Research Team: Dr Nicoletta Nicolaou, Lorena Goncalves de A. FreitasDr Timothy Constandinou

Collaborators: Dr Geoffrey Lockwood (Hammersmith Hospital), Dr Marcela P. Vizcaychipi (Chelsea and Westminster Hospital), Professor Nick Franks FRS (Dept. of Life Sciences), Dr Julius Georgiou (University of Cyprus)

Funding: EU FP7 Programme/Marie Curie Actions (FP7/2007-2013) under REA grant agreement no623767. 

Suddenly, I was aware something had gone very wrong. I could hear what was going on around me, and I realised with horror that I had woken up in the middle of the operation, but couldn’t move a muscle. I heard the banal chatter of the surgeons, and I was aware of many people in the room bustling about, doing their everyday clinical jobs and minding their own business, with absolutely no idea of the cataclysmic event that was unfolding from my point of view. While they fiddled, I lay there, frantically trying to decide whether I was about to die, and what options were open to me"

Excerpt from 5th National Audit Project (NAP5) of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland, 'Accidental Awareness during General Anaesthesia in the United Kingdom and Ireland', Sept. 2014

Modern anesthesia is a chemical cocktail of agents, each one targeting a different integral part of anesthesia (unconsciousness, amnesia, analgesia and immobility). Given that there are no strict dosages for these combinations of agents, the anesthetist follows a set of approximate dosage guidelines and adjusts these based on patient characteristics and past experience. However, administering an incorrect dosage could have serious complications. Overadministration leads to unnecessarily deep anesthesia, with dangerous and potentially lethal consequences (e.g. cardiovascular depression). Under-administration leads to light anesthesia, with increased risk of accidental regaining of awareness during surgery.

The patient testimony above highlights the severity of accidental regaining of awareness during surgery. Even though intra-operative awareness (IOA) does not happen often, the consequences for patients who do experience it during their surgery are traumatizing. Such an experience can lead to long-term psychological problems, including post-traumatic stress disorder and fear of having another surgery. In addition, the majority of surgically-related insurance compensation claims to patients are related to accidental awareness during surgery.

The Association of Anesthetists of Great Britain and Ireland has recently published the findings of a comprehensive study (NAP5) of accidental awareness during general anesthesia in the UK and Ireland [1]. The study reports that approximately 300 patients in the UK and Ireland have experienced awareness during their surgery in one year, resulting to an estimated incidence of awareness at 1 patient in 15,000. Other similar studies in the USA report a higher incidence at approximately 0.1% (e.g. [2]).

Putting this into perspective, considering that an estimated 234.2 million patients undergo surgery with general anesthesia every year worldwide [3], a conservative estimate of 15,613 patients will experience intraoperative awareness. These estimates are likely to be even higher, as some patients who experience awareness may not remember this due to the amnesic effects of the administered agents and, hence, a number of IOA cases remain unreported.

To address the problem of intra-operative awareness, the state-of-the-art has led to the development of commercial devices that monitor the patient level of hypnosis. Their operation is based on information extracted from the patient’s electrical brain activity (electroencephalogram – EEG), as some of the effects of anesthetics cause identifiable changes in EEG activity [4].

The most widely used devices are the BIS® (Aspect Medical Systems, USA) and E-Entropy (GE, Germany). Despite their existence, they failed to become part of routine surgery (reported use in 2.8% of surgeries [1]). This is due to a number of issues related to robustness, intersubject variability and the large delay between the actual time of awareness and the time of change in the monitoring index [5].

An additional factor is cost of initial purchase, as well as long-term operational cost. The biggest cost is associated with the purchase of consumable sensors, whose prices vary more widely. The NHS cost for the BIS® Vista and the BIS® Vista Bilateral monitoring systems comes to £4,350 and £5,025 respectively, while the BIS® Quatro sensors cost £362.50 per box of 25 and the BIS® bilateral sensors cost £210 per box of 10 [6].

As part of a past project at University of Cyprus, we collected EEG activity from 47 patients undergoing routine surgery at Nicosia General Hospital. This activity was analysed with different methods (e.g. permutation and approximate entropy [7], granger causality [8], synchrony methods [9] [10]). Our general findings verified a decrease of EEG complexity during anesthesia and we identified specific changes in brain connectivity and synchrony during anesthetic induced unconsciousness (an example can be seen in figure 1). Even though the majority of features investigated showed high performance in wakefulness / anesthesia discrimination, our interest focused more on granger causality-based features, as these provided high discriminatory ability (98%) while also capturing general mechanisms of anesthetic-induced changes in brain connectivity. More specifically, we identified a stable and reversible increase in granger causality in the frontoposterior direction during anesthesia, independently of the particular anesthetic protocol [8].

Based on our previous findings, “AnaeWARE” (August 2014 – July 2016) challenges the stateof-the-art and addresses the question whether EEG alone is sufficient for reliable monitoring of anesthetic state. A promising direction for a new generation of monitoring devices is the extension from a single- to a multi-modal approach, utilizing additional information that is already available as part of routine monitoring during surgery, e.g. heart rate. This will not impose additional costs to already limited national healthcare funds and could offer a solution for more reliable monitoring.

To pursue this direction of research relies, firstly, on the ability to link these multi-modal observations to the underlying mechanisms of anesthetic action; and, secondly, on the ability to take this knowledge and turn it from theory to practice (hardware implementation). The project will involve the collection of anonymous multi-modal signals from patients undergoing elective surgery at Hammersmith Hospital, London.

The data will be analysed in order to identify how anesthetic administration affects the relationships between the different modalities and investigate whether such changes provide increased discriminatory power between wakefulness and anesthesia, or even prediction of wakefulness. The latter in particular is highly non-trivial and we envisage to explore this through the aid of theoretical models that describe the effects of anesthetics on neural connectivity.

The outcome of the project will be an index of awareness that is robust and takes into account inter-subject variability. A secondary aspect of the project is the “real-time” estimation of this index of awareness. This will involve the translation of the developed methodologies to hardware form that is capable of performing “real-time” discrimination of wakefulness and anesthesia.

We believe that the shift to a multi-modal approach will improve performance, allow fast prediction of intraoperative awareness and, thus, provide the necessary push to lead the way for the development of the next generation of devices for monitoring the patient state of hypnosis.

Relevant Publications