General anesthesia and coma appear to share important similarities said US researchers who concluded the brain isn’t “asleep” under general anesthesia, as surgery patients are often led to believe, but goes into a state that is more like a reversible coma.

They hope their findings will lead to new approaches to general anesthesia and also improve the diagnosis and treatment of sleep abnormalities and emergence from coma.

Dr. Emery Brown of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard Medical School, Dr Nicholas D Schiff, of Weill Cornell Medical College and NewYork-Presbyterian Hospital/Weill Cornell Medical Center, and Dr Ralph Lydic from the University of Michigan, published their extensive review of general anasthesia, sleep and coma in the 30 December online issue of the New England Journal of Medicine, NEJM.

It took three years for, Brown, who has expertise in general anesthesia, Lydic, a sleep expert, and Schiff, an expert in recovery from coma, to synthesize the newest studies in these three areas, including their own work.

In their review they discuss the clinical and neurophysiological features of general anesthesia and how they relate to sleep and coma, paying particular attention to the mechanisms of unconsciousness brought on by certain intravenous anesthetics.

Schiff told the press that:

“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 anesthesia.”

“By reframing these phenomena in the context of common circuit mechanisms, we can make each of these states understandable and predictable,” he added.

Brown said their findings “show that general anesthesia is a reversible coma, and learning about the different ways we can safely place the brain into this state, with fewer side effects and risks, could be an important advance in general anesthesiology.”

“Also, in a scientific sense, monitoring brain function under general anesthesia gives us new insights into how the brain works in order to develop new sleep aids and new ways for patients to recover from coma,” he added.

In their review, Brown, Lydic and Schiff explain how a fully anesthetized brain more closely resembles the deeply unconscious brain seen in coma patients, and is less like that of a person asleep.

They conclude that general anesthesia is a drug-induced coma, which as a consequence, is reversible, and the two states operate on different time scales: general anesthesia in minutes to hours, and recovery from coma in hours to months to years, if ever.

However, they say that the states of sleep, general anesthesia and coma have more similarities than differences, and suggest they are part of a continuum of brain activity that uses the same brain circuit mechanisms whether it be for waking up from sleep or recovering from coma or general anesthesia.

The idea of a continuum of activity is “very exciting, because it gives us new ways to understand each of these states,” said Schiff.

Understanding more about the brain mechanisms involved and how they vary across the continuum could help us develop new drugs that “tweak the circuits as needed”, and improve in the areas we are currently not so good at, such as “abnormalities of sleep and, especially, emergence from a coma”, he added.

More knowledge in this area may also shed light on why general anesthesia, which Schiff describes as an “incredibly safe technique”, can adversely affect elderly patients, who sometimes recover more slowly with impaired cognitive function afterwards.

The authors describe one circuit in particular as critically important. This links three brain regions: the cortex, the layers of neural tissue on the periphery of the brain, the thalamus, the ball of neural tissue at the centre of the brain, and the basal ganglia, within the front of the brain.

The regions communicate with each other via nerve cell axons, which act like signalling highways passing information back and forth.

The authors say that the cortex and the thalamus appear to communicate with each other in a pattern that changes over a 24-hour cycle.

Also, the basal ganglia controls certain actions, in part by setting up two feedback loops. One of the loops is a negative feedback that acts as a brake on behavior, and is always active when overall brain activity is reduced, said Schiff. For example, it stops us physically acting out our dreams while we are asleep.

The second loop releases the brake imposed by the first loop, and certain pharmacological compounds like the sleep drug zolpidem (Ambien), and propofol, a powerful general anesthetic with similar properties, can activate it, producing an effect known as “paradoxical excitation”, said the researchers.

They explain that paradoxical excitation, a state characterized by increased energy, restlessness, nervousness, that can sometimes be seen in patients in the early stages of general anesthesia, appears to be common across all three states because the drugs are triggering this same feedback loop.

For example, some patients who take Ambien can walk, eat and exhibit other complex behaviors in an altered state of consciousness arising from sleep, and surprisingly, there are reports that the drug has also restored communication and behavioral responses in people with severe brain injury.

But eventually, the negative feedback loop regains control, restoring the brake on behavior, in all three states, and sedation and deeper sleep ensue. And in the case of the severely injured brain patient, he or she goes back to a state of diminished responsiveness.

The authors said being able to bring these disparate observations together into one common circuit model is one of the main insights of their review.

Brown said there was also a “flip side” to the common circuit, the phenomenon of “emergence delirium”.

“For example, when bringing a person out of general anesthesia, the brain is woken up enough to be active, but it is not coherent or organized, which can explain the slower recovery time we see in some patients,” he explained.

These are the two areas where the authors expect their review to make the biggest contribution: losing consciousness and returning to consciousness.

They believe their research will help new therapies for sleep, emergence from coma and general anesthesia, to target these areas more effectively with fewer side effects.

Funds from the National Institutes of Health, the James S. McDonnell Foundation and the National Institutes of Health Director’s Pioneer Award, helped pay for the study.

“Mechanisms of Disease: General Anesthesia, Sleep, and Coma.”
Emery N. Brown, Ralph Lydic, and Nicholas D. Schiff.
N Engl J Med, 2010, 363: 2638 – 2650, published online 30 December 2010.

Additional source: New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College (press release).

Written by: Catharine Paddock, PhD