General Anesthesia is Pharmacological Coma, not Sleep

Instead of a deep sleep, general anesthesia is more like a reversible drug-induced coma.

“General anesthesia is pharmacological coma, not sleep,” said Dr. Nicholas Schiff of Weill Cornell Medical College in New York, who worked on the study with Dr. Emery Brown of Massachusetts General Hospital and Dr. Ralph Lydic of the University of Michigan.

Their findings, published in the New England Journal of Medicine, represent a three-year exploration of the similarities and differences of sleep, anesthesia and coma. They said while doctors and patients commonly describe general anesthesia as going to sleep, there are significant differences between the states, with only a bit of overlap between the deepest states of sleep and the very lightest phases of anesthesia. While sleeping usually involves moving through a series of phases, in general anesthesia, patients are typically taken to a specific phase or state and kept there.

The use of general anaesthesia is a routine part of surgical operations at hospitals and medical facilities around the world, but the precise biological mechanisms that underlie anaesthetic drugs’ effects on the brain and the body are only beginning to be understood. A review article in the December 30 New England Journal of Medicine brings together for the first time information from a range of disciplines, including neuroscience and sleep medicine, to lay the groundwork for more comprehensive investigations of processes underlying general anaesthesia.

‘A key point of this article is to lay out a conceptual framework for understanding general anaesthesia by discussing its relation to sleep and coma, something that has not been done in this way before,’ says Emery Brown, MD, PhD, of the Massachusetts General Hospital (MGH) Department of Anaesthesia, Critical Care and Pain Medicine, lead author of the NEJM paper. ‘We started by stating the specific physiological states that comprise general anaesthesia – unconsciousness, amnesia, lack of pain perception and lack of movement while stable cardiovascular, respiratory and thermoregulatory systems are maintained – another thing that has never been agreed upon in the literature; and then we looked at how it is similar to and different from the states that are most similar – sleep and coma.’

After laying out their definition, Brown and his co-authors – Ralph Lydic, PhD, a sleep expert from the University of Michigan, and Nicholas Schiff, MD, an expert in coma from Weill Cornell Medical College – compare the physical signs and electroencephalogram (EEG) patterns of general anaesthesia to those of sleep. While it is common to describe general anaesthesia as going to sleep, there actually are significant differences between the states, with only the deepest stages of sleep being similar to the lightest phases of anaesthesia induced by some types of agents.

While natural sleep normally cycles through a predictable series of phases, general anaesthesia involves the patient being taken to and maintained at the phase most appropriate for the procedure, and the phases of general anaesthesia at which surgery is performed are most similar to states of coma. ‘People have hesitated to compare general anaesthesia to coma because the term sounds so harsh, but it really has to be that profound or how could you operate on someone?’ Brown explains. ‘The key difference is this is a coma that is controlled by the anaesthesiologist and from which patients will quickly and safely recover.’

In detailing how different anaesthetic agents act on different brain circuits, the authors point out some apparently contradictory information – some drugs like ketamine actually activate rather than suppress neural activity, an action that can cause hallucinations at lower doses. Ketamine blocks receptors for the excitatory transmitter glutamate, but since it has a preference for receptors on certain inhibitory neurones, it actually stimulates activity when it blocks those inhibitors. This excess brain activity generates unconsciousness through a process similar to what happens when disorganised data travels through an electronic communication line and blocks any coherent signal. A similar mechanism underlies seizure-induced unconsciousness.

Brown also notes that recent reports suggest an unexpected use for ketamine – to treat depression. Very low doses of the drug have rapidly reduced symptoms in chronically depressed patients who had not responded to traditional antidepressants. Ketamine is currently being studied to help bridge the first days after a patient begins a new antidepressant – a time when many may be at risk of suicide – and the drug’s activating effects may be akin to those of electroconvulsive therapy.

Another unusual situation the authors describe is the case of a brain-injured patient in a minimally conscious state who actually recovered some functions through administration of the sleep-inducing drug zolpidem (Ambien). That patient’s case, analysed previously by Schiff, mirrors a common occurrence called paradoxical excitation, in which patients in the first stage of general anaesthesia may move around or vocalise. The authors describe how zolpidem’s suppression of the activity of a brain structure called the globus pallidus – which usually inhibits the thalamus – stimulates activity in the thalamus, which is a key neural control centre. They hypothesise that a similar mechanism may underlie paradoxical excitation.

‘Anaesthesiologists know how to safely maintain their patients in the states of general anaesthesia, but most are not familiar with the neural circuit mechanisms that allow them to carry out their life-sustaining work,’ Brown says. ‘The information we are presenting in this article – which includes new diagrams and tables that don’t appear in any anaesthesiology textbook – is essential to our ability to further understanding of general anaesthesia, and this is the first of several major reports that we anticipate publishing in the coming year.’

Schiff adds, ‘We think this is, conceptually, a very fresh look at phenomena we and others have noticed and studied in sleep, coma and use of general anaesthesia. By reframing these phenomena in the context of common circuit mechanisms, we can make each of these states understandable and predictable.’

Source: Massachusetts General Hospital

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