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Newly discovered pre-synaptic mechanisms of general anaesthesia point the way towards designing potential reversal agents that could help expedite recovery.
Most of us will undergo multiple procedures requiring general anaesthesia in our lifetime, during which we will be rendered unconscious in a medically induced coma for the duration of the intervention. Ideally, we will not remember the procedure afterwards, nor experience any adverse effects. Globally, over 300 million major surgeries and 200 million gastrointestinal endoscopies are performed annually under anaesthesia or sedation to induce unconsciousness. Modern anaesthetic agents, such as the inhalation gas sevoflurane or the intravenous drug propofol, are highly effective and safe for these interventions.
However, recovery from anaesthesia can be unpredictable and may pose health risks, particularly in elderly patients or those with pre-existing cognitive conditions, who may experience delayed recovery, transient memory loss, or short-term cognitive impairment. In some cases, these interventions may result in longer lasting effects such as brain fog, delirium, exacerbation of dementia or other neurological conditions.
Recovery from anaesthesia has attracted little attention in part because there has been some ambiguity in what constitutes recovery, which is more complex than simply regaining consciousness. Consequently, and despite the frequency of such procedures, recovery from general anaesthesia remains a passive process without a dedicated antidote to actively restore normal brain functions. Delayed cognitive recovery prevents patients from resuming their normal activities, and often results in ongoing medical care and costs. Given the prevalence of anaesthesia use, it is remarkable that no effective reversal agent exists to accelerate recovery and ensure a quicker return to baseline cognitive functions.
Our research
Since William Morton demonstrated the use of inhaled diethyl ether for effective general anaesthesia in 1846 (Boston, USA), inducing unconsciousness during surgery, the precise mechanism of action remains elusive. Over the years, leading theories have emerged, including the lipid membrane theory, protein and receptor modulation, and ion channel theories. However, none have fully explained how these drugs disrupt the complex network dynamics that render a brain completely unresponsive to external stimuli.
While a single anaesthetic target seems unlikely, most research has focused on post-synaptic receptors in the brain, primarily inhibitory GABAA receptors that are potentiated by many general anaesthetics. So far, most tested antidotes or putative anaesthetic reversal agents therefore target these post-synaptic receptors, or alternatively act as stimulants through excitatory pathways that counteract these post-synaptic inhibitory effects. Although some agents have shown promise in accelerating recovery, none have proven entirely effective or achieved widespread use in reversing anaesthesia or improving recovery. Recent research suggests that this could be because many general anaesthetics also target pre-synaptic functions, alongside post-synaptic receptors.
Research on animal models at the Queensland Brain Institute (at The University of Queensland) and elsewhere has revealed that general anaesthetics act on a variety of pre-synaptic proteins, leading to a common endpoint: impaired excitatory neurotransmission. Together with the inhibitory post-synaptic effects that lead to sedation, this provides a more comprehensive explanation for why all animals are rendered behaviourally unresponsive by these drugs: it is a two-step process.
Our research has uncovered that many commonly used general anaesthetics (including propofol) target the pre-synaptic vesicle release machinery, thereby impairing chemical communication among billions of nerve cells throughout the brain. These disruptions in protein function within trillions of communication points (synapses) across the brain may explain the recovery inertia observed after anaesthesia, as well as the post-operative cognitive dysfunction experienced by many patients. To uncover effective reversal agents for general anaesthesia therefore requires a better understanding of these pre-synaptic effects, as any reversal agent would likely be acting on the same mechanism. Ideally, such pre-synaptic agents would be used in combination with existing post-synaptic drugs.
The benefits of reversal agents against general anaesthetic agents
A properly anaesthetised patient remains unconscious throughout surgery and does not respond to surgical stimuli, thanks to the combined use of sedatives, painkillers and muscle relaxants. These drugs have specific durations of action that typically outlast the actual surgical procedure.
By employing reversal agents to terminate the complex effects of general anaesthetics (pre-synaptic as well as post-synaptic), we aim to achieve several significant benefits in post-operative care. These include enhanced patient safety and comfort, a more positive patient experience, a quicker return to baseline function, and improved operational efficiency. Faster recovery would allow for quicker operating room turnover, reduced time in recovery, faster discharge to home or to the ward, lower overall operational costs, and better utilisation of health care resources, ultimately leading to cost savings across the health care system.
Appropriately deployed reversal agents could also play a critical role in improving outcomes for high-risk patient groups, such as frail elderly individuals or those with comorbidities (e.g., dementia), by reducing side effects like confusion, grogginess, pain, post-operative delirium, and confusion. Minimising the time patients spend in a vulnerable state — marked by risks such as hypoxia, respiratory complications, and airway obstruction — would promote faster and safer emergence from anaesthesia, contributing to improved patient care.
Through a better understanding of how general anaesthetics impair pre-synaptic neurotransmission, we are testing candidate reversal agents that may directly counteract the effects of general anaesthetics, in animal models. This research aims to test the efficacy of these agents while avoiding side effects, paving the way for eventual testing in humans. To effectively link this research to human patients, recent advances in stem cell biology now enable the creation of lentil-sized brain organoids derived from pluripotent stem cells, which can be patterned into specific brain regions (e.g., cortex) for drug screening trials. The effectiveness of reversal agents can thus be tested across a variety of systems, from animal models to laboratory-grown brains.
Candidate reversal agents are typically non-anaesthetic analogues of the drugs that render animals unconscious and unresponsive. For example, a fluorinated propofol analogue — propofluor — has shown promise in rapidly awakening zebrafish exposed to clinical concentrations of propofol. It is unknown how propofluor might do this, although a pre-synaptic mechanisms of action seems likely. This is being tested by an ANZCA-funded project at The University of Queensland.
Conclusion
A new understanding of the multiple target mechanisms of general anaesthetics will point the way to developing novel reversal agents, which should help improve recovery from the procedure, especially in patients who are potentially susceptible to post-operative cognitive dysfunction.
This exciting project is a collaboration between Prof. Bruno van Swinderen, a world expert in the molecular mechanisms of anaesthesia; Dr Drew Cylinder, who completed a PhD-Doctorate on the subject at QBI; and Prof. André van Zundert, an acknowledged clinical expert on general anaesthesia who always strives to advance improvements in better patient care and upholds the highest standards of excellence in clinical medicine. Recently, he was awarded the 2024 ANZCA Medal Award from his College (Australian and New Zealand College of Anaesthetists) and the 2024 AMA Excellence in Healthcare Award from the Australian Medical Association for his contributions to medicine.
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Definitely an interesting proposal & certainly would be a major advance if such an agent could be developed. However, given that certainly inhaled agents & possibly propofol also act via more than just a single receptor, it’s difficult to conceive that a single antagonist would reverse all the effects. It would very likely have to act pharmacokinetically by binding or inactivating the agent in question – as sugammadex & protamine do to rocuronium & heparin respectively.
Alternatively, the future may lie in developing better intravenous hypnotics with ultrashort half-lives due to organ independent clearance – e.g. via ester hydrolysis. Agents with this property have already been developed in other drug classes such as opioids (remifentanil), neuromuscular blockers (cisatracurium) & beta-blockers (esmolol).
There is actually already one total intravenous anaesthetic regime – albeit not widely used outside intensive care practice – that can be fully reversed: midazolam/opioid/rocuronium – with flumazenil, naloxone & sugammadex again. But other factors probably preclude its routine use.
At the end of the day, perhaps the most fascinating paradox is that we have been able to sequentially develop better & better inhaled anaesthetic agents such as sevoflurane & desflurane, while still not being exactly sure how they work!
Another approach to this problem is getting the anaesthetic agent unchanged and out of the body as quickly as possible. This happens mostly with volatile agents, notably desflurane, so much so that the term ‘emergence phenomena’ was used to describe the startle effect of rapid awakening. Due to environmental concerns, desflurane is currently being withdrawn. I would like to suggest that it would have been better for patients, especially aged patients with the risk of confusion, for efforts to have been directed to the capture of desflurane from the expired gases and either its subsequent recycling or destruction.