Brain Damage From Anesthetics

Say it aint so.....

So far no one has shown a direct effect of anesthetics to produce brain damage in people.  However, there are some disturbing reports about post operative cognitive dysfunction after surgery, especially in the elderly.  The Mayo group published data suggesting a link between age of onset of alzheimers and cumulative lifetime anesthetic exposure.  Moreover, Monk's group has shown an association between depth of anesthesia by BIS and one year mortality.  So what's up?

Pretty much every category of anesthetic has been impugned:

Opioids.

I am pretty sure I (and my colleagues) published the first papers showing histologic injury from a clinically used anesthetic drug (Anesth Analg 75:953‑964, 1992.   see fig).  We showed that high doses of alfentanil in paralyzed ventilated rats produced seizures and limbic system  brain damage in paralyzed ventilated physiogically controlled rats.  The doses were about ten times higher than analgesic, a dose range commonly used in cardiac surgery.  Similar results were produced with sufentanil, fentanyl, and remifentanil.  Given to monkeys in a PET scanner we saw FDG temporal lobe activation with fentanyl.  We gave brief high dose remifentanil to five humans fully paralyzed and ventilated also showing limbic system activation.  I just published another paper reporting limbic system activation at low doses of remifentanil in 29 volunteers with a variation in the activation pattern according to apolipoprotein E genotype.  Kearse and Tempelhoff have shown limbic epileptiform activity from fentanyl in humans.  Sullivan et al and Augoustides et al have shown that the proconvulsant properties of  remifentanil make for easier ECTs.  I had one patient seize from a remi injection before ect (do we shock or not?) and another developed post remi-ect status epilepticus.

     So the evidence seems overwhelming that opioids can produce limbic activation and in the right setting   produce brain damage, but we still don't know about people.(NB: when i suggested to several NIH study sections and the AHA in the early 90's that what we were seeing in rats might be relevant they returned non scored critiques...real visionaries there...)

Gabergic drugs

Drugs like barbiturates and benzodiazepines have been long considered to be protective.  Thus the chagrin from many quarters when todorovic, olney and colleagues showed that neonatal exposure to midazolam and nitrous oxide produced later histologic damage and cognitive dysfunction. 

NMDA antagonists: Nitrous oxide and ketamine

Todorovic's group has also shown that N2O and ketamine both produce cingulate lesions in rodents.  worse with higher age.  I gave N2O to young and middle aged wild type and transgenic amyloid overproducing mice and let them age. The old  N2O exposed WT mice did worse on cognitive testing but no effect was seen on the dumb transgenics (histology pending).   Also, collaborating with Biegon at Stonybrook,  N2O was associated with persistent opening of glutamate channels the day after exposure.

Volatile anesthetics

Eckenhoff and colleagues showed that in vitro halothane produced precipitation of amyloid that on EM looked like alzheimer plaques and was associated with in vitro cytotoxicity of cultured cells.  In later studies his group showed worse cognitive test results in elderly mice given isoflurane with histologic evidence of injury.  Of interest however, is that this effect was only seen in wild type mice...those transgenic mice that overproduced amyloid precursor protein became dumb in old age but the isoflurane did not make them dumber.  Others have also seen this phenomenon.
    Wei etal have shown that isoflurane produces apoptosis and that sevoflurane does not.  something to do with calcium, sarcoplasmic reticulum, and calpain.  Anyone interested  in more details will have to look up work by Hua Fung Wei.  Of interest that sevo produces epileptiform activity on induction of anesthesia.  Now I am really confused.

  So in summary, every major category of anesthetics has been linked both mechanistically and phenomenologically to brain damage in non humans.  Some physiologic congruent effects have been seen in humans and in some humans surgery (and anesthesia) have been linked to post operative cognitive deficits.  Notably the lab findings seem to focus on the limbic system,  where cognition is based.

It is daunting to test an hypothesis of harm in humans.  Moreover, anesthesia is given to millions and millions and no ill effects seem obvious.  This is work in progress and the full answers are not yet in.

Comments

[Rather_Not_Say]

In my late 50s, I've had 'twilight' anesthesia twice -- to reset a broken radius, and for a gastric scope exam. I was "goofy" friends' word) and had multiple falls just walking on flat sidewalks, and memory trouble, for a couple years after each one. Got lost walking across the town I've lived in 30 years; forgot where my commuter bus stopped. Three years later I've still lost the thread of all my projects. My dad had the same sort of problems. And we both are extraordinarily slow to wake up after anesthesia, even after telling the doctor about this problem in advance each time.

Outliers, I expect.

Is there anything appropriate to say to a regular doctor about this, before considering optional anesthesia?

I'm overdue for a colonoscopy -- but comparing perhaps a 3 percent chance of colon cancer (no primary relatives) versus what seems like certainty of another couple of years of falling down on the street repeatedly and forgetting things is -- a tradeoff.

It's a tradeoff I can't balance. I have no idea how even to explain to a treating MD who works on the basis of statistical averages.

Of course I never see the same MD twice and they don't have time to read my file, that's medicine these days.

Thoughts or pointers to more appropriate place to ask welcome.

[Jackie]

I have a suggestion about the anesthetics used for colonoscopy. DON'T LET THEM USE VERSED/MIDAZOLAM if you value your mind. VERSED is the drug from hell for a lot of patients who previously were fine. I had problems with GA also, but the effects from VERSED have lasted 2 years and counting!!! I get along fine with a small amount of Fentanyl only without all the rest of the brain disabling drugs. Good luck convincing your provider not to knock you in the head with VERSED however! They love this stuff.

[Willie Owen]

I have a record for memory losss by anesthesia. I feel it is not all anesthesia. I suffered an electrocuted brain 20 years before and then an electric shock a few weeks before surgery. I woke up a few weeks ago in a completely different world from the one I went to sleep in the night before. It took a couple of days before I remembered the last thing I knew was counting backwards before rotator cuff surgery. It took me another day to realize that ten years had passed since the surgery. Any record of such happening to any one else? I feel like the alterations to my brain cells by the electricity interfered with normal operation of the anesthesia and an alter ego emerged and rn my life for all this time. Any comments?

[Willie Owen]

I have a record for memory losss by anesthesia. I feel it is not all anesthesia. I suffered an electrocuted brain 20 years before and then an electric shock a few weeks before surgery. I woke up a few weeks ago in a completely different world from the one I went to sleep in the night before. It took a couple of days before I remembered the last thing I knew was counting backwards before rotator cuff surgery. It took me another day to realize that ten years had passed since the surgery. Any record of such happening to any one else? I feel like the alterations to my brain cells by the electricity interfered with normal operation of the anesthesia and an alter ego emerged and rn my life for all this time. Any comments?

[johny republic]

What about fluoride levels from the florine based gases? Fluoride is a potent neurotoxic poison. What role does that play in memory loss and cognitive function?

[kofke]

my knowledge about flourine and volatile anesthetics:

methoxyflurane: bad, heavily metabolized and caused renal failure from F. not around anymore

enflurane: signif metabolism and with prolonged use an occasional F induced kidney failure. not around anymore

halothane: less metabolism, Br released too, pretty much gone now.

Isoflurane: hardly any metabolism but some. i once measured urine F when i gave it to a patient for two days, and could not detect a toxic amount

desflurant and sevo I think produce negligible flouride

so its a good question but i am pretty sure that with the modern anesthetics this is not an issue anymore

ak

[wisdom]

Thanks for the information on anesthetics and a potential link to brain damage.

[Distressed Daughter]

Three years ago my then 76 yr old mother underwent bypass surgery to replace the aortic valve. Due to complications with the new valve, she was in surgery for 8.5 hours. In addition, the night before she underwent catheterization and was under anesthesia for an hour.

She woke up 24 hours later a different person. She did not recognize her family and thought she was 10 years old in Japan. Although she has spoken English most of her life she no longer understood it well.

Three years and many tests later, we are told she suffered brain damage from prolonged anesthesia and now has alzheimer's as a result. She is like two people - one who is my sweet mother and one who screws up her life by doing irrational things. She always says "someone else did this or that, not me". To her, her history since the operation is all made up in her head since she can only remember from the day before the surgery three years ago and nothing since. Its very very sad for her and for all of us who love her.

Does anyone know of any treatments for this type of brain damage?

[Laurie]

I had liposuction and facelift in September of 2007 at Thailand. I was put under anesthesia two times - once during the surgeries and again to remove surtures at my request. They also offered a "No Pain Surgery" for an additional $50, which I decided in favor of. My comprehension has since been difficult and I am now more forgetful. I have been checked by a neurologists who claims there's nothing wrong with me. I know he is wrong. I feel it and live it everyday. I have been surfing the net to find out if anesthesias can indeed cause brain damage. Your site so far has provided the best info for me. If I can help your studies in any way, feel free to contact me. I tried to find out tonight exactly what kinds of anesthesias were used on me, but they refused to give me this info without first getting a copy of my passport. It could've been isoflurane and/or sevoflurane. The hospital said that those were the two gas anesthesias most commonly used. I will find out what exactly I was given. Hope to hear from you. Aloha!

[Hank Roberts]

http://upennanesthesiology.typepad.com/upenn_anesthesiology/2009/06/consensus-statement-first-international-workshop-on-anesthetics-and-alzheimers-disease.html

June 29, 2009:

".... Given the available evidence, the potential for anesthetics to have long term cognitive effects needs serious attention and further study. ..... Consensus statement: First international workshop on anesthetics and Alzheimer’s disease. Anesth Analg 2009;108:1627-30

[Dipankar Dhar]

Almost since a year now, increasingly I am asked, especially, by parents of toddlers,during pre-anesthesia visit, about the potential of anesthetics causing any brain damage, especially in children.

With insufficient information available it is extremely difficult to allay such apprehension.

Emergence agitation with sevoflurane, especially in children is not uncommon... is it some temporary manifestation of limbic system dysfunction?

[andrew kofke]

dont know what to make of the sevo delirium. It is proconvulsant so one wonders about that as an issue but probably not. hua fung wei at our place finds that isoflurane promotes apoptosis and sevo and des do not so from that perspective it should be a good drug.

ak

[Ann]

My dearest friend of 42 years underwent plastic surgery in office and was under for at least one hour. She was not the same when she came out. A month later she is cognitively impaired and often cannot discern between reality and dreams. She has also suddenly become obsessive/compulsive about a number of things...combing hair, cleaning hands and a number of other not normal behaviors. We are all worried that we won't get her back.