AAGBI/Anaesthesia Small Research Grant
PECaN-ED (Probiotic E. coli Nissle 1917 - Efficacy & Dosing) - Evaluation of the efficacy and dosing of probiotic Escherichia coli Nissle 1917 in ventilated intensive care patients
Dr Neil Crooks
Introduction
Intensive Care Unit (ICU) patients are a small subgroup of patients who account for approximately 25% of all hospital infections. Thirty per cent of ICU patients suffer from infection as a complication of critical illness, increasing length of stay by up to 10 days. Their ICU and hospital mortality is more than doubled, and the increased economic burden is approximately £10,000-£30,000 per patient. We are interested in preventing the ICU-related pneumonia that occurs as a direct result of being attached to a ventilator (breathing machine) - known as a ventilator associated pneumonia (VAP).
Ventilator-associated Pneumonia
When patients are critically ill e.g. with serious infection or injury, they are likely to be attached to a ventilator. This means that they will have a breathing tube going through the mouth, down the throat and into the lungs.
In ICU patients the bacteria that are normally present in the stomach change to other bacteria that have the potential to cause infections. This is called gastric colonisation and is due to the effects of antibiotics and acid suppression medication. We know that these potentially harmful bacteria can move from the stomach into the lungs (aspiration). This may cause a VAP which will need treatment with further antibiotics.
Antibiotic Resistance
An additional problem is that these bacteria are becoming resistant to the available antibiotics, and the supply of new antibiotics is limited. The prevalance of infection caused by Gram-negative bacteria has increased dramatically in critically ill adults worldwide and concerns are growing about multi-drug resistant strains which are associated with substantial morbidity and mortality. We therefore need new, non-antiobiotic strategies to prevent infections.
Probiotics
Probiotics are live bacteria that have a beneficial effect on the host organism. Recent probiotic trials have shown a reduction in the incidence of ICU-acquired infection, in particular VAP. Morrow et al demonstrated a clear modification of oropharyngeal and gastric colonisation by harmful opportunistic bacteria and a statistically significant reduction in VAP.
These studies have all used Lactobacillus species, yet, no other probiotic species have been used in VAP-prevention trials. Gram-negative bacteria, particularly Enterobacteriaceae and Pseudomonas aeruginosa, cause most gastric colonisation and VAP. Hence, we believe consideration should be given to a Gram-negative probiotic species such as E.coli Nissle 1917 (ECN).
ECN is used for the treatment of inflammatory bowel disease and other gastro-intestinal disorders. ECN has proven safety and efficacy in this area and has been shown to displace harmful bacteria and reduce gut colonisation. In addition, ECN has demonstrated systemic anti-inflammatory effects in animal models of infection.
Study Aim
We would like to use ECN in a study of ventilated ICU patients. We believe giving ECN via the feeding tube will reduce the number of harmful microorganisms in the stomach, potentially reducing the incidence of VAP.
This study will help to demonstrate feasibility of this strategy. A positive outcome would help us move forward in obtaining funding for a multi-centre RCT. It has potential to lead to a change in widespread clinical practice, provide a novel non-antibiotic therapy and improve patient outcomes.
Prognostic value of SSEPs in hypoxic brain injury with therapeutic induced mild hypothermia at different time intervals
Dr Raghavendran Krishnaiyan
Each year in the UK approximately 48,000 people suffer a cardiac arrest. A cardiac arrest happens when the heart stops pumping blood around the body and this almost immediately leads to oxygen starvation in the brain. Lack of oxygen can cause permanent damage to the brain. Emergency resuscitation in and out of the hospital may restart the heart, but there is almost always a period of oxygen starvation and the risk of developing permanent brain damage still remain. The extent and severity of brain damage varies and may be fatal. Of those who survive after resuscitation from cardiac arrest, many have problems ranging widely from mild forgetfulness to severe disability and dependence on others. This has significant impact to the patients themselves, their carers and health service providers.
Over the last decade it has been shown that cooling the body temperature protects the brain after cardiac arrest. This is now standard treatment in the immediate care for the survivors of cardiac arrest in Intensive Care Units in the UK and worldwide. However this treatment is complex and can have side-effects. In order to be beneficial cooling treatment must be started within a few hours after cardiac arrest and continued for at least 24 hours. Even so, around 50 % of patients treated with cooling do not survive, because they have already suffered extensive and irreversible brain damage before the
cooling is started.
However, currently we have no reliable method or test to identify whether a patient would benefit from cooling treatment. Therefore many patients currently treated, have already suffered brain injury of such a severe degree that they will die anyway. In Intensive Care, it is considered unethical to start treatment which is futile especially when resources are scarce.
Somatosensory evoked potentials (SSEPs), is a test performed to measure brain activity in response to a small and safe electric current applied at the wrist. SSEPs are established as an important method to predict the degree of brain injury and the chance of recovery in survivors of cardiac arrest. SSEP tests can be performed easily without causing pain or potential risks to the patient. However their value is established only when performed 1-3 days after cardiac arrest. To date no studies have been performed to see their value in predicting brain injury and recovery in the immediate period after
resuscitation from cardiac arrest before cooling treatment.
We therefore, propose to study whether SSEP can predict brain injury and survival when performed early after resuscitation from a cardiac arrest to try and identify patients most likely to benefit from cooling. The initial study of early SSEPs before cooling will be used to demonstrate the feasibility, reliability and validity of SSEPs before cooling. The fact that SSEP are proven to reliably predict severe brain injury when used later in the course suggests that they may have potential early on.
A pilot study into the non-invasive measurement of oxygen delivery and consumption after elective major upper abdominal surgery
Dr Gary Minto and Dr Richard Struthers
The human body reacts to major surgery by going into a "healing" phase, known as the "stress response." This requires the heart and lungs to work a bit harder to deliver more oxygen to the tissues to allow healing.
Research in the 1980's confirmed that the body consumes more oxygen after surgery (VO2). By giving intravenous fluids and drugs doctors could increase oxygen delivery (DO2) and greatly improve mortality and other outcomes. Patients went to an intensive care unit (ITU) and had invasive monitoring lines inserted into their heart and lungs to guide treatment. This concept is broadly referred to as Goal Directed Fluid Therapy (GDT). We know not all patients are the same going in to surgery. In the 1970's research showed that patients with poor heart function before surgery did very badly after surgery. Simple measures such as exercise testing before surgery may allow us to measure fitness and plan care appropriately.
The way we care for patients has changed in the past two decades and these
advances are reflected in greatly reduced mortality and complications. Recent
changes include "enhanced recovery" which attempts to reduce the stress response and return the patient to normal as quickly as possible - even after major surgery. Fewer patients have the "lines" and go to ITU than before but results are better. The less fit patients who might have done badly in the 1990's now do well. Research by us and others has suggested GDT may nowadays have a much smaller impact on outcomes. It may be that in 2012 surgery puts less stress on the body and we don't see the increased VO2 seen in the 1990's. But as we are putting fewer lines in the patients we can't measure this easily.
We want to investigate what happens to VO2 and DO2 change after modern major surgery because the patterns may help us to spot early which patients are struggling. However we wish to avoid using invasive monitoring lines. Our hospital has previously researched measuring VO2 in normal children. This is done by asking them to breath normally while they have their head in a large "goldfish bowl". This technique has been used a few times after surgery but we aren't sure how well it will work in adult patients after major abdominal surgery. Likewise we have new technology which will allow us to estimate DO2 by attaching the patient to normal monitors (ECG machine, blood pressure cuff and pulse oximeter) rather than using lines.
A key step in the evaluation of these technologies is to see how well they agree with more invasive methods to measure VO2 and DO2. We can only do this in patients who are routinely looked after with invasive monitoring in ITU after surgery.
In a small number of patients (20) we would make measurements using both
systems contemporaneously at 6 time points during for the first 24 hours after
surgery.
The effect of chronic opioid therapy on respiratory control during sleep
Dr Kyle Pattinson
Painkillers such as morphine (known as opioids) carry substantial risk of severe injury and death due to their depressant effects on breathing, particularly during sleep. This is particularly dangerous in the treatment of chronic pain because patients are unmonitored, unlike when they are in hospital. In this study we shall determine how opioids work in the brain areas that control breathing during wakefulness and during sleep. This will help us design new pain killers that are much safer.
This research stems from the realisation that deaths from opioid poisoning have increased approximately threefold since 1999, and abnormal breathing during sleep has been identified as an important risk factor in these deaths.
Long term opioid administration leads to alterations in the way the brain controls breathing, and although tolerance develops to the pain killing actions of opioids (meaning that more painkiller is required for the same effect), there is less tolerance to the breathing effects of these drugs. Therefore, for breathing, opioids become more dangerous over time.
Opioids have a profound effect on sleep, particularly during deep sleep. It is during this deep sleep that that the incidence of opioid-related breathing disturbances is the greatest.
It has been a long held (and incorrect) view that non-dreaming sleep is a period of total inactivity in the brain. However, new evidence from direct recordings in animals and in humans proves the opposite and shows distinct periods of intense brain activity alternating with periods of less activity.
Importantly, the brain areas that are responsible for maintaining this non-dreaming sleep are also some of the same brain areas that are important for breathing control. Opioid painkillers act in these areas, and hence lead us to believe that their effects on breathing and sleep may be related.
This study aims to find out the brain mechanisms by which opioid painkillers interfere with breathing during sleep by combining magnetic resonance imaging of the brain with measures of breathing and measures of brain activity. A better understanding of these mechanisms will help us develop new pain killers that would relieve pain but not affect breathing.
Blast Brain Injury: Use of genetic probes to identify key cell types involved in the cerebral inflammatory response to blast exposure
Dr Jane Risdall
Blast injuries are an increasing problem in both current military conflicts and recent terrorist incidents. Blast brain injury has risen to prominence and represents a specific form of primary brain injury, with sufficiently different physical attributes (and possibly biological consequences) to be classified separately from blunt and penetrating injuries. Blast brain injury, in isolation, is associated with severe early brain swelling (cerebral oedema) and the swelling associated with other forms of brain trauma that may also be present will exacerbate this. This oedema can lead to life-threatening elevations of the pressure within the skull (raised intracranial pressure) requiring major neurosurgery to control it and save life. The blood brain barrier, which normally protects the brain from harmful circulating compounds, is also disrupted under these circumstances, as the walls of the blood vessels become more permeable. Inflammation would appear to be the key response of the brain to blast exposure and may well represent the trigger for cerebral oedema. However, the genetic changes and molecular mechanisms underlying this response remain to be elucidated.
Using a model of blast brain injury in current use at Dstl Porton Down, we have been able to demonstrate the presence of inflammatory markers in the brains of terminally anaesthetised rats, eight hours after a significant, but survivable, unilateral blast exposure to the head. These markers were not seen in rats treated identically, except for the blast exposure. Genetic analysis supports this finding, since the genes responsible for producing these markers, are also shown to be activated. However, what remains to be determined is which types of cells, within the brain, are expressing these genes and which region or regions of the brain are affected. Knowing where the drivers of this inflammatory response are located will represent an initial step that can be used to direct future research for potential therapies to minimise the adverse effects of blast exposure.
We propose to compare blast exposed and non-blast exposed sections of rat brains. The tissue sections will be stained to identify the various cells types (neurone, vasculature, supporting tissues etc) and their locations. Genetic probes for two of the 'inflammatory' genes that we have identified will then be applied together with their coloured markers. By overlaying the results of the genetic probing onto the structural staining, we hope to identify which regions and which cell types show genetic activation after blast exposure.
The impact of blood pressure thresholds on perioperative mortality in non-cardiac surgery in a United Kingdom database
Dr Rob Sanders
Surgery is conducted, annually, in millions of patients with hypertension and on chronic cardiovascular medication, yet we know relatively little about how we should conduct perioperative care of these individuals. For example, there is little information available about whether preoperative blood pressures should be reduced below a certain value to reduce perioperative risk. Furthermore it is unclear whether certain drugs, used for lowering hypertension, may be particularly beneficial or, conversely, detrimental when
given until the day of surgery. The purpose of this study is to define whether there are certain blood pressure values (such as very high values) that are associated with increased perioperative risk and to determine how much raised blood pressure contributes to this increase risk. We will also seek to determine if certain drugs used for blood pressure management offer benefits over others. For example certain "first line" blood pressure
lowering drugs may actually increase perioperative mortality and in our study we will seek to determine if a certain regime offers benefits over others on perioperative mortality. We hope that we will identify blood pressure thresholds associated with increased risk and find evidence of a safe regime for lowering blood pressure. It would then be possible to conduct a randomized controlled trial to show whether the approach of lowering blood pressure below a specific threshold, with a specific regime would improve perioperative mortality.
Understanding the mechanisms of sedation: Effects of GABAergic and non GABAergic sedatives on magnetoencephalographic visual gamma responses
Dr Neeraj Saxena
Background
While safe anaesthetic drugs are used daily in hospitals around the world, the way in which they work to cause sedation and unconsciousness remains poorly understood. Other aspects of anaesthesia which are of great importance such as loss of awareness and pain relief are also not very well understood. Gamma-Aminobutyric Acid (GABA) is a chemical that causes suppression of brain activity at the level of nerve cells. The balance between
activation and suppression is vital in maintaining the right level of functioning of the brain. GABA not only plays an important role in normal activities such as sleep but also in sedation (caused by sedative drugs) and even diseases such as epilepsy and schizophrenia. Nerve cells receiving signals through GABA are considered responsible for controlling rapid firing of nerve cells (gamma oscillations, at rates of 30 - 80 per second). Such rapid firing of nerve cells is considered key in the different parts of the brain communicating with each other, while doing different functions, thus helping maintain conscious states. It has been suggested that anaesthetic drugs may cause sedation and unconsciousness by affecting this communication mechanism.
Our project aims to understand better the changes in the human brain during sedation. We propose to use techniques known as magnetoencephalography, which measures the brain's electrical activity, in response to various actions such as watching a computer display or during rest. This electrical activity may respond and change differently during sedation. We have recently shown that propofol (one of the commonest clinically used sedative drugs), which is known to promote GABA activity, may cause a breakdown of such long-range communication - possibly due to a local grouping of nerve cells to fire simultaneously. This may be a critical mechanism in sedation caused by propofol. We wish to address whether
this mechanism is critical for any drug causing clinical sedation or specific to drugs such as propofol by comparing these effects of propofol with another drug, dexmedetomidine, which works through a different mechanism (not GABA) and on different parts of the brain.
Methods
We will do a placebo-controlled randomized crossover trial of healthy volunteers while being sedated with anaesthetic drugs (either propofol or dexmedetomidine). We will measure changes in the brain's electrical activity while the subjects are inactive and while involved in watching a high-contrast pattern on a computer screen.
Outcomes/benefits
The information gained from this experiment will not only help us understand the mechanisms of sedation by different sedative drugs, but also help us to understand physiological functions of the brain such as memory. This would then drive forward our understanding of what goes wrong in diseases such as dementia, schizophrenia and epilepsy and problems in postoperative patients or those in intensive care such as delirium and postoperative cognitive dysfunction, which may be caused by drugs working through GABA.
This may further help in the development of better treatments of these conditions. Also, development of specific tasks to monitor activity of GABA in the human brain may also help predict development of such diseases and monitor their treatment responses.
