Present Tense – Neurotoxicity Part 4

After 3 other posts we finally got to here. What do we do in the here and now on the topic of neurotoxicity? If you haven’t read the other instalments you might like to check out the one on animal research here, the human research one here or the one on the unknowns here. Now, what about right now? Andrew Weatherall has a version of the lowdown. 

The animals aren’t going to have to chat to anyone. The researchers won’t be next to us when we’re talking with families. All the research in the world is good and useful, but it’s up to clinical anaesthetists to figure out what to do with it every day.

Well, not every day. That’d be a little obsessive. Take a day off at some point.

But after all those bits of evidence, weak or disputed or compelling or slightly off mark, what are we supposed to say in the real world?

Well don’t look at me. There must be people with cleverer things to say than I’m offering up on this little website?

Everyone Agrees We Might Agree

We do have large collections of those cleverer people. For a long time the Smart Tots group have been driving research in this area and they are no stranger to the sort of consensus statement that probably requires a few phone conferences, a few cups of dodgy tea in meeting rooms and a depressing number of emails.

Let’s look at the consensus statement they released in 2015 with a few key messages:

  • Millions of small people have anaesthesia for surgery all the time.
  • The concern started with animals where there are real effects.
  • Studies in kids are mixed and have enough limitations to make it unclear if issues that you see are related to the drugs or all the other stuff going on.

Interestingly in their advice for clinical types they offer the idea of telling parents that all the drugs are about as bad as each other in the animal work. They also stress the fact that any decision to delay would have to be weighed up against the risks of waiting for the clever surgical bit. A delay might not matter for a skin tag. It might matter a whole lot more for actual health things.

Except for When We Don’t Agree

Good on Smart Tots then. That’s not even a joke, they’re really leading things along. They even did a bunch of work with the FDA to make sure everyone in the US was on the same page.

Until the point where the FDA decided to go right ahead and release something they magicked up all by themselves. In late 2016 they decided to come out with their own statement.

When you read the statement it might not seem that controversial. But it opens by saying that the labelling for general anaesthesia is getting warnings, and sort of plucking this “under 3 years and over 3 hours” theme a bit out of the air. They do get onto a statement about the general tendency not to do unnecessary surgery in kids or late pregnancy women anyway but the framing was there and the process was unpopular. (For a little more of the flavour of this you can check this podcast released shortly after IARS 2017.) Really unpopular.

The Europeans Aren’t Keen on People Going it Alone

Now this won’t be news to anyone enjoying the spectacle of Brexit. (I am sorry to British readers for whom that reference might be a little triggering. Let’s just pause here for a second, and reflect quietly on all the things that make you happy that won’t change. There you go.)

Anyway, the Europeans had things to say about that FDA intervention. It was like they tried to stage their own intervention in the form of an even more strongly worded letter. And look it might seem like that might be a rather 1890s way of settling a disagreement but it’s a good step up from slapping someone with your gauntlet and demanding satisfaction.

They again stress the uncertainty around the evidence in humans. Their statement also features the following zingers:

  • The FDA statements about the risks over 3 hours and under 3 years of age aren’t supported by the evidence because it’s insufficient and incomplete.
  • If an invasive procedure is necessary adequate anaesthesia is non-negotiable (you can almost hear them say “you scoundrels!”)
  • There is good evidence that inadequate anaesthesia and analgesia may result in significant and serious complications.
  • There is no evidence to support the idea that any change from established techniques for prolonged or repeated procedures would influence neurocognitive outcomes in kids.
  • The implied “safe cut-off points” are bollocks-y hearsay.

Look, they may not have used the words “bollocks-y hearsay”. I can only assume it was dropped in the edit.

And Don’t Forget the Appendix

Not a giant koala appendix or anything. Just a little update from the US Smart Tots group.


This image came up when I searched for ‘giant koala’. They’ll probably figure it out some time I guess.

In response to the release of the GAS study they did feel the need to highlight that it was reassuring. A little bit.

They also wanted it noted that the real measures might be at age 5; a single cognitive test might not be enough; we use multiple agents so that might matter; this was sevoflurane so what if it’s just that and who knows about other agents; what about the older children; and, what about repeated exposures or those super long cases. That’s a lot of qualifiers.

Amazingly for the last point they didn’t say anything about how much surgeons don’t understand the concept of time. Missed opportunity that.

So after all that the consensus is that the world is still a confusing place. Awesome.

Real World Discussions

So how do you go about talking about this tricky topic if it comes up? What do you say when someone asks about ‘any bad effects’? Because that’s the usual context. At this stage I don’t tend to mention it up front. It’s something I get to if I’m asked.

And I don’t have any particularly clever answers but here’s a rough practical rundown:

1. Check what they’re after

There’s enough out there at this point that people are definitely cottoning onto the fact that neurotoxicity might be a thing. It’s not always what someone means when they ask about bad effects though. It seems fair to start by answering the actual question they have. So maybe the first thing to ask is “What sort of bad effects are you thinking about?”

2. ‘It’s a good question…’

It’s worth mentioning that it’s a pretty good question. I mean there’s part of me that doesn’t want to start on a difficult discussion but ultimately it’s a pretty fair question about the sort of thing engaged people are likely to want to hear about.

But I’ve certainly had a few people seem pretty uncertain about asking it. It seems like a pretty simple thing to acknowledge it’s a fair question and that they are asking the same questions we are. Most people seem relieved.

3. ‘There are things we don’t know’

Well there’s no point not being honest. So I’d usually start by pointing out that this is something people are actively looking at because there are things we don’t know but there are plenty of things we know that are reassuring too.

4. Point out easy things

Where there are simple things that make the whole situation less worrying I generally get straight on with that. So if we’re talking about an 8-year-old, I’d usually open early with something including ‘most of the research is being done on younger kids because that seems to be the time where there might be effects that matter’.

4. ‘Let’s remember the surgery’

As is pointed out in the various consensus statements, in younger kids we don’t tend to do surgery just as a fashion statement. So early in the piece I mention that we’re here because the surgical crew think that not doing the surgery has its own risks and the potential risks we’re exploring in kids’ anaesthesia need to be weighed up against the real world risks of no surgery that we have more definite means to describe.

5. ‘It started with animals…’

Sometimes, but not always, I’ll actually mention that we started asking the questions because of animal research. It can be a useful way to explain where we started from and why that early stuff might not be much like actual anaesthesia. It’s a judgment call as to whether people want that much info and I can’t say I always get it right.

6. If it’s short surgery…

This is an easier one to cover because there’s just more there. It’s pretty easy to say “so far when we’ve checked back in with kids later in life who had anaesthesia early on, when you weigh up the evidence it doesn’t suggest huge changes in brain development. The same is true in small studies who have followed kids from the time they had anaesthesia for a couple of years”.

7. What if it’s long or repeated surgery…

Then it’s back to the need for the surgery. All you currently seem to be able to say about the evidence is that we’re still not sure. But we do know that the surgery is planned for a reason that matters, and that having the surgery without the anaesthesia is really bad for lots of reasons.

And ultimately most parents thinking about this stuff have already been having conversations weighing up some pretty difficult pros and cons around the care of their kids. This is not even the toughest chat many of them have had.

For this group I also think it’s fair to say that some of the changes, if they are there, seem to be pretty subtle, rather than huge and profound differences in development.

8. Does that sort of answer your questions?

Well of course I get to here.

Is that the perfect approach? Probably not and I’ve probably missed things in the retelling. But it seems a fair summary of where we are.


Oh, and What Should we Change?

All this talk of neurotoxicity should also start prompting other thoughts for clinical anaesthetists – what other ways are there?

On balance I’m not sure that widespread changes in our approach to anaesthesia will be justified. But I guess that’s why we need more evidence.

Still, as an exercise that might not stay academic it’s worth having a think about what you’d do differently if you have to avoid gabaminergic and NMDA-antagonising agents?

Well if our aim is to minimise things that fit those categories then it seems there’d be a few things to start working on:

  • Exercise balance – as opioids seem to be neurodevelopmentally OK, higher dose opioids seem to be a starting point so you can lean on the anaesthetic agents a bit less to achieve a cruisy snooze.
  • Be efficient – you now have a whole extra reason to try not to mess about and tarry as you give that anaesthetic. Extra time spent getting the perfect line might have implications other than a delayed dinner.
  • Think about regional options – this might be another way to work on the balance/less anaesthetic agent bit. Or maybe we’ll see a swing all the way to entirely regional procedures in kids. This would represent a pretty profound shift in many institutions and healthcare settings. It would certainly mean we need to work on our skills of distraction and focus-shifting through procedures, which might not be all bad.

It’s not an exhaustive list but it’s a start.

So imagine you were going to design a ‘non-neurotoxic’ anaesthetic, if that’s actually a thing. Or a thing we need to aim for. What would it look like?

Well there’s actually people already running through that hypothetical. The T-REX study has already gone through a bit of pilot testing and is now into the main show. It’s looking at lower extremity surgery with a combination of dexmedetomidine, remifentanil and a caudal (with either ropivacaine or bupivacaine).

It’s early days but at the very least it’s a reminder that there are lots of ways to turn a combination of drugs into an experience that achieves the goals of anaesthesia and analgesia.

I guess it’ll just be a big of a long trudge to figure out where we’re going to end up though.


An actual neurotoxicity researcher in action.



The images are from and here under Creative Commons with no changes from the posts from Chester Ho (that giant koala) and Daniel Cheung.

Want those consensus statements?

Here’s the one from Smart Tots, as well as the update post-GAS.

Here’s the FDA thing.

And here’s the European response. Burn.

Here’s that link to the T-REX details again.

And of course, neurotoxicity just isn’t worth talking about without a Rube Goldberg machine that someone spent too much time on.








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