In 2004, Mario Cibelli was preparing a 75-year-old patient for major heart surgery when the patient’s daughter asked for a quick word. “She explained to me how worried she was about the operation,” said Cibelli, anesthesia and intensive care consultant at University Hospitals Birmingham. “I said, ‘Look, everyone’s afraid of heart surgery, it comes with risks, but normally people benefit.’ And then she told me that her father underwent heart surgery two years ago and changed dramatically. ”
Cibelli listened as the woman described how her father, a former physics professor, showed signs of a marked cognitive decline after initial surgery. Once a passionate chess player, he was now unable to play the game and even tried to solve basic crossword puzzles.
For Cibelli, this was the first time he had encountered what is now called postoperative cognitive dysfunction (POCD) – cognitive problems associated with surgery that persist even after the effects of anesthetics have subsided. “I have published several articles on this topic,” he says. “And people started finding my e-mail address and saying that their father or mother had changed a lot in the past after the operation.” So I began to realize that this was not such an isolated case. “
We have known for a long time that operations can have hidden consequences for the brain. As early as 1887, the British Medical Journal published an article describing cases of delirium after anesthesia. A century later, researchers in the 1980s began looking at cases of elderly patients who showed a decrease in memory and concentration after heart surgery, but only recently did this prove to be a risk factor for everyone over the age of 65. who are undergoing surgery, especially when in deep sedation.
In the last 20 years, studies have shown that POCD symptoms can affect everything from memory to attention, judgment and perception, and people with pre-existing health problems are particularly vulnerable. One survey of patients who underwent hip fracture surgery found that those who developed POCD had a poorer ability to function socially and perform routine activities, such as writing, managing money, or remembering lists, with a tangible impact on their daily lives. .
Currently, estimates suggest that the overall incidence of POCD in elderly patients may be as high as 50-80% at discharge, 20-50% at six weeks, and 10-30% at six months postoperatively. With the NHS performing about 5.1 million operations each year, a disproportionate number of them over the age of 65, Cibelli says there are a significant number of patients who remain permanently disabled.
Postoperative cognitive dysfunction can affect both younger and older patients. Photo: Jan Hakan Dahlstrom / Getty Images
In recent years, POCD has attracted the attention of researchers working on Alzheimer’s disease, who have wondered whether it can accelerate the decline towards dementia in some cases. Jenny Barnett, general manager of Monument Therapeutics, a Cambridge-based biotechnology startup that develops new therapies in neurology, says people who already have underlying memory and attention disorders are particularly vulnerable to POCD and should be considered a risk factor. significant operations.
“Many of us have experienced that our grandmother broke her hip, went to the hospital, and then when she went out she was not cognitively the same and she was no longer able to live alone,” says Barnett. “I think it’s something that resonates with a lot of people.”
But exactly what causes POCD remains a mystery. Some point the finger at anesthetics – some animal studies have found that inhalation anesthetics, the most commonly used form of general anesthesia, can cause degradation of the cholinergic system in the brain, which is involved in learning and memory – but have proven difficult to study in humans.
We have long assumed that anesthesia is very transient, so when it subsides, it is gone. That’s probably not true David Warner, a pediatric anesthesiologist
Instead, many scientists point to the possibility that these symptoms are caused by the body’s response to the operation itself. Major surgeries set off a firestorm of inflammation in response to acute tissue damage that can cross the blood-brain barrier. Because the brain contains the highest density of inflammatory receptors in the body, it is particularly vulnerable to the effects of inflammation, which can damage sensitive areas. Some brain scans have found that the hippocampus – a complex and vulnerable structure that plays a key role in memory – has reduced volume in patients with POCD.
All this emerging evidence could lead to changes in medical practice. Research is already underway into ways to identify patients at risk before surgery, with the idea of potentially using a regional rather than a general anesthetic.
But it’s not just older, more fragile patients who are most at risk for POCD. The same can be said for the very young, in significantly different ways.
Can anesthetics cause behavioral problems in children?
As a pediatric anesthesiologist at the Mayo Clinic in Minnesota, David Warner tried to understand the possible causes of a number of behavioral problems in children. He began to wonder if surgery and anesthesia could affect the fragile brains of young children.
“I go to the hospital in the morning and take care of the children during the operation, they wake up and go home at night and they seem to be fine,” he says. “So we’ve long assumed that anesthesia is very transient, so when it’s gone, it’s gone.” That’s probably not true. “
The reason Warner became interested in anesthetics was that in studies in monkeys, exposure to childhood anesthesia led to altered behavior, such as increased emotional reactivity to threats and impaired learning and memory formation. However, it is difficult to pass on these changes to people whose child development is much more complicated than to our closest relatives.
In 2018, Warner decided to test his theories. He conducted a study on 1,000 children in Minnesota and compared three groups: children who had not been anesthetized before the age of three; children who had a single exposure; and children who had multiple exposures.
“Basically, we found that children who were repeatedly exposed to anesthesia had these problems with fine motor skills and more often reported behavioral problems,” he says.
Further research has also found an association between multiple exposure to anesthetics before the age of three and cognitive, memory, listening and language deficits. Further studies have found correlations between multiple exposures to anesthetics and children who were later diagnosed with Attention Deficit Hyperactivity Disorder (ADHD).
Until now, however, it has been difficult for scientists to establish a direct causal link between anesthetics and damage to the developing brain. In 2019, a study in the Lancet suggested that there might be alternative explanations. Children who require more surgery at a young age may already be prone to neurodevelopmental problems due to injuries or illnesses they suffer from: anesthetic doses can only be accidental.
We don’t know right now, but later this year, Warner will perform a brain scan on the same children to see if the structural changes in the brain associated with anesthesia may be associated with the onset of behavioral problems.
“We have some preliminary evidence that children who have been exposed to multiple anesthetics have something different in some parts of their brains,” he says. “That’s just our first look at it, but I suspect there’s going to be something.”
What to do with the problem
In 2015, the American Society of Anesthesiologists launched the Brain Health Initiative to raise awareness of post-operative cognitive issues.
Warner believes that growing awareness of these risks means that physicians will be increasingly careful when using anesthetics in young children when performing non-surgical procedures such as radiotherapy or endoscopy.
Researchers are focusing on ways to help better prepare older patients for surgery. Sukanya Sitthikongsak / Getty Images pictures
He says it is clear that there is a need to focus more on longer-term care for children who have received more anesthetics in the early stages of their lives. The brains of young children are highly malleable, or “plastic,” as neuroscientists like it, and Warner suggests providing these vulnerable children with specific cognitive enrichment activities that stimulate them to protect them from cognitive impairment.
At the other end of the age spectrum, more and more attention is being paid to ways to prepare elderly patients for surgery to be more cognitively resilient, or to treat POCD as a result.
In the early 1990s, Danish surgeon Henrik Kehlet created a program known as ERAS (enhanced recovery after surgery) to study ways to maximize postoperative recovery. Some of the latest research suggests that a “rehabilitation” program consisting of simple muscle exercises, nutritional supplements, and mind stimulation training may have a protective effect for six to eight weeks before major surgeries.
Monument Therapeutics has reformulated the generic anti-inflammatory drug to have access to the brain and potentially suppress some of the inflammations that can occur after surgery. It is preparing to start the study, initially on healthy volunteers, and if it proves successful, it will target patients with POCD in the coming years.
But scientists are …