Looking for Death in Little Cells

When we do the bit of kids’ anaesthesia that involves the drugs, we’re generally not trying to poison our patients. That was something you probably assumed. We use lots of medicines as part of anaesthesia that have their own side-effects and potential complications but they’re generally things we can make adjustments for and are only likely to cause issues for a small percentage in the first place. We can get on with the making people comfortable part of the job confident that we’re not causing big, long-term complications for simple cases.

Which is why there has been a lot of quiet sweating going on since one very particular possibility was raised: what if every time we gave anaesthesia, our drugs were causing little deaths in brain cells?

 

Talk to the Animals

A lot of this has come about from talking to animals. Well, not so much talking as giving them an anaesthetic trip and closely examining neurons at a later moment under some form of beady microscopic vision.

It turns out that when you expose very young animals to a lot of our anaesthetic and sedative agents (ones that can’t reliably produce full blown lack of awareness) cells from the central nervous system die. The initial suggestion was that something about the anaesthetic agent switched on or accelerated a thing that can happen in cells anyway – apoptosis (a process of cell death). Apoptosis is actually a normal bit of development. Except for when there’s too much and it’s triggered by other agents.

There’s more than just a microscopic version of this picture though. Rodents exposed seem to be not quite as good with learning and memory behaviours down the track. This is … not great.

Animals don’t always speak clearly though. Well, not without a bit of CGI or some very good peyote. Lots of flaws have been pointed out in that animal research. The first complaint was that the doses of anaesthetic agents used weren’t equivalent to what gets used in babies, or was even the equivalent of a huge overdose.

Sometimes the duration of anaesthesia equated to a brain development epoch of weeks and weeks in the life of a newborn. We don’t give anaesthesia continuously for weeks. It’s hard to get good coffee into the theatre late at night, you understand.

There were even concerns that the ages of the animal subjects didn’t match newborn humans because of the relative maturity of each. A newborn rodent might just equate with the sort of newborn human that’s about 4 months away from being newly born. All of these things make it hard to know what to make of the animal information.

The changes in the cells are real though and a worry. So what was the next step? Try to look at humans. Starting with humans that we sort of already know.

 

Allsorts

The next wodges of research that came out were mostly observational studies. This would be those sorts of studies where people known to be exposed to anaesthesia get followed up to see if they show signs of injury to those precious brain cells.

The findings? Well, mixed. Some studies have seemed to suggest there might be subsequent issues with neurodevelopment. Some have found no evidence of an issue. Those ones that might show an association also have a lot of fuzz about them, partly because they tend to show an association in those patients who have multiple anaesthetics.  The sorts of patients getting exposed often have other significant illnesses.

The studies often rely on pretty non-specific outcomes too. Things like grades at school or did they turn up for tests. What if the kid just didn’t get to school that day?  It’s hard to control for public transport scheduling in your observational study.

Those confounders have always got in the way. So wouldn’t it be good if we could try to get away from those splotchy bits of paint now messing up the redecoration job?

Three owls Tambako.jpg

Well two of them have got the idea.

Needles and Lumps

Just as well Australians came to the party with some observational work. Well, other people might be coming up with research too but a team led by Prof. Andrew Davidson at The Royal Children’s Hospital in Melbourne has done some excellent work to look at this.

Across a bunch of hospitals, small patients under 3 months pitching up to get hernias fixed up (yep, hernias aren’t just for old people wearing girdles) were randomized to one of two anaesthetic options – general anaesthesia with the smelly gases or an injection at the back while awake to make their lower half completely lacking in sensation so they couldn’t feel stuff. So that’s one group getting the knock out stuff, and one group avoiding it entirely.

That latter one is a legitimate technique for providing anaesthesia in this group so they weren’t coming up with anything revolutionary on that front. The advantage of choosing a procedure like this is that it’s mostly not associated with other health problems, you probably only need the one operation and you don’t need lots of other pain relievers or confounding medications. They’re also not long operations. Well, mostly.

They got a pretty good number of kids into it too (although that took 5 years and lots of participating centres). 722 kids randomized (with a few dropping out along the way naturally). The plan is to follow the kids out to 5 years to see if there’s a difference in cognitive function and this time around they’re reporting on the results on the 2 year screening.

 

The Report Card

So what about those findings? Equivalence. Sweet, boring equivalence. Which is what the study was set up to try and look for. That was across the combined cognitive score as well as the subgroup bits on motor scores, language scores and adaptive behaviour scores.

Phew. Wrap it up. Send that coffee I mentioned earlier. It’s all good.

Well, not quite. This study is a huge and impressive effort, but it’s not at all the end of the story. For starters, it doesn’t answer that key question about dose and exposure: get exposed to long anaesthetics (rather than the average 57 mins here) or lots of them and this isn’t your study. It’s still reassuring for the vast majority of young kids who only get the sleepy gas once though.

The other thing is that screening for cognitive stuff is probably best done when the kids are a little older. Like 5 years old. Which is why the investigators plan to do just that.

The other obvious question is whether there are particular types of developmental issue that are more common. Autistic spectrum disorders or cerebral palsy are the candidates probably of most interest. This study has no hope of really assessing that but didn’t spot a difference.

I can say that we’re not routinely inducing the death of all of the brain cells every day we pick up the mask and kick off kiddy karaoke time. Well, not with the drugs anyway. Can’t comment on the singing.

And like pretty much every other bit of research in this area, I can also say now that we have some better answers, we just need a few more.

 

Notes:

That owl image was posted to the Flickr Creative Commons area by Tambako the Jaguar and is unaltered.

As for the references, the original paper appeared in The Lancet and is here:

Davidson AJ, Disma N, de Graaff JC, et al. Neurodevelopment outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multi centre, randomised controlled trial. Lancet 2016;387:239-50. 

There’s quite a nice accompanying editorial too:

Warner DO, Flick RP. Anaesthetics, infants, and neurodevelopment: case closed? Lancet 2016;387:202-204.

I’ve also posted on one of the earlier observational studies here.

 

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