By David Cox

In 2004, Mario Cibelli was preparing a 75-year-old patient for a big cardiac operation when the patient’s daughter asked for a quick word. “She explained to me how worried she was about the surgery,” says Cibelli, a consultant in anesthesia and intensive care at the University Hospitals Birmingham. “I said: ‘Look, everybody’s worried about heart surgery, it comes with risks, but normally people benefit from it.’ And then she told me that her father had undergone a cardiac procedure two years before and he had changed dramatically.”

Cibelli listened as the woman described how her father, a former physics professor, had shown signs of significant cognitive decline after the initial operation. Once a keen chess player, he was now unable to play the game and struggled to even do basic crosswords.

For Cibelli, it was the first time he had encountered what is now termed postoperative cognitive dysfunction (POCD) – cognitive problems associated with surgery that persist well after the effects of anesthetics have worn off. “I published some articles on the subject,” he says. “And people began finding my email address, saying their father or mother had changed a lot after a surgery in the past. So I began to realise that this wasn’t such an isolated case.”

We have known for a long time that operations can have hidden consequences for the brain. As far back as 1887, a paper was published describing cases of delirium after surgery with anesthesia. A century later, scientists in the 1980s began to look at cases of older patients who had shown a decline in memory and concentration after cardiac surgery, but it has only been more recently that this has become apparent as a risk factor for all over-65s who undergo surgery, especially when under deep sedation.

In the last 20 years, studies have shown that POCD symptoms can affect everything from memory to attention, judgment and perception, and those with pre-existing health conditions are especially vulnerable. One survey of patients who received surgery to repair hip fractures found that those who developed POCD had a poorer ability to function socially and carry out normal activities such as writing, managing money or remembering lists, with a tangible impact on their daily life.

At the moment, estimates suggest that the overall incidence of POCD in older patients can be as high as 50-80% at discharge, 20-50% at six weeks and 10-30% at six months post-surgery. Given that the NHS carries out about 5.1m operations every year, a disproportionate number of which are in the over-65s, Cibelli says that there are a considerable number of patients being left with lasting impairment.

In recent years, POCD has caught the attention of Alzheimer’s researchers, intrigued to see whether it can accelerate decline towards dementia in some cases. Jenny Barnett, chief executive of Monument Therapeutics, a Cambridge-based biotech startup developing new therapies in neurology, says that people who already have underlying impairments in memory and attention skills are particularly vulnerable to POCD and it needs to be considered as a risk factor before significant surgeries.

“Many of us have had the experience of granny breaking her hip, goes into hospital and then by the time she comes out, she isn’t the same cognitively and isn’t able to live independently any more,” says Barnett. “I think that’s something that resonates with a lot of people.”

But exactly what causes POCD remains something of a mystery. Some point the finger at anesthetics – certain 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 it has proven hard to study this in humans.

Instead, many scientists are pinpointing the possibility that these symptoms arise through the body’s reaction to surgery itself. Big operations unleash a firestorm of inflammation in response to the acute tissue damage that can cross the blood-brain barrier. Because the brain contains the largest density of inflammatory receptors in the body, it is especially vulnerable to the effects of inflammation, which can damage sensitive regions. Some brain-imaging scans have found that the hippocampus – a complex and vulnerable structure that plays a key role in memory – has a reduced volume in patients with POCD.

All this emerging evidence could lead to changes in medical practice. Research is already taking place into ways of identifying at-risk patients before operations, with the idea of potentially using a regional rather than a general anaesthetic.

But it is not only older, frailer patients who are most at risk of POCD. The same can be said for the very young, in a markedly different way.

Can anesthetics cause behavioral issues in children?

As a paediatric anaesthetist at the Mayo Clinic in Minnesota, David Warner had been attempting to understand the possible causes of a wide range of behavioral issues in children. He began to wonder whether surgery and anesthesia could affect the fragile brains of young children.

“I go into hospital in the morning and I take care of kids during surgery, and they wake up and they go home at night, and they seem to be fine,” he says. “So for a long time, we just assumed that anesthesia was very transient, so when it wears off, it’s gone. That’s probably not true.”

The reason why Warner became concerned about anesthetics is because in studies of monkeys, anesthesia exposure in infancy has led to altered behaviours such as heightened emotional reactivity to threats, and impaired learning and memory formation. However it is difficult to translate these changes to humans, in whom child development is far more complex than in our closest relatives.

In 2018, Warner decided to put his theories to the test. He carried out a study on 1,000 children in Minnesota and compared three groups: children who had not been exposed to anesthesia before the age of three; children who had a single exposure; and children who had multiple exposures.

“Basically, we found that kids who had multiple exposures to anesthesia had these problems with their fine motor skills and increased reports of behavioral problems,” he says.

Other investigations have also found an association between multiple exposures to anesthetics before the age of three and cognitive, memory, listening comprehension, and language deficits. Further studies have found correlations between multiple exposures to anesthetics and children later being given a diagnosis of attention deficit hyperactivity disorder (ADHD).

But so far it has been hard for scientists to prove a direct causative relationship between anesthetics and damage to the developing brain. In 2019, a study pointed out that there could be alternative explanations. Children who require multiple operations at a young age could already be predisposed to neurodevelopmental problems because of the injuries or illnesses they are suffering from: the doses of anesthetics may be merely incidental.

Right now, we do not know, but later this year, Warner will be carrying out brain-imaging scans on the same children to see whether structural changes in the brain related to anesthesia can be linked with the onset of behavioral issues.

“We have some preliminary evidence that there’s something different in a particular part of the brain in the kids who had multiple anaesthetic exposures,” he says. “That’s just our initial look at this, but I suspect that there’s going to be something there.”

What to do about the problem

In 2015, the Brain Health Initiative was launched to raise more attention about the issue of cognitive problems in the aftermath of surgery.

Warner feels that the growing awareness of these risks means that doctors will be increasingly cautious of using anesthetics on young children when conducting non-surgical procedures, such as radiotherapy or endoscopy.

He says it is clear that there needs to be a greater focus on the longer-term care of children who have had multiple anesthetics in the early stages of life. The brains of young children are highly malleable, or “plastic”, as neuroscientists like to say, and Warner suggests providing such vulnerable children with specific cognitive enrichment activities to stimulate them, as a protection against cognitive impairments.

At the other end of the age spectrum, increasing amounts of attention are being devoted towards ways of either preparing older patients for surgeries to make them more cognitively resilient, or treating POCD in the aftermath.

In the early 1990s, the Danish surgeon Henrik Kehlet created a programme known as ERAS (enhanced recovery after surgery) to study ways of maximising postoperative recovery. Some of the latest research suggests that a “prehabilitation” programme consisting of simple muscle exercises, nutritional supplements and education to stimulate the mind over a period of six to eight weeks before big operations can have a protective effect.

Monument Therapeutics has reformulated a generic anti-inflammatory drug so that it can access the brain and potentially dampen down some of the brain inflammation that may be occurring post-surgery. It is preparing to launch a trial, initially in healthy volunteers, and if that proves successful, it will look to target POCD patients in the coming years.

But scientists are also searching for ways of pinpointing the patients most at-risk of developing POCD so that they can be specifically targeted with some of these interventions. Studies in cardiac patients have found that people with low levels of antibodies against bacterial endotoxins are particularly at risk of POCD, suggesting that infection could also play a role in these symptoms. Monument Therapeutics has also identified a biomarker that it claims can predict POCD with 90% accuracy.

“In future, we want to be able to measure people’s cognitive function before they go in for surgery, to get a measure of how vulnerable or resilient their brain is, and if they’re vulnerable, have a way to treat that,” says Barnett.

Time will tell whether these approaches can help reduce the incidence of postoperative cognitive problems in the very young and the very old. But one thing is now clear, even when surgery is over, the risks are far from over.

“We’ve got to stop thinking that when the anaesthetic wears off, everything’s fine,” says Warner. “Whether it’s the anesthesia, the trauma of surgery, or the other effects of acute illness, people’s brains have a hard time around operations.”