Despite their use in approximately 60,000 surgeries per day in the U.S. alone, medical researchers don’t know exactly how anesthetics cause unconsciousness – or what the true long-term impact of their use could be on the brain and the rest of the body.
"The development of anesthetic drugs has been hailed as one of humankind's greatest discoveries in the last thousand years," Max B. Kelz, MD, PhD, assistant professor of Anesthesiology and Critical Care, said in a recent US News & World Report article. "Anesthetics are annually given to over 230 million patients worldwide. Yet as a society, and even within the anesthesia community, we seem to have lost our curiosity for how and why they work."
But research advances by Dr. Kelz and other faculty in the Penn Medicine Center for Anesthesia Research, one of the largest programs of its kind in the world, are helping to get to the bottom of this 160-year-old mystery.
With regard to pinpointing how anesthetics cause a state of unconsciousness, Kelz focuses his work on the overlap between the neurobiology of sleep and anesthesia. In October, his research team published a paper in Current Biology that showed in an animal model certain anesthetics don't just turn wakefulness "off," they also force important sleep circuits in the brain "on," essentially hijacking our natural sleep circuitry.
In this study, Kelz and colleagues focused on a particular part of the brain, deep within the hypothalamus, which is known to increase in activity as one drifts off to sleep. Through a combination of direct electrical recording and other methods, they found that isoflurane – a type of anesthetic – boosts activity in this sleep-promoting brain area in mice. As further evidence of a connection, animals lacking the function of those neurons exhibited acute partial resistance to entering states of anesthesia.
Dr. Kelz and his team also published another paper in the November issue of the journal Anesthesiology that looked at a specific anesthetic drug called dexmedetomidine – primarily used in operating rooms and intensive care units in hospitals because it induces a state of anesthesia that is most similar to that of natural sleep. “If we can determine exactly where and how a medication such as dexmedetomidine works to cause unconsciousness, that unique drug may provide better clues into the workings of other anesthetics, as well as insights into control and regulation of natural sleep,” he says.
In the area of long-term consequences of anesthetics on the brain and the rest of the body, Roderic Eckenhoff, MD, Austin Lamont Professor of Anesthesia and neuroscientist Maryellen Eckenhoff, PhD, investigate the interaction between anesthesia, surgery, neuroinflammation, and chronic neurodegenerative disorders, such as Alzheimer's disease. In a human study published last year that examined Alzheimer's biomarkers found in cerebral spinal fluid (CSF) after surgery, their team found evidence that anesthesia and surgery may accelerate neurodegenerative dysfunction.
In order to separate anesthesia from surgery as the culprit, the team performed a separate animal model study, published in September in Annals of Surgery. In this study, the research team exposed mice with human Alzheimer’s disease genes to either anesthesia alone, or anesthesia and an abdominal surgery. “In the animals we studied, there was a clear and persistent decrement in learning and memory caused by surgery as compared with inhalational anesthesia alone,” says Maryellen Eckenhoff. This paper is the first to indicate that surgery itself, more than anesthesia, is the trigger for decline in patients with Alzheimer’s disease.
Both studies also suggest that neuroinflammation has a profound impact on a dementia-vulnerable brain. “More studies will be needed to first confirm these findings and then begin to deploy anti-inflammatory strategies to minimize injury,” adds Rod Eckenhoff. “As a profession, doctors need to understand the long-term implications of our care, both positive and negative, and do all we can to delay the onset of dementia.”
Their group is also looking at how to develop newer anesthetics that won’t have the same neuroinflammatory impact as older anesthetics. Rod Eckenhoff explains this research, done by studying different compounds in tadpoles, in a video interview with Chemistry & Engineering News.