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

Lead Research Organisation: University of Oxford
Department Name: Clinical Neurosciences

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description Clinical Interpretation of SWAS 
Organisation University of Auckland
Department Faculty of Medical and Health Sciences
Country New Zealand 
Sector Academic/University 
PI Contribution We identified slow wave activity saturation (SWAS), generated the Bayesian model to determine whether an individual had achieved SWAS and applied this to our experimental data.
Collaborator Contribution Professor Jamie Sleigh, a world leader in electroencephalography under anaesthesia research, provided clinical EEG datasets acquired under surgical anaesthesia that allowed us to test and refine the SWAS Bayesian modelling in the clinical environment.
Impact Jamie Sleigh and I have co-authored five papers to date: . The collaboration is multi-disciplinary covering the fields of neuroscience and clinical anaesthesia.
Start Year 2014
 
Title PERCEPTION LOSS DETECTION 
Description The present invention relates to a device for detecting a state of true perception loss of a human, the device including processing means operable to detect from information on electrical signals sensed adjacent to the scalp of the human the activity of oscillations present in the electrical signals as a marker for the state of true perception loss of the human. 
IP Reference WO2013179048 
Protection Patent application published
Year Protection Granted 2013
Licensed No
Impact This patent describes the discovery of slow wave activity saturation (SWAS)
 
Title SWAS depth of ananesthesia monitor 
Description We have developed the first prototype of the SWAS depth of anaesthesia monitor and are currently applying this in a pre-surgery clinical trial. 
Type Diagnostic Tool - Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2019
Development Status Under active development/distribution
Impact refinement and assessment of the prototype is still ongoing as part of the MRC DPFS grant 
 
Description Anaesthetic Research Society Committee Member 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Member of the Anaesthetic Research Society Committee that organising national British Journal of Anaesthesia Research Forum conferences on a biannual basis.
Year(s) Of Engagement Activity 2017,2018,2019
 
Description Clinical Research Network (CRN) Thames Valley and South Midlands: Anaesthesia, Peri-Operative Medicine & Pain Management, and Critical Care Specialty Group Meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Member of Clinical Research Network (CRN) Thames Valley and South Midlands Anaesthesia, Peri-Operative Medicine & Pain Management), and Critical Care Specialty Group Meeting. This group aims to encourage and foster new clinical research in anaesthesia across the Thames Valley and South Midlands region.
Year(s) Of Engagement Activity 2018,2019
 
Description Member of Thames Valley Perioperative Medicine Partnership 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Member of Thames Valley Perioperative Medicine Partnership that aims to encourage perioperative research throughout the region.
Year(s) Of Engagement Activity 2018,2019
 
Description NIAA/ CRN special interest group on Discovery Science / Experimental Medicine in Anaesthesia, Peri-op Medicine and Pain 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Member of the newly launchd NIAA/ CRN special interest group on Discovery Science / Experimental Medicine in Anaesthesia, Peri-op Medicine and Pain that aims to encourage basic science research within these fields.
Year(s) Of Engagement Activity 2018,2019
 
Description OMCAN 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Committee member of the Oxford Mathematics of Consciousness Applications Network is a University of Oxford network to encourage collaborations in the field of consciousness research
Year(s) Of Engagement Activity 2018,2019
 
Description UNIQ 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact I lead the UNIQ Spring and Summer schools program for potential Medicine, Biomedical Science and Psychology students at the University of Oxford on behalf of the Wellcome Centre for Integrative Neuroimaging. I organise neuroimaging-based demonstrations and give lectures that are tailored for each subject area. I typically run 3-4 sessions a year, reaching 100-120 sixth-form students.
Year(s) Of Engagement Activity 2016,2017,2018