Developing slow wave activity saturation as a marker of depth of anaesthesia

General anaesthesia is delivered to individuals during an operation to stop them being aware of what is going around them, prevent any pain and immobilise the body so surgery can be carried out safely. Unfortunately the anaesthetists, who are the specialist doctors responsible for delivering the anaesthesia, do not currently have a reliable way of measuring the exact point when an individual's brain becomes unconscious during the surgery. They tend to judge the amount of anaesthetic they give depending on when the average person would lose consciousness. They then increase or decrease the dose for that person depending on how their heart or the lungs react during the operation.

We believe that we have discovered an interesting change in the brain's electrical activity that indicates the point when an individual person having surgery loses perception of what is happening in the outside world. This potentially means that anaesthetists could give just the right amount of drug for that particular person. This is important because, whilst anaesthesia is very safe, some patients who are older or particularly sick may suffer from long-term side effects if they are given too much anaesthesia. It will also prevent the very rare event that someone is aware during the operation.

Our interesting observation is that when the anaesthetic dose is increased, slow waves in the brain reach a maximum level, and then do not increase any further even though much more anaesthetic drug is given. These slow waves are low frequency oscillations in the brain (at around 1 Hz or 1 cycle per second) and are also an important feature of deep sleep. We have called this observation slow wave activity saturation (or SWAS) and it can be measured by applying electrical sensors to the scalp - a technique called electroencephalography (or EEG for short).

When we discovered SWAS, we also performed simultaneous brain imaging with a technique called functional magnetic resonance imaging (FMRI), and found that brain's response to pain and words altered dramatically when the individual's electrical activity reached this SWAS level. The brain network activated in response to these stimuli at SWAS was very different to the one that was activated when they were awake, or even the brain network that was activated at lower anaesthetic concentrations. It was this change in how stimuli are processed in the brain that makes us believe that the person is no longer aware of the outside world.

We have recently developed a mathematical model that, when applied to an EEG system, can dynamically track the changes in slow wave activity in real-time. The model will allow us to predict when an individual has entered this SWAS state. We hope that, by delivering the anaesthesia to achieve this state, we can make sure everyone who has surgery is unaware of what is going but also doesn't receive too much medication so that it takes them longer to recover.

To test this, we plan to use our system in 200 patients having surgery and deliver just enough anaesthesia so that their brain's activity reaches the saturation state. We will then check whether SWAS is a good measure to assess how deeply someone is anaesthetised in two ways. Firstly, we will use a technique called the isolated forearm test before the surgery to confirm that the patient is not aware of what is going on around them. Secondly, we will check how they recover from the operation by measuring how sick they feel afterwards and how much pain they are in. We hope that we can show that patients who receive anaesthesia delivered to the SWAS state have an improved recovery after surgery than patients who have anaesthesia delivered in the usual way.

If we can show that this study is a success, we hope that in the long-term we can create a depth of anaesthesia monitor that will enable patients all over the world to be given just the right amount of anaesthetic for their operations.

Anaesthetists currently have no robust way of detecting when a patient under general anaesthesia stops perceiving the outside world. Knowledge of the precise point when an individual's brain becomes unresponsive allows delivery of the optimum anaesthetic dose, thus reducing the risks associated with over- and under-anaesthesia particularly in vulnerable and at-risk patients.

We propose a depth of anaesthesia monitor using a potential individualised biomarker for loss of perceptual awareness called slow wave activity saturation (SWAS). Our previous experiments, using electroencephalography (EEG) and functional magnetic resonance imaging (FMRI), indicate that the brain's electrical activity at slow wave frequencies (0.5-1.5Hz) saturates with increasing propofol anaesthetic dose. Our FMRI data show that at SWAS, thalamocortical isolation from sensory stimuli occurs and an alternative brain network persists. We believe this network, and the SWAS endpoint, represents the key transition when an individual's brain becomes disconnected from the external world and sensory events. Subsequently, we have shown that SWAS occurs during surgical anaesthesia for different hypnotic agents and in the presence of anaesthetic co-induction agents, such as opioids and muscle relaxants.

We have recently developed a real time Bayesian prediction model (SWAS-BPM) that will allow titration of surgical anaesthesia to the SWAS endpoint, thus achieving perception loss within that individual. After optimisation of the SWAS-BPM for real-time titration, we will apply the prototype SWAS-BPM system in a feasibility study of 200 patients. We will confirm clinical effectiveness of SWAS based: on 1) no evidence of conscious cognitive state, 2) improved cardiovascular stability and 3) improved post-operative recovery compared with standard clinical monitoring. This study will enable a larger late-stage clinical trial of a SWAS-based depth of anaesthesia monitor with a commercial partner.

The development of a reliable depth of anaesthesia (DOA) monitor using slow wave activity saturation (SWAS) has the potential to optimise the patient's safety and experience, as well as advance the science of anaesthesia and surgery.

Accidental awareness during surgery has a reported incidence between 1 in every 1,000-15,000 patients. Although rare, this is highly distressing for the patient. These patients, as well as those who experience painful/distressing procedures when sedated in intensive care, are at significant risk of developing long-term psychological sequelae, such as post-traumatic stress disorder. A reliable depth of anaesthsia monitor that allows optimum dosing for unconsciousness will ultimately improve the quality of life of surgical patients and those who have prolonged intensive care admission. Furthermore, public knowledge that anaesthetists have a reliable and individualised brain monitor will allay the fears of many that they will wake up during an operation. This could result in patients seeking medical help earlier, reducing disease severity at the time of surgery and ultimately decreasing the financial healthcare burden on society.

More frequent than awareness is the administration of excess anaesthetic dose to avoid its occurrence. Excessively deep anaesthesia has been linked to an increased risk of adverse outcomes such as death, stroke, heart attack, delirium and cognitive dysfunction. Patients at higher risk of these adverse outcomes will benefit most from a reliable depth of anaesthesia monitor. These include the elderly and people with poor cardiovascular function and high body mass indices. With an aging population, post-operative cognitive impairment outcome measures have become increasingly important in the risk-benefit decision of whether to operate or not. Improved recovery due to optimal dosing will reduce the time to discharge, enabling patients to return home more quickly. Faster discharge will mean less hospital resources are used. Primary, social care and mental health providers could also see reductions in the degree of long-term cognitive dysfunction and psychological distress following surgery or intensive care admission.

The development of the SWAS-based depth of anaesthesia monitor and the resulting optimization of anaesthetic dose has cost implications for all sectors of the health care system. Despite limited evidence of efficacy in reducing intraoperative awareness, the National Institute for Care and Health Excellence recommend current DOA monitors for patients receiving total intravenous anaesthesia and operations at high risk of adverse outcomes. In a systematic review they showed that even the sub-optimal anaesthesia monitors currently in use produce reductions in general anaesthetic consumption and anaesthetic recovery times. Even a small reduction in the quantity of anaesthetic drugs required for the 2.9 million anaesthetics delivered annually in the UK would have significant cost savings.

Finally, the development of accurate depth of anaesthesia monitoring has a regulatory aspect. The Association of Anaesthetists of Great Britain and Ireland already have a minimum standard for anaesthetic monitoring. A reliable depth of anaesthesia monitor using SWAS would become a standard of care and a requirement for the safe and efficient delivery of every anaesthetic. The anaesthetic community would welcome any reduction in the unpredictability of patient responses that ultimately allows a more consistent anaesthetic delivery with improved patient outcomes.