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:
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...)
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.
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.