Beneath green surgical sheets and a tangle of tubes, a healthy young ewe is undergoing a heart-lung bypass procedure to help answer one of several urgent questions about a pillar of modern medicine: anesthesia.
Almost two centuries after anesthetics revolutionized surgery, a growing body of research is pointing to disturbing side effects that range from delirium to cancer-proliferating immune suppression. Researchers knocked out the sheep last month at the University of Melbourne to try to understand why common open-heart procedures lead to acute kidney injury in up to a third of patients -- part of a broader effort to study the impact of anesthesia on the immune system, brain and other major organs.
The findings are already undermining decades of soothing messages about the harmlessness of being put into a sleep-like state. "Anesthetists are now trying to say actually it's not that safe," said Andrew Davidson, head of anesthesia research at the Murdoch Children's Research Institute in Melbourne. "You don't die on the table, but quite a lot of you don't get home."
Of the 200 million adults worldwide who undergo non-cardiac surgery annually, more than 1 million will die within 30 days. That risk jumps to 1 in 20 for patients 70 years and older.
Less than a mile from Davidson's center at the Royal Children's Hospital in Melbourne, separate groups at the Florey Institute of Neuroscience and Mental Health and the Peter MacCallum Cancer Centre are working to understand whether inhaled volatile gases like isoflurane and sevoflurane -- used by anesthetists to render some 80 percent of patients unconscious -- may be more harmful than intravenous agents, such as propofol and fentanyl.
With 313 million operations undertaken each year, the findings may have significant global economic and social implications, and could herald a paradigm shift in surgical care, researchers say.
The science is conflicting and incomplete. A study by Davidson and colleagues, published late Thursday in the Lancet medical journal, found an hour of general anesthesia in early infancy has no lasting impact on the developing human brain. But some surgery may last longer, and Mayo Clinic doctors found an association between anesthesia and attention-deficit hyperactivity disorder in children.
The ADHD link is "scientifically plausible, but the evidence is not strong," according to Davidson.
On the fourth floor of a University of Melbourne laboratory building, scientists at the Florey Institute are using fiber optic probes to measure blood flow and oxygen levels in different regions of the kidney of the 2-year-old Merino undergoing open-heart surgery.
The research, conducted by a team of clinicians and scientists under human surgical conditions, is designed to track kidney changes before, during and after the procedure, as well as identify risks attributable to two kinds of anesthetic agents, and find ways to protect the blood-filtering organ.
As many as 30 percent of patients who undergo open-heart surgery develop an acute kidney injury that increases their risk of chronic kidney disease and death, according to Yugeesh Lankadeva, a researcher studying the interaction.
Lankadeva and colleagues showed in a paper published last month that volatile-gas anesthesia was associated with higher activity in a key nerve that corresponded with a potentially damaging reduction in blood flow to the kidneys of sheep during abdominal surgery. Intravenous anesthesia had less impact.
Lankadeva's current study aims to understand the mechanism in the context of heart-lung bypass procedures -- routinely used for cardiac grafts and valve replacements -- when the kidney is susceptible to further injury due to a rush of blood after normal circulation resumes.
It's possible that the nerve activation associated with anesthesia, especially the inhaled gas form, is also impairing the immune system, according to Clive May, head of the Florey Institute's preclinical critical care unit, who developed the kidney probe technique.
"There is a well-known link between the nervous system and the immune system, and activation of the nervous system can inhibit the immune system," May said.
That link is being explored across the road at the Peter MacCallum Cancer Centre. Researchers there will lead an international clinical trial this year involving 5,700 patients randomized to receive either type of anesthesia for lung or colorectal cancer surgery, and followed for five years to compare cancer recurrence and survival.
Laboratory research and clinical observations indicate volatile gases may be harmful, said Bernhard Riedel, who is leading the study. "But what we really need is a big prospective, randomized study to look at the body of evidence where we can change guidelines."
Previous research suggests that inhaled anesthetics have a pro-inflammatory effect that may paralyze the immune system for about a week around the time of surgery, Riedel said. That could provide an opportunity for any cancer cells remaining in the body to gain a foothold at the same time as the gas anesthesia inadvertently encourages blood-vessel growth to support nascent tumors.
Propofol, on the other hand, may have an anti-inflammatory effect, causing less immune perturbation, he said.
When it comes to anesthetic's effects on the brain, both anesthesia types appear to be implicated in damage to neurons, the organ's basic working units -- similar to what occurs from a concussion or a minor acute brain injury, according to Lis Evered, a University of Melbourne researcher.
Evered, who is also a neuroscientist at the city's St. Vincent's Hospital, and colleagues showed last year increases in two biomarkers of neurological injury -- neurofilament light and tau protein -- in patients 60 years and older undergoing anesthesia on whom blood samples were taken before and sequentially up to 48 hours after surgery.
Studies in elderly patients have also linked a longer duration of anesthesia to an increased risk of post-surgery delirium -- a transient complication associated with poorer neurocognitive function longer term. These raise questions about the risk-versus-benefit of some surgeries in older adults, Evered said.
"For 140 years, we were just concerned about safety," she said. "In the last 30 years, we've actually become a bit more concerned about other sorts of impacts because people are living longer. Now, we want people to survive the procedure and have a good quality of life for the next 10 to 20 years."
The findings of neurotoxicity are further challenging traditionally held beliefs that general anesthesia simply "turns the brain off" for a period after which it reverts to its pre-anesthesia state, said Davidson at the Murdoch Children's Research Institute.
"Anesthesia is a very abnormal state for the brain to be in," he said. "So it makes sense that your brain circuitry is actually not the same after the anesthetic as it was before."
That probably doesn't matter for young adult patients, Davidson said. "But if you're old or very young, then maybe it does begin to matter."
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