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 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 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. “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 and older.

Less than a mile away, 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 about 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 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 in the Lancet medical journal, found an hour of general anesthesia in early infancy has no lasting impact on the developing brain. But some surgery may last longer, and Mayo Clinic doctors found an association between anesthesia and attention-deficit hyperactivity disorder in children.

Inside the University of Melbourne laboratory building, scientists 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 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, said researcher Yugeesh Lankadeva.

It’s possible that the nerve activation associated with anesthesia, especially the inhaled gas form, is also impairing the immune system, said Clive May, head of the Florey Institute’s preclinical critical care unit. “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 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.

“What we really need is a big prospective, randomized study to look at the body of evidence where we can change guidelines,” said Bernhard Riedel, who is leading the study.

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. 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, said Lis Evered, a neuroscientist. Evered and colleagues last year showed increases in two biomarkers of neurological injury — neurofilament light and tau protein — in patients 60 and older undergoing anesthesia.

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 are challenging traditionally held beliefs that general anesthesia simply “turns the brain off” and then reverts to its pre-anesthesia state, Davidson said. “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.”

That unlikely to matter for young adults, he said. “But if you’re old or very young, then maybe it does begin to matter.”