How to avoid cognitive dysfunction after surgery

Winston Ross’s mother believed her son had bugged her house and somehow hacked her car keys to make her car undrivable. The fact that she could drive it did not disturb her delusion. 

She drove to a local car dealership, parked the car—blocking the driveway—and then demanded keys to replace the set that she said had been tampered with. Ross later found a police report describing the odd scene that had unfolded: “While [Toyota Manager Brian] Carter was talking to her she began to raise her voice and ask each person present if they were a Democrat . . . Officer Ray tried to talk to the female and she continued to ask him if he was a Democrat loudly. She then looked and started to walk towards the employees and shouting ‘ARE YOU A DEMOCRAT?’” 

The officer warned she’d be arrested if she didn’t leave, and began to count 1. . . 2 . . . She started counting with him: “2 . . . 3 . . .” The cop handcuffed her and asked her name. She revealed only her maiden name. Then, the day she was born. “It was a Wednesday,” she replied. 

“And with that, my 73-year-old mother was off to the clink,” Ross recounts.

Just months before this scene unraveled, Ross describes his mother as living “her best life” after she’d retired at age 68. She had not had things easy before that; her father had committed suicide when she was 18, she’d entered a marriage that didn’t last, she’d self-medicated her emotional pain with food and alcohol, and the arthritic pain in her joints (she’d had both knees and hips replaced) with opiates. 

After retiring, though, she’d settled down with her dog, Bosley, and seemed as happy as she’d ever been to her son. Ross described their relationship as “at a high point.”

Then, in 2018, seeking relief from years of unrelenting arthritic pain in her shoulder, she scheduled her fifth replacement surgery. “The surgery fixed her shoulder, at the cost of her mind,” Ross states in a harrowing description of his mother’s postoperative delirium. It extended into mental illness and turned both their lives into a circus of misadventures, including the delusional incident that saw her land in jail, a number of hospitalizations and an escape from long-term care.1 

‘Never quite the same’

Ross’s is definitely a more dramatic version of a sad story that is surprisingly common among carers. The story usually begins something like, “Grandpa was doing okay until the surgery . . .” 

Maybe he underwent a hip replacement, maybe a heart bypass, but regardless of what was being operated on, Grandpa was “just never quite the same” after leaving the operating room. He came out of surgery confused and delirious. He recovered, but he couldn’t remember as well afterward and could no longer focus on tasks like he used to. Sometimes the details, as in Ross’s mother’s case, are more tragic. 

The immediate post-surgery condition, called postoperative delirium, affects more than half of patients over the age of 65 who undergo surgery with general anesthesia. This is when patients emerge from surgery and don’t know where they are, or they are weepy and emotional or even aggressive. 

“In older patients, delirium can be a key factor in initiating a cascade of events that may lead to a loss of independence, decline of executive function, institutionalization, and ultimately death,” according to a 2017 review of the phenomenon by a team of anesthesiologists from the Navodaya Medical College and Research Center in India.2 

According to a recent review in the Journal of the American Medical Association, some 65 percent of patients over the age of 65 experience postoperative delirium after surgery, and for 10 percent, this progresses to a chronic condition known as postoperative cognitive dysfunction (POCD). 

Surgery has also been linked to small, usually undetectable (so-called “covert”) strokes in about 7 percent of cases, and this can elevate the risk of POCD.3 Both delirium and POCD now fall under the umbrella term, “perioperative neurocognitive disorder,” or PND.4 

According to the University of Rochester Medical Center (URMC), the extra care costs incurred for these conditions total more than $150 billion a year in the US alone.5 

Now, research is snowballing on the subject, partly because the population most affected is the elderly, and there is a swell of aging baby boomers experiencing the phenomenon. 

“Postoperative neurocognitive decline . . . represents a significant and expanding challenge to health care in the US and worldwide,” says a 2021 review paper of the condition.3 

What causes POCD and PND is still somewhat of a puzzle, but it’s fair to say there’s frequently more than one aggravating agent. Often, the patients are ill to begin with, in need of surgery. Then there’s the trauma and inflammation of the surgery itself, and on top of that, the effects of the anesthetic drugs.

Altered states

Anesthesia’s triumph over pain in surgery in 1846 is one of the most celebrated milestones in medicine. Today, more than 230 million surgeries are performed annually worldwide using general anesthesia. In the US, about 60,000 people undergo surgery with anesthesia every day. Remarkably though, more than 160 years after the first ether surgery, how these drugs act on the brain and central nervous system to create their anesthetic effects has remained somewhat of a mystery.

Emery Brown, professor of anesthesia at Harvard Medical School, Massachusetts General Hospital and professor of medical engineering and computational neuroscience at the Massachusetts Institute of Technology, is working on the cutting edge of unraveling that mystery.

What Brown and his team have discovered is that all anesthetics work by altering electrical current flows in the brain, changing brain wave patterns to a slow-delta rhythm or oscillation frequency by targeting the brainstem. He’s described these dynamics in more detail in an animated TedMED talk and many other presentations.6 

When an anesthesiologist is preparing a patient for surgery, says Brown, he might say something like, “Now, Mr. Jones, we’re going to have you go to sleep for your surgery.” It’s not accurate, but it’s more reassuring than saying, “We’re going to put you into a reversible, drug-induced coma for your hernia repair.”

“General anesthesia is not sleep,” explains Brown. Whereas sleep involves brain waves that move between distinctive non-REM and REM oscillating patterns, and people still process their day’s events and experience dreams that they can recall, Brown describes the unique dynamics of a brain under the influence of an anesthetic cocktail as being starkly different. 

Anesthetized, a person’s brain is not inactive but in an altered, aroused slow brain-wave oscillation pattern that disrupts communication between different regions of the brain. They are unconscious, they have no memory, they don’t experience pain and they are immobilized (to hinder movement during surgery). 

“We hold you there in that pathological state,” Brown told WDDTY. “It’s pathological because it’s not natural.” The doctor maintains the patient’s physiological stability—breathing and heart rate, etc., which would be impaired otherwise—in this dysfunctional state, and then brings them out of the pathological state when the surgeon is finished.

Fragile elderly brain

Brown and his colleagues have been studying the effects of these drugs using electroencephalogram (EEG)—a test that looks at brain waves, the electrical activity of the brain. The activity can also be captured in brightly colored spectrogram images that show the impact of the drugs on the frequency and period of oscillation of the brain waves. 

These range from high-frequency, short-wavelength bursts of fluorescent orange and yellow on a blue background to dim, low-frequency oscillations. These characteristic features are unique to the drug used, but also show patterns that correspond to the age of the patient. They are generally far more intense in a three-year-old compared to an 80-year-old. This illustrates how the older brain, with weaker oscillations, may be more impacted by anesthetics.

As people age, the number of synapses in their brains declines, meaning there are fewer branch-like dendritic connections between brain cells. There is also decreased cerebral blood flow along with a corresponding constriction of the brain’s ability to respond to stress—like the stress from surgery and drugs that affect the brain. 

“The aging brain is more prone to be affected by drugs,” a group of anesthesiologists offered by way of explanation in their 2017 paper on the subject. “The sum of all these effects leads some older adults to be teetering on the edge of neurodysfunction.” Throw in surgery trauma, and they exceed the brain’s “reserve limits.” In other words, something gives.2

Sometimes Brown’s spectrogram images don’t correlate to peoples’ ages, however. Some younger patients may have images that correspond to an older brain dynamic, and people who are older may have more youthful-looking responses to the drugs. “We age differently physically. Perhaps our brains age differently as well,” says Brown. “What’s even more intriguing about it is we might discover it under anesthesia.” 

In other words, your brain’s response to anesthetic drugs could reveal its state of health more generally.

Not surprisingly, many factors come into play besides age to put people “teetering on the edge” of dysfunction. Recognized risk factors for POCD include uncontrolled blood pressure and blood sugar, patient frailty, alcohol abuse, use of other drugs at the time of surgery, depression, sleep patterns, pre-surgery cognitive abilities and the number of previous general anesthetics.7 

The trouble with dosing

Brown describes general anesthetic drugs as “super strong.” Given the unnatural energy of the oscillations they produce—as seen in his spectrogram imaging—it’s a wonder everyone isn’t delirious after surgery. It’s to be expected that many “don’t just pop back to normal,” he says.

These lingering effects of anesthetic drugs, surgery or both have been missed—or ignored—for most of their medical history. Postoperative cognitive decline was observed decades ago, but it didn’t receive much attention in the medical literature until very recently, especially in the past five years. 

 “There’s a sense that it just comes with the territory, that it’s part of the accepted risk,” Brown told WDDTY. Anesthesiologists in general don’t often think about anesthesia with an appreciation for “how potent they are.” 

Brown describes how he carefully titrates his dosing of patients using EEG to determine the minimum dose to bring them to full unconsciousness. Most anesthesiologists don’t do this. 

The drug dosages are usually “cavalierly based on convention” and start with a standard dose based on age. That dose might be increased a bit if you are on another prescription drug that is stimulating, for example, or adjusted slightly perhaps based on weight.

Currently, he says, research estimates that only about 25 percent of anesthesiologists use EEG in the operating room, and only a small fraction of those use the very obvious patterns that it generates to titrate a minimally effective—and safer—dose for patients. You need to practice, says Brown, “as if everybody’s at risk.” 

Inflammation

Another part of the story is the body—and brain’s—inflammatory response to the insult of surgery and anesthesia. The trauma of cutting a person open and doing whatever procedure needs to be done will cause inflammation throughout the body including the brain. 

A research team led by Niccolo Terrando at Duke University and Harris Gelbard at the University of Rochester is testing a drug called URMC-099, which is designed to tamp down the body’s immune response and reduce inflammation, to treat animal models of postoperative cognitive dysfunction. 

Untreated mice show a buildup of activated microglia—a specialized population of cells in the central nervous system that act as immune sentinels, capable of orchestrating a potent inflammatory response. Activated microglia and a leaky blood-brain barrier are hallmarks of POCD. Treatment with URMC-099 prevented the activation of microglia.8 

It may be a long time before such drugs move from mice to humans and are deemed safe to use, but there are a number of things people can do right now to prevent postoperative cognitive effects or counter them after surgery.

Bugs for POCD

There’s growing evidence that damage to gut microbiota is strongly associated with central nervous system diseases, and abnormalities in the composition of the gut microbiota might underlie postoperative cognitive dysfunction (POCD) and postoperative delirium, too, suggesting a promising avenue for healing the condition.1 

In one intriguing study published in 2020, albeit in animals that had undergone surgery, Chinese researchers discovered that POCD, exacerbated by antibiotics after surgery, was reversed by the application of the probiotic Lactobacillus and the microbe-produced short-chain fatty acid sodium butyrate, which has been linked to good blood-brain barrier integrity.2 

Another study found that pretreatment with short-chain fatty acids attenuated these effects by reversing microglial overactivation, inhibiting inflammatory responses and other actions.3 

#1: Weigh the risks

First, it’s important to carefully weigh the risks and benefits of any proposed surgery, especially one under general anesthetic. POCD is only recently recognized, and many doctors may not consider it or mention it when describing surgical risks. Sometimes nonessential surgeries, like some knee replacements, have overstated benefits and produce results no better than placebo.9 

How much can you reasonably expect an invasive surgery to change your quality of life? Have you considered alternative and nutritional therapies that don’t carry the risk? If it’s something you do consider essential and you are concerned about POCD, ask about your options. 

If you are getting a hip replacement, for example, Dr Brown says surgery might not need a full general anesthetic. There may be an opportunity to use a spinal epidural with some sedation to relax—thereby mitigating the brain risk tremendously. 

Is there an anesthesiologist at your hospital familiar with using EEG to titrate anesthetic dose to your requirements? If not, introduce them to the work of Emery Brown’s team at the Harvard Brain Science Initiative. 

#2: Optimize your nutritional status 

Retired neurosurgeon Russell Blaylock, author of Prescriptions for Natural Health (Humanix Books, 2016) and many other books on the dangers of environmental toxins to the brain, reported his own mother-in-law’s poor nutritional assessment and treatment when she was hospitalized following a stroke and the importance of nutrition not only in brain function but also in systemic organ function, wound healing and especially immunity.10 

Vitamins and minerals are essential for the brain to function, and water-soluble vitamins are depleted within hours following stresses such as those from surgery or stroke, says Blaylock. 

One of the nutrients he views as critical to top up before and after surgery is magnesium. “Stress causes significant depletion of magnesium,” he wrote. “Magnesium depletion is especially common in the elderly because of poor diets and the use of many magnesium-depleting pharmaceutical drugs.” 

Magnesium for neuroprotection requires a higher dose for several months to increase levels in the brain. Generally, Blaylock has recommended 500 mg twice a day in the form of magnesium malate or magnesium citrate (see page 24 for more on the different forms of magnesium). 

A time-release brand will allow you to reach these doses without having problems with diarrhea. Additionally, he suggests trying to convince your surgeon to add several grams of magnesium sulfate to your IV during surgery.11 

Paradoxical lithium

One important factor to preventing dementia after surgery may be the essential trace mineral lithium. Lithium is prescribed in very high doses for mood conditions like bipolar disorder and is considered a hazard for surgery, as it can lead to lithium toxicity with neurological effects.1 Discontinuation at least 72 hours before surgery is recommended.2 

Paradoxically, a 2020 study from researchers at McGill University in Canada showed that, when given in a formulation that facilitates passage through the blood-brain barrier, lithium in doses up to 400 times lower than psychiatrists currently prescribe for mood disorders can halt signs of advanced Alzheimer’s pathology and is associated with recovery of lost cognitive abilities. 

These microdoses minimize the levels of lithium in the blood that lead to adverse effects. The lead researcher, Dr Claudio Cuello of McGill’s Department of Pharmacology and Therapeutics, predicted the treatment would find “immediate therapeutic applications.” 

Although the researchers did not think it likely that lithium would help advanced Alzheimer’s patients, Cuello said, “It is very likely that a treatment with microdoses of encapsulated lithium should have tangible beneficial effects at early, preclinical stages of the disease.”3 

Considering that chronic postoperative cognitive dysfunction can increase the risk of Alzheimer’s, low-dose lithium may be a promising treatment for those who don’t recover from initial surgical delirium.

#3: B vitamins and omega-3s

Vitamins known to protect against other forms of dementia such as Alzheimer’s disease include B12, B6 and folate (B9, or folic acid in its synthetic form). Conversely, high levels of the amino acid homocysteine are associated with brain shrinkage, cognitive impairment and postoperative cognitive decline.12 

Increasing folate, vitamin B6 and vitamin B12 levels causes homocysteine to decrease. 

In one six-year study, Italian researchers studying a large group of patients aged 60 years or older attending a treatment center for cognitive disorders found that higher folate concentrations were correlated with better cognitive performance, while folate deficiency was associated with worse cognitive performance. Cognitive impairment was even more severe when the folate deficiency was observed in combination with high levels of homocysteine.13 

While omega-3 fatty acids have been implicated in brain health, supplementation with fish oils may depend on also supplementing with B vitamins. In one placebo-controlled trial, 168 seniors diagnosed with mild cognitive impairment were randomly assigned to receive either a placebo or a relatively high daily dose of 0.8 mg folic acid, 20 mg vitamin B6 and 0.5 mg B12. After two years, the researchers analyzed how omega-3 fatty acid blood levels at baseline influenced the effect of vitamin B supplementation on cognitive scores. Only those seniors who had high omega-3 levels at the start of the study experienced neuroprotective effects of the B vitamins.14 

An anti-inflammatory diet high in real, whole foods including meats, pesticide-free vegetables and fruits and avoiding inflammatory vegetable oils (also found in virtually every processed food) before surgery could be an important game-changer.

#4: Get fit for surgery

Going into surgery overweight or with a sedentary lifestyle is going to be riskier than going in fit and active. And rather than lying in bed after surgery, it’s critical to get moving as soon as possible. 

The American Geriatrics Society Clinical Guideline for Post-Operative Delirium recommends that patients walk multiple times a day after they awaken
from anesthesia.15

Both physical and mental activity influence brain recovery after surgery. A team of researchers from the Albert Einstein College of Medicine found that people who enjoy activities such as reading, doing puzzles or playing games experienced lower rates of postoperative delirium. 

In their study, participants who were physically active six to seven days a week had a 73 percent lower chance of experiencing postoperative delirium. And those who were mentally active—they regularly read newspapers or books, knitted, played games, used e-mail, sang, wrote, worked crossword puzzles, played bingo or participated in group meetings—had an 81 percent lower chance of developing postoperative delirium.16

#5: Have a loved one near

Having the support of family or other loved ones after surgery can be critical to avoiding or coming out of delirium. The people who know you best are going to recognize if you are not yourself. They answer questions that orient you to what has happened and where you are, help you walk or find your glasses, and ensure you have enough hydration and the right pain control.

Other small factors like having a room with natural window light have also been shown to offset disorientation and sleep problems following surgery.17

#6: Review your medicine 

Drugs like high-dose lithium, used for mood disorders, can be toxic in surgery. Drugs used for anxiety, itching, insomnia, depression, Parkinson’s disease, irritable bowel syndrome and overactive bladder can all produce delirium symptoms as well.  Make sure you discuss the medications you are already taking—both prescription and over-the-counter— with your doctor and anesthetist and find out if you have to wean off of them before surgery.

Light therapy

Photobiomodulation (PBM) is being tested as a new approach to modulate the microbiome in central nervous system conditions like Parkinson’s disease.

PBM involves the use of red or near-infrared light to heal and regenerate injured or degenerating tissue. It’s been used extensively to help ameliorate neurological conditions caused by traumatic brain injury and stroke, as well as conditions like Parkinson’s and Alzheimer’s, by applying the light directly to the head.1 

Dr Ann Liebert, coordinator of photomolecular research at the Australasian Research Institute in Sydney, noticed that some of her patients who had red light therapy before major surgery seemed to recover more rapidly and experience less delirium and postoperative cognitive dysfunction compared to those who did not. This observation led her to explore whether infrared light might modulate Parkinson’s disease. 

She worked with Dr Daniel Johnstone, a lecturer at the University of Sydney’s Bosch Institute, who previously found that exposure to infrared light altered the gut microbiome in mice.2

In a case study, Liebert, who is also vice president of the Australian Medical Laser Association, along with her colleagues found that infrared light therapy could modulate the human microbiome in a single subject receiving infrared light therapy to his abdomen three times a week for 12 weeks. 

Bacterial species considered beneficial to the gastrointestinal tract, including Akkermansia muciniphila, Bifidobacterium and Faecalibacterium, flourished under the light.3 (See our March 2020 issue for more on this research.)

In another study of Liebert’s, 12 patients with Parkinson’s disease who underwent two weeks of light therapy at a clinic followed by home-based light therapy experienced improvements in a range of clinical signs and symptoms that continued for up to a year, as opposed to the typical decline. There were no side-effects.4 

If the light therapy proves to be beneficial in entrenched neurocognitive diseases like Parkinson’s, there may be promise it will help those in whom Liebert first saw its benefits—patients having surgery.

 
Main Article

Bugs for POCD

Paradoxical lithium

Light therapy