This is the third in a series of posts on the topic of paediatric anaesthetic neurotoxicity. The first post provided a review of some of the animal research, while number two went into the unsatisfying ‘meh’ of a conclusion from the human research. In this post, Andrew Weatherall goes into the research that maybe we need to see next.
So we tried out animals. And we tried big data. And we tried randomising. And we still don’t have answers for now.
We don’t get to stop there of course. This is not an ‘I guess I’ll just shrug and reflect on how there’s nothing you can do about it not working out., like that time when I tried that cheesemaking class and when I tried to eat the cheese my tongue shrunk back somewhere into my inner ear because that cheese was not good’ situation. We have to come up with practical ways to still get the job done.
But before the now we also need to take a moment to understand the gaps that really need to be addressed in the research still to come. And you probably have a bunch of clever ideas about what the next bit of research you want to read will tackle.
I don’t just mean “the answer to everything” because isn’t that 42?
Science doesn’t really work like that. So the next time I read something (and the time after that, and the time after … well pretty much all the times I read things for decades) I’ll be hoping to see things that fall into the following groups:
1. More of the same
I’ll do the responding for you.
“Whiskey tango foxtrot? You just wrote a bunch of posts saying we don’t have adequate answers from the stuff that’s been done and now you want more of the stuff that’s been done?”
Well, yes. At least a bit. Even the bigger cohort studies aren’t enough to tackle subtle things like this, and in at least some cases the assessments or grading scales used to try and detect neurodevelopmental changes are probably a matter of expediency rather than being the best scale to use.
And the randomised trial work needs longer for follow-up and more than just one or two prospective bits of research ticking along.
Plus there is the substantial issue that is still being looked at with the current wave of research – what about prolonged exposure and what about repeated exposure? We definitely need more efforts in the same direction on that front.
Gathering evidence isn’t done with an earth-shattering kaboom. We’ll need consistent efforts and long-term efforts to collate enough relevant evidence.
So yeah, I want more of the same. Things that look pretty much alike in design to what we have now.
2. A Lot More About Neurodevelopment
One of the striking problems we face in our current understanding seems to be a really primitive understanding of which bit of what is developing when. And that really matters.
You’ll remember that there’s lots of uncertainty over what the correlation is between when you expose an animal to anaesthetic agents and when the corresponding period in a kid might be. Well it’s not even as simple as that.
One of the earlier podcasts touches on the problem of what develops when. You can listen to it here (and I’ll give you the tip, the most relevant bit is around minute 16).
If you don’t quite have the opportunity to go and have a listen, here’s the quick written version:
- We all think of neuroplasticity as this is wondrous thing that allows kids brains to recover from insults. Well at least I did. This is true. Sort of.
- Really what we should realise is that neuroplasticity really just means that neurons are susceptible to influence. The neurons are not in a position to choose what influences they fall under. They just respond. Influences can also be bad or lead to damaging changes.
- It seems that when your inhibitory pathways mature that period of susceptibility probably ends. The timing for when that happens is still being established. What’s more is that neurons and groups of cells that look the same under the microscope turn up in different parts of the brain and in each part of the brain the timing of maturation, and hence the period of susceptibility to influences, is different.
This has quite profound implications. It seems like we probably need to know which parts of the brain are susceptible to our agents at particular times. That information could be key in understanding which parts of neurodevelopment are at risk when we give an anaesthetic at a particular time. If there is an impact of our agents on development, then it might not be as simple as “kids are at risk under 2”. We might need to frame it as “a kid’s functioning in the area of speech is at risk when we give an anaesthetic between these months, but spatial elements are not at risk at that age”.
I don’t pretend to know how you design your research to figure that out. But I do get the feeling we need to know more about neurodevelopment to understand what we might be affecting when. Because of course that leads us onto …
3. A Heap About Scales
When you read any of these papers do you immediately think ‘oh well that’s obviously the particular neurodevelopmental scale I’d choose…’ or ‘why that’s as outrageous as a slow retrieve with a Clouser Deep Minnow’*?
At least some of the time the papers reporting associations or reporting ‘this might not be an association’ report on IQ scoring, as an example. But is that even the best scale to use or is it just easy or convenient? Even for me it seems like a fairly blunt tool for picking out the details of sublet developmental changes in particular areas.
WISC? Well, still maybe not. And when should we use Bayley, or Griffiths? And looking back at the point above, should we be using different scales for exposure at different times?
I’m not pretending I have good answers, and maybe I’m not looking for research here as much as clarity. or maybe I’m after is the evidence that flows from understanding development better – which scale for which exposure.
4. Stuff for After the Exposure
Those things are all about the pulling out the details about what exposure means. But there is something that popped up recently that hints at some of the stuff we should really also be hearing about.
Zhang et al enrolled a total of 179 kids and divided them into short-duration (< 1 hour; 49 in the group), moderate duration (1-3 hours; 51 in the group) and long duration (3 hours or more and with 79 in the group). They used Raven Standard Progressive Matrices as their measurement and reported on IQ for age. They had preoperative scoring as well as follow-up testing at 1 month, 3 months and 1 year after exposure. Of note these kids were all aged 6-12.
The finding they pull out is in the long duration group where the median intelligence levels at 1 month was significantly down, and hadn’t resolved at 3 months (but basically had at 1 year). At the same time they ran multivariable logistic regression analysis to look at confounders and found correlations with lower intelligence scores and being at the younger limits of their recruitment, having a history of premature birth and having a mother with a low education level.
So it could be another paper that contributes to that broader discussion about the relative influence of all the other influences around the trip to the operating theatres.
But there could also be a really interesting avenue in there somewhere. Let’s assume that there is something in it for a second and that there is an initial change produced by long duration anaesthesia that resolves over a year. Then what would be the ways to influence that recovery?
It might be a little bit of putting the cart before the horse, but if there’s a chance that those longer duration or repeated anaesthetics do have neurodevelopmental impacts, then just as urgently as we need to be defining that part of the story, we need to be pursuing anything that can help with recovery.
If there’s a problem, we need to work on solutions too.
Now that might not be all the research we will ever need (well of course it’s not). It’d be enough for plenty of us to sink our teeth into though.
It might be a while before we get to test those teeth though. And in the meantime we have to do things in the here and now.
But maybe that can wait for the next post.
That Zhang paper is this one:
Those images are from that Creative Commons unsplash.com joint and were posted by David Menidrey (the pumpkins) and David Clode (the snake).
And you don’t even have to go that far to enjoy this week’s epic Rube Goldberg.