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.
Does Increased Non-Linear Behavior Caused By Dynamic Variables Increase Ventilatory-Induced Lung Injury (VILI)?
Funder
National Health and Medical Research Council
Funding Amount
$109,625.00
Summary
Acute lung injury (ALI) is precipitated by a variety of different insults, either directly to the lung or elsewhere to the body. Approximately 50% of the patients die. ALI is characterized by an increase in the leakiness of the barrier that normally separates the blood from the airspaces. The fluid which consequently floods the airspaces not only makes it difficult for patients to adequately obtain oxygen, but also dramatically increases the work of breathing by changing the surface forces withi ....Acute lung injury (ALI) is precipitated by a variety of different insults, either directly to the lung or elsewhere to the body. Approximately 50% of the patients die. ALI is characterized by an increase in the leakiness of the barrier that normally separates the blood from the airspaces. The fluid which consequently floods the airspaces not only makes it difficult for patients to adequately obtain oxygen, but also dramatically increases the work of breathing by changing the surface forces within the lungs. As a result, the patients must be mechanically ventilated. However, the very act of using a positive pressure to inflate the lungs often creates further damage, either through repeated opening and closing of collapse tissue or through its over distension. Ventilatory-induced lung injury (VILI), in itself is estimated to contribute to ~30% of the mortality. The best way shown to minimize VILI is through the use of small programmed breaths so as not to overinflate the lungs while still allowing adequate gas exchanges, superimposed upon a background pressure, in order to pre-inflate the lungs and prevent them from repeatedly collapsing. A remaining problem is that just as a rubber band changes its elasticity as it is stretched, so too the lung changes its mechanical properties during distension. Moreover, the lung is considerably more complex since different regions have different elasticities, which change differentially as air flows in and out of them. Airflow in turn depends on regional differences in the location, size, and number of conducting airways. Indeed, we have recently shown for the first time that dynamic changes in lung mechanics may contribute to VILI in patients, despite the use of safe ventilation modalities. This application proposes to examine the extent to which dynamic changes in lung mechanic contribute to VILI in an animal model, as a prelude to more costly, large scale clinical trials aimed at improving mortality.Read moreRead less
Management Of Burn Injury: Fluid Dynamics And Antibiotic Pharmacokinetics
Funder
National Health and Medical Research Council
Funding Amount
$342,375.00
Summary
It is well known that major burns, as well as being relatively common injuries, are notoriously difficult to manage. Patients exhibit significant variability due to a combination of anatomic, physiologic, hormonal and immunologic alterations occurring both at the wound site and, more importantly, in other body compartments and vital organ systems. Skin burn injury results in the release of multiple inflammatory mediators in addition to significant fluid loss. The distribution of inflammatory med ....It is well known that major burns, as well as being relatively common injuries, are notoriously difficult to manage. Patients exhibit significant variability due to a combination of anatomic, physiologic, hormonal and immunologic alterations occurring both at the wound site and, more importantly, in other body compartments and vital organ systems. Skin burn injury results in the release of multiple inflammatory mediators in addition to significant fluid loss. The distribution of inflammatory mediators and wound bacteria to central organs can cause complex physiological changes that may lead to multiple organ failure, with serious infections occurring in around 50% of patients with serious burns. Antibiotic distribution kinetics, such as bioavailability, clearance, volume of distribution, elimination half-life and unbound fraction in plasma can be significantly altered in burn patients. Without detailed knowledge of changes and relationships between factors such as wound pH, tissue oxygenation, protein concentrations of fluid leaked from the local wound microvasculature, tissue binding, oedema and changes in burned and non-burned tissue induced by resuscitation therapies, the optimisation of both local and systemic infection contriol therapies can hardly be expected to advance. This project aims to determine how changes the physiology of burn patients, in particular in the burn wound environment, affect antibiotic penetration and distribution into tissues. We also believe that these changes will vary between patients and are aiming to determine whether certain parameters can be used to give an indication of the best antibiotic dosing regimens for individual patients.Read moreRead less
Multi-centre Randomised Trial Of Early Decompressive Craniectomy In Patients With Severe Traumatic Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$490,500.00
Summary
Despite optimal neurosurgical and intensive care therapy, many trauma patients with severe brain injury (typically young males) have very poor long term neurological outcomes. Current knowledge suggests that a key contributor to secondary brain damage which occurs after injury and to poor neurological outcomes is brain swelling and subsequent increase in brain pressure. Present intensive care therapies to control brain pressure are often not effective, and favourable neurological outcomes occur ....Despite optimal neurosurgical and intensive care therapy, many trauma patients with severe brain injury (typically young males) have very poor long term neurological outcomes. Current knowledge suggests that a key contributor to secondary brain damage which occurs after injury and to poor neurological outcomes is brain swelling and subsequent increase in brain pressure. Present intensive care therapies to control brain pressure are often not effective, and favourable neurological outcomes occur in only 20-30% of these patients. Small studies suggest that a surgical operation called decompressive craniectomy (DC) may decrease brain pressure and improve neurological outcomes in these patients. DC involves temporarily surgically removing a piece of skull bone (during the swelling period) and replacing it when the swelling has subsided. DC is done under general anaesthetic in unconscious patients and is used occasionally at present, although due to insufficient research the benefits are controversial. The proposed study is a multi-centre randomised controlled study of best current therapies plus early decompressive craniectomy vs best current therapies alone in selected unconscious patients with severe head injury. The study outcome is patient neurological function measured 6 months after the injury. A study of this type is required before early DC could become a routine therapy in Australia. Next of kin will sign informed consent for the study and then also for the surgery if patients are randomised to surgery. The study will be managed at the Alfred Hospital-Monash University in Melbourne and includes fifteen collaborating ANZ neurotrauma centres over 3.0 years. There are >200 patients in Australia annually in this category with potential for DC to increase favourable outcomes in >40 patients annually. Lifetime costs for these patients with severe disability are > $2.4 million, so there may be substantial economic and social impact.Read moreRead less
A Randomised, Placebo-controlled Trial Of Erythropoietin In ICU Patients With Traumatic Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$1,950,735.00
Summary
Patients who suffer a moderate or severe head injury (traumatic brain injury) have a 50% chance of having a long term neurological disability or death. Erythropoietin is a medication which encourages red blood cell formation but its other beneficial effects are likely to improve outcomes after traumatic brain injury. This study will examine the safety and effects of erythropoietin on long term neurological function in patients who have suffered a traumatic brain injury.
Randomised Comparison Of Fluid Resuscitation With Human Albumin Solution Or Normal Saline Among Critically Ill Patients
Funder
National Health and Medical Research Council
Funding Amount
$611,728.00
Summary
Human albumin solution is widely used for the emergency treatment of severely ill patients requiring fluid replacement, both in Australia and worldwide. However, a recent report suggests that compared to the other standard treatment (salt solution), the use of human albumin solution may be associated with a higher death rate (about six additional deaths among every one hundred patients treated). But, this report was based on data from a relatively small number of patients among whom there was a ....Human albumin solution is widely used for the emergency treatment of severely ill patients requiring fluid replacement, both in Australia and worldwide. However, a recent report suggests that compared to the other standard treatment (salt solution), the use of human albumin solution may be associated with a higher death rate (about six additional deaths among every one hundred patients treated). But, this report was based on data from a relatively small number of patients among whom there was a relatively small number of deaths, and there is widespread uncertainty among doctors about the reliability of the evidence and the implications for patient care. This is reflected in the large difference between intensive care units in the use of human albumin solution (in Australia, its use ranges from 10-90% of all patients needing fluid). Human albumin solution costs, about thirty times more than salt solution, and during 1998 more than 200,000 bottles of human albumin solution were administered to patients in Australia, at a cost of about A$35 million. In an effort to provide definitive evidence about the effects (and cost-effectiveness) of fluid replacement with human albumin solution, the Australia and New Zealand Intensive Care Society, in collaboration with the Australian Red Cross Blood Services and the Institute for International Health, has proposed the conduct of new large-scale study (SAFE - Saline vs Albumin Fluid Evaluation). This study will involve 7,000 patients from 15 intensive care units in Australia and New Zealand. These patients (all of whom require fluid replacement) will be randomly assigned to receive either human albumin solution or salt solution and outcome in terms of deaths and other serious events will be monitored over 28 days. Results will be available within 2 years of starting the study, and these are likely to influence the care of the majority of seriously ill patients admitted to intensive care units worldwide.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
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
Hormonal Resuscitation And P38 MAP Kinase Inhibition To Enhance Quality Of Cadaveric Donor Organs For Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
The transplantation of organs such as the heart, lung, liver, kidney and pancreas from brain-dead donors is limited primarily by the shortage of donor organs. It is now recognised that as many as 25% (one in four) potentially usuable donor organs are lost after brain death due to the rapid deterioration that occurs in organs after brain death. There is evidence that this deterioration is due to loss of the normal hormones that are essential to the normal functioning of these organs. In this proj ....The transplantation of organs such as the heart, lung, liver, kidney and pancreas from brain-dead donors is limited primarily by the shortage of donor organs. It is now recognised that as many as 25% (one in four) potentially usuable donor organs are lost after brain death due to the rapid deterioration that occurs in organs after brain death. There is evidence that this deterioration is due to loss of the normal hormones that are essential to the normal functioning of these organs. In this project, we will use a pig model of brain death that we have extablished in our laboratory to examine the effects of hormone replacement on the function of organs that are used for transplantation. We will also test a novel drug aimed at protecting donor organs during the period between removal of the organ and transplantation. If successful, these treatments have the potential to markedly increase the numbers of organ transplants and to improve the outcomes for recipients of these transplants. In the Australian and New Zealand setting, a 25% increase in the number of donor organs would results in approximately 220 more people per year receiving these life-saving operations.Read moreRead less