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The hidden long-term risks of surgery


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The hidden long-term risks of surgery 💖

The Observer


The hidden long-term risks of surgery: ‘It gives people’s brains a hard time’


Operations can have cognitive side-effects, particularly in the over-65s but also in the very young. How can science

minimise the danger?

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

anaesthesia 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 anaesthetics 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


We have known for a long time that operations can have hidden consequences for the brain. As far back as 1887,

the British Medical Journal published a paper describing cases of delirium after surgery with anaesthesia. 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.
Postoperative cognitive dysfunction can affect younger as well as older patients.

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 anaesthetics – certain

animal studies have found that inhalation anaesthetics, the most commonly used form of general anaesthesia, 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.

    For a long time, we assumed anaesthesia was very transient, so when it wears off, it’s gone. That’s probably not


David Warner, paediatric anaesthetist

Instead, many scie
ntists 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


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 anaesthetics cause behavioural 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 behavioural issues in children. He began to wonder whether surgery and

anaesthesia 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 anaesthesia was very

transient, so when it wears off, it’s gone. That’s probably not true.”

The reason why Warner became concerned about anaesthetics is because in studies of monkeys, anaesthesia

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 anaesthesia 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 anaesthesia had these problems with their fine motor

skills and increased reports of behavioural problems,” he says.

Other investigations have also found an association between multiple exposures to anaesthetics before the age of

three and cognitive, memory, listening comprehension, and language deficits. Further studies have found

correlations between multiple exposures to anaesthetics 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 anaesthetics and damage

to the developing brain. In 2019, a study in the Lancet 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 anaesthetics may be merely


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 anaesthesia can be linked with the onset of

behavioural 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 American Society of Anaesthesiologists launched the Brain Health Initiative 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

anaesthetics on young children when conducting non-surgical procedures, such as radiotherapy or endoscopy.
Researchers are focusing on ways to help prepare older patients for surgery better.


He says it is clear that there needs to be a greater focus on the longer-term care of children who have had multiple

anaesthetics 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



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

anaesthesia, the trauma of surgery, or the other effects of acute illness, people’s brains have a hard time around



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