receiving large amounts of intravenous sugar is not known. This is of particular interest as reducing blood glucose to abnormally low levels can cause serious side effects and even result in permanent brain damage. The Australian and New Zealand Intensive Care Society proposes to conduct a new study involving 4,000 patients from intensive care units in Australia and New Zealand and will study all patients regardless of whether or not they have had an operation. These patients will be randomly assigned to receive insulin to control blood sugar levels to normal or to slightly above normal levels as has been tradition in intensive care units around the world. Outcome and serious side effects will be closely monitored. The results will be available within three years of starting the study, and these are likely to influence the treatment of the majority of patients admitted to intensive care units both in Australia and worldwide.Read moreRead less
A Phase II Randomised Controlled Trial Of Atorvastatin Therapy In Intensive Care Patients With Severe Sepsis
Funder
National Health and Medical Research Council
Funding Amount
$622,148.00
Summary
Infections are common in patients in the intensive care unit and produce inflammation that may spread throughout the body. Despite improved therapies, when infections cause failure of the body's vital organs, up to 40% of patients may die. The medication atorvastatin and other statins have been used for many years to treat and prevent conditions such as heart attack and stroke. They act primarily by reducing cholesterol production. In addition, they also modify inflammation and the immune system ....Infections are common in patients in the intensive care unit and produce inflammation that may spread throughout the body. Despite improved therapies, when infections cause failure of the body's vital organs, up to 40% of patients may die. The medication atorvastatin and other statins have been used for many years to treat and prevent conditions such as heart attack and stroke. They act primarily by reducing cholesterol production. In addition, they also modify inflammation and the immune system which may make them a useful treatment for patients with established infections. Although the statin drugs are usually safe, rare side effects may affect muscle and the liver. Because of concerns about increased risk of side effects it is currently recommended that statins should be stopped when patients become unwell. However, a number of studies have suggested that patients on statins for heart disease are less likely to develop infections and that their infections are less likely to be severe or result in death. Other studies have suggested that stopping statins in patients that present with infections (as suggested by current guidelines), may worsen infection outcomes. However, these studies have not been detailed enough to exclude all factors affecting outcome, such as patient age, severity of the infection, and the presence of other diseases. We plan to perform a study to assess the effect of atorvastatin on the outcome of infections in the intensive care unit. We will study 250 patients presenting with severe infections. We will randomly assign patients to receive either atorvastatin or placebo and monitor the effect on signs of inflammation and levels of life support. Outcomes and side effects will be carefully monitored. The study will help us decide whether to perform a larger study to determine if atorvastatin can reduce the risk of dying from serious infections.Read moreRead less
Impact Of Gastrointestinal Dysmotility On Enteral Nutrition In The Critically Ill
Funder
National Health and Medical Research Council
Funding Amount
$533,792.00
Summary
Critically ill patients require nutrition for optimum recovery. Ideally, this is provided via the gut, but oesophageal reflux, slow gastric emptying and small intestinal dysfunction frequently prevent adequate delivery of nutrients to these patients, exposing them to complications such as pneumonia and gastrointestinal bleeding. The work performed by the applicants will improve the ability of doctors in the Intensive Care Unit to feed patients and prevent the development of such complications.
Upper Gastrointestinal Motor And Absorptive Function In Critically Ill Patients
Funder
National Health and Medical Research Council
Funding Amount
$260,760.00
Summary
A major concern in critically ill patients is the provision of adequate nutrition to facilitate recovery from devastating metabolic insults. Abnormal contractions of the oesophagus, stomach and small intestine appear to be common in critically ill patients. These may prevent effective feeding of patients at a time when they are especially vulnerable to malnutrition and also result in major complications such as pneumonia, septicaemia and gastrointestinal haemorrhage. However little is known abou ....A major concern in critically ill patients is the provision of adequate nutrition to facilitate recovery from devastating metabolic insults. Abnormal contractions of the oesophagus, stomach and small intestine appear to be common in critically ill patients. These may prevent effective feeding of patients at a time when they are especially vulnerable to malnutrition and also result in major complications such as pneumonia, septicaemia and gastrointestinal haemorrhage. However little is known about the reasons underlying these dysfunctions. The applicants, with ongoing support from the NH and MRC have had a longstanding interest in motility disorders of the gut and have made important contributions to knowledge about both the causes and treatments of these conditions. These contributions have been underpinned by pioneering the development of new methodologies to examine gut function. In collaboration with the intensive care specialists in Adelaide, we now seek to apply this knowledge to evaluate gut function in patients in the Intensive Care Unit. The proposed studies will provide the most comprehensive studies to date of the gut function in critically ill patients and have important implications for treatment.Read moreRead less
The appropriate dosing of antibiotics for patient admitted to ICU after a traumatic injury is poorly defined and based on intuition rather than evidence. Doctors need to predict which patients may develop very high antibiotic clearances and dose accordingly so that potentially life-threatening infections do not occur. Given these patients are unknown, this research seeks to identify such patients and recommend which antibiotic and which dose is appropriate to ensure adequate treatment.
Oesophageal, Gastric And Small Intestinal Motility In Critical Illness
Funder
National Health and Medical Research Council
Funding Amount
$494,250.00
Summary
A major concern in critically ill patients is the provision of adequate nutrition to facilitate recovery from devastating insults. Abnormal contractions of the oesophagus, stomach and small intestine occur commonly in critically ill patients. These may prevent effective feeding of patients at a time when they are especially vulnerable to malnutrition and also result in major complications such as pneumonia, septicaemia and gastrointestinal haemorrhage. The applicants, with the support of the NH ....A major concern in critically ill patients is the provision of adequate nutrition to facilitate recovery from devastating insults. Abnormal contractions of the oesophagus, stomach and small intestine occur commonly in critically ill patients. These may prevent effective feeding of patients at a time when they are especially vulnerable to malnutrition and also result in major complications such as pneumonia, septicaemia and gastrointestinal haemorrhage. The applicants, with the support of the NH and MRC, have had a longstanding interest in motility disorders of the gut and have made important contributions to knowledge about both the causes and treatments of the disturbances that occur in the oesophaus, stomach and small intestine. In the previous grant (207753) these studies have provided the most comprehensive studies to date of the motor abnormalities associated with gut dysfunction in critical illness which have important implications for treatment. The applicants now seek to continue their work by investigating the mechanisms underlying these motor abnormalities and the impact of therapeutic strategies designed to enhance delivery of nutrition to critically ill patients.Read moreRead less
The Australasian Resuscitation In Sepsis Evaluation - Randomised Controlled Trial
Funder
National Health and Medical Research Council
Funding Amount
$2,424,807.00
Summary
Patients with severe infections often present to Emergency Departments and early treatment with particular fluids, blood transfusions and stimulants, may improve survival rates. To determine whether early treatment is safe and effective in reducing deaths, the Australian and New Zealand Intensive Care Society Clinical Trials Group, in conjunction with the Australasian College of Emergency Medicine, plan to perform a large trial of early goal directed therapy in patients with severe infections.