meIn 2004 Mario Sebeli was preparing a 75-year-old patient for a major heart operation when the patient’s daughter asked for a quick word. “She explained to me how worried she was about the surgery,” says Sibley, a consultant anesthesiologist and intensive care unit at University Hospitals Birmingham. “I said, ‘Look, everyone is worried about heart surgery, it comes with risks, but usually people benefit.’ Then she told me her dad had a heart operation two years ago and it has changed dramatically.”
Sebele listened as the woman described how her father, a former physics professor, showed signs of significant cognitive decline after the initial operation. Once an avid chess player, he was now unable to play the game and had difficulty even solving basic crossword puzzles.
For Sibelle, it was the first time he had experienced what is now called postoperative cognitive dysfunction (POCD) – cognitive problems associated with surgery that persist long after the effects of the anesthesia wear off. “I have published some articles on this topic,” he says. “And people started finding my email address, saying that their father or mother had changed a lot after surgery in the past. So I started to realize that this was not an isolated case.”
We’ve known for a long time that processes can have subtle consequences for the brain. As far back as 1887, it was British Medical Journal A research paper has been published describing cases of delirium following surgery with anesthesia. A century later, scientists in the 1980s began looking at cases of older patients who showed decreased memory and concentration after heart surgery, but it was only recently that this emerged as a risk factor for all people over 65 years of age. who are undergoing surgery, especially under deep anaesthesia.
Studies in the past 20 years have shown that OCPD symptoms can affect everything from memory to attention, judgment and cognition, and that those with pre-existing health conditions are especially at risk. One survey of patients who had surgery to repair hip fractures found that those who developed CPD had a poorer ability to function socially and carry out normal activities such as writing, managing money or remembering lists, with a measurable impact on their daily lives.
Currently, it is estimated that the incidence of this disease in older patients can be as high as 50-80% at discharge, 20-50% at six weeks and 10-30% at six months after surgery. Given that the NHS performs about 5.1 million operations each year, and a disproportionate number of them by age 65, Sibley says there are a significant number of patients with permanent disability.
In recent years, cognitive dysfunction has caught the attention of Alzheimer’s researchers, and they have been fascinated to see if it can accelerate the regression toward dementia in some cases. People who already have basic impairments in memory and attention skills are particularly vulnerable to this disease and it should be considered a risk factor beforehand, says Jenny Barnett, CEO of Monument Therapeutics, a Cambridge-based biotech startup that is developing new neuroscience therapies. that. Major surgeries.
“Many of us have had the experience of a grandmother’s fracture of her thigh, she went to the hospital, and by the time she was discharged she was not the same cognitively and she couldn’t live independently anymore,” Barnett says. “I think that’s something that resonates with a lot of people.”
But what causes CPD remains a mystery. Some are pointing the finger at anesthetics—some animal studies have found that inhaled sedation, the most common form of general anaesthesia, can deteriorate the brain’s cholinergic system, which is involved in learning and memory—but it has proven difficult to do. So. Study this in humans.
Instead, many scientists determine the likelihood of these symptoms arising from the body’s reaction to the surgery itself. Large processes unleash a firestorm of inflammation in response to severe tissue damage that can cross the blood-brain barrier. Because the brain has the greatest density of inflammatory receptors in the body, it is particularly vulnerable to the effects of inflammation, which can damage sensitive areas. Some brain-imaging scans have found that the hippocampus – a complex and weak structure that plays a key role in memory – has a reduced volume in POCD patients.
All of this emerging evidence could lead to changes in medical practice. Research is already underway on ways to identify patients at risk prior to operations, with the idea possibly of using a local anesthetic rather than a general anesthetic.
But it is not only the elderly and the weakest patients who are most susceptible to this disease. The same can be said for the very young, in a markedly different way.
Can anesthesia cause behavioral problems in children?
As a pediatric anesthesiologist at the Mayo Clinic in Minnesota, David Warner has been trying to understand the potential causes of a wide range of behavioral problems in children. He began to wonder if surgery and anesthesia could affect the brains of young children.
“I go to the hospital in the morning and take care of the kids during surgery, and they wake up and go home at night, and they seem fine,” he says. “So, for a long time, we assumed that the anesthesia was very transient, so when it wears off, it goes away. Maybe that’s not true.”
The reason Warner is concerned about anesthesia is that in studies in monkeys, exposure to anesthesia in childhood has led to altered behaviors such as increased emotional reactivity to threats, and impaired learning and memory formation. However, these changes are difficult to translate to humans, where child development is much more complex than in our closest relatives.
In 2018, Warner decided to put his theories to the test. He conducted a study of 1,000 children in Minnesota and compared three groups: children who were not exposed to anesthesia before the age of three; children who have been exposed once; And children who have been exposed to several cases.
“Basically, we found that children who were exposed multiple times to anesthesia had these problems with their fine motor skills and increased reports of behavioral problems,” he says.
Other investigations have also found associations between multiple drug exposure before age three, cognitive deficits, memory, hearing comprehension, and language deficits. Other studies have found associations between multiple drug exposures and children’s subsequent diagnosis of attention deficit hyperactivity disorder (ADHD).
But until now it has been difficult for scientists to prove a direct causal relationship between anesthesia and damage to the developing brain. In 2019, a study was conducted in Lancet He indicated that there could be alternative explanations. Children who require multiple surgeries at a young age may already be at risk of developing neurodevelopmental problems due to injuries or illnesses they suffer: the doses of anesthesia may be just accidental.
Right now, we don’t know, but later this year Warner will run brain imaging scans on the same children to see if the structural changes in the brain associated with anesthesia can be linked to the onset of behavioral problems.
“We have some preliminary evidence that something is different in a particular part of the brain in children who have been exposed to multiple anaesthesia,” he says. “This is just a preliminary look at this, but I suspect there will be something.”
What do you do about the problem
In 2015, the American Society of Anesthesiologists launched the Brain Health Initiative to raise interest in the issue of cognitive problems in the aftermath of surgery.
Warner believes that increased awareness of these risks means that doctors will be more cautious about using anesthesia for young children when performing non-surgical procedures, such as radiotherapy or endoscopy.
He says it’s clear that there should be a greater focus on the long-term care of children who have had multiple anaesthesia in the early stages of life. Young children’s brains are very flexible, or “plastic,” as neuroscientists like to say, and Warner suggests providing these at-risk children with specific cognitive enrichment activities to stimulate them, as a protection against cognitive impairments.
At the other end of the age spectrum, an increasing amount of attention is being devoted toward ways to either prepare older patients for surgeries to make them more cognitively resilient, or treat POCD in the aftermath.
In the early 1990s, Danish surgeon Henrik Kilt created a program known as ERAS (Enhanced Postoperative Recovery) to study ways to maximize recovery after surgery. Some of the latest research suggests that a “rehabilitation” program consisting of simple muscle exercises, nutritional supplements, and brain training over six to eight weeks before major operations can have a protective effect.
Monument Therapeutics has reformulated a generic anti-inflammatory drug so that it can reach the brain and potentially relieve some of the encephalitis that may occur after surgery. It is preparing to launch a trial, initially in healthy volunteers, and if that proves successful, will look to target POCD patients in the coming years.
But scientists are also looking for ways to identify patients at high risk of developing the disease so that they can be specifically targeted with some of these interventions. Studies of heart patients have found that people with low levels of antibodies against bacterial endotoxins are at particular risk of developing CHD, suggesting that infection could also play a role in these symptoms. Monument Therapeutics has also identified a biomarker that it claims can predict coronary artery disease with up to 90% accuracy.
“In the future, we want to be able to measure people’s cognitive function before they have surgery, to see how weak or flexible their brain is, and if they’re weak, we have a way to treat that,” Barnett.
Time will tell if these approaches can help reduce the incidence of postoperative cognitive problems in very young and old people. But one thing is clear now, even after the surgery is over, the risks aren’t over yet.
“We have to stop thinking that when the effect of the drug wears off, all is well,” Warner says. “Whether it’s anesthesia, the trauma of surgery, or other effects of acute illness, people’s brains have a hard time with surgeries.”