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.

 

The Connections

You may already have an idea about anaesthetists. You might think we’re up the back of the theatre doing sudoku. Perhaps you think we just want people to shut up and the drugs are a convenient way to deliver some peace and quiet. Maybe you’re not quite sure what we are.

Perhaps we’re to blame for that. So maybe I should explain the things that anaesthetists do. Except that would take way too long.  Years of electronic tapping. But I can cover one part of our job. Anaesthetists produce connections.

Connections Anaesthesia Probably Isn’t Responsible For

This post is also about something else. This post is a little bit about autism. And a little about the different things you can focus on when you start with those two words: anaesthesia and autism.

If you do a quick search for those two words it won’t take long to find stuff claiming a big link between anaesthesia and the development of autism. On some sites it gets put in a basket with vaccinations. Or toxins. All sorts of things.

On the one hand you might assume I’ll be quick to dismiss this particular connection. You might think I’d be jumping at the chance to rip into a bit of pseudoscience. I’m just not sure taking a swing at people wrestling with something helps anyone.  So let’s not.

The other reason I’m not that keen to go down that road is there are legitimate questions to ask about the effects of anaesthesia on the developing brain. There’s more on this topic here, but the simple version is: we’re still elucidating the way anaesthetic agents work; in some animal models anaesthetic agents at big enough doses for long enough cause damage to neurones; researchers are still trying to figure out what this means in actual human-type creatures.

It’s also an understandable response when you’re trying to fill in a space where there is only a hole. You need some sort of truth to fill the hole and researchers haven’t done much of a job of making sense of that space for those families. The research is starting to catch up though.

In May this year a group from Taiwan published the results of a retrospective review looking for any association between general anaesthesia and autism. They looked back through a health database including 114,435 patients and then sifted out the 5197 who had an anaesthetic before the age of 2. They then matched a bunch of features  of these individuals to a cohort of controls. Not just a few controls either – 20,788 of them. The plan was to then follow them out to 5 years of age to see what the rates of autistic spectrum diagnoses were during that time frame.

Why those time points? Well, it’s generally held that the exposure needs to be before the diagnosis, and that most vaguely related things should have declared themselves by the age of 5. It’s worth noting that kids having anaesthesia after the age of 2 could still be in the control group because the time critical exposure still hadn’t occurred.

So what did they find? No difference in rates of an autistic disorder. No difference with repeat exposure to anaesthesia or surgery either. Age at the first exposure to anaesthesia? That made no difference.

Will this settle the concerns? Probably not, but it’s a start.

It’s also not the only important connection that we need to look at more.

Making Connections

To get to the point where you can give the anaesthetic to a kid, it helps to make a connection that lets you find a better way there. Sometimes parents help with that. Sometimes we get there in the light of bubbles. Sometimes we have a song.

Other times I bring a rocket. Well I usually start with the mask for the space crew, and then we add the space gas. (You all know it’s called space gas because it makes you feel like you’re starting to float up into space, right?)

Floating is good but you need to fire up the rocket to really get going. And sometimes you can smell the fuel for the rocket, which is a little bit smelly. Not as smelly as the stars when you get right up there of course. Once you’re really travelling you can smell the stars because everyone forgets to wash them. Have you ever seen someone washing the stars?

And then you’re asleep.

A connection helps you share the story. So what about those kids who you really, profoundly fail to make those connections with?

Here's one of the rockets I sometimes bring to work. [via the NASA Apollo photos just released]

Here’s one of the rockets I sometimes bring to work. [via the NASA Apollo photos just released]

Time and Space 

For the clinical anaesthetist, the most pressing research we need is how to make the whole experience better. Kids in the autistic spectrum (and it’s a big spectrum so let’s just allow for a huge amount of variability in this discussion) can find the hospital environment challenging. Turning up for an operation is a pretty extreme microcosm of hospital care.

As the autistic spectrum is actually a big range of conditions you see a big range of personalities and behaviours. And fears.

Some kids with a diagnosis in the autistic spectrum will have a degree of intellectual disability. Plenty won’t. Some have changes to fine motor control or the way they walk. Some have significant anxiety issues. Some can’t cope with touch. Some self-harm, particularly at times of stress.

All of these are part of a couple of main groups of characteristics: social communication difficulties (the sort that make a space story not always that exciting)  and ritualistic and repetitive behaviours.

So plenty of these kids will find social interaction and understanding really challenging. And usually they might find solace in a stable environment or repetitive movements or focussing on special, quite intense interests.

Step back for a second and consider what we ask of kids when they come for an operation. A procedure they don’t always understand. A total disruption to their routine. A long time with no food and a slightly shorter time with no drink. A quick succession of new adults doing a bunch of things you might not have tried before then finally a trip to a small room with lots of monitors and things on the wall. Then a mask, dizziness and the smell. And at the end it’s all so quick.

Contrast that with the things we probably should do for a lot of kids in the autistic spectrum. Prepare them slowly. Establish familiarity beforehand. Make sure the perioperative team understand particular things that make this patient more or less anxious. No sudden introductions to an environment with huge amounts of new stimuli. Maintain a degree of routine. Perhaps a premedication to help get things going. Get out of there as quickly as possible afterwards.

Where is the connection between those two scenarios?

The hospital setting is almost purpose-built to fail a lot of these kids at every step along the way. And these facilities are being built and expanded all the time. We need to carve out space for a slow, quiet lane in care. The needs that can be served by quick forward movement are always pressing.

So there’s another connection in anaesthesia we need to make. More research into ways to make the experience better for autistic patients so we can argue for the things they need.

Maybe starting with a bit more time to make that trip to space.

References and Notes:

I looked at a few papers for this one but the most useful were these ones:

Ko, W-R, Huang, J-Y, Chiang, Y-C, et al. Risk of autistic disorder after exposure to general anaesthesia and surgery: A nationwide, retrospective matched cohort study. Eur J Anaesthesiology. 2015;32:303-10. 

Taghizadeh N, Davidson A, Williams K, Story D. Autism spectrum disorder (ASD) and its perioperative management. Pediatr Anesth. 2015;25:1076-84.

And for a story around autism this Radiolab episode, “Juicervose”, is an interesting listen. I’m sure it can’t cover the experience of all people and families with an autistic spectrum diagnosis, but it’s still worth the time.

 

 

 

Not that Sort of Eye Disease in Research

You’d think that a humble anaesthetist would be happy. A really big study on anaesthesia and awareness gets released in the media and gets people talking. About time. No more of people asking to “See the Doctor” when you go for the preoperative review. Less Sudoku jokes. Except then I read this coverage in The Guardian.

Shock. Horror. Calamity. People are sometimes aware when they should be super unconscious during surgery.

Except that reporting is sort of baloney. The report has been messed up by another example of “I” disease, where a very clever research team have let it be about them and not the problem of interest. It’s a problem in other branches of medicine. You can usually spot it when a medico uses the word “I” too much when discussing a story that should be about a patient.

Here is my reaction in snow leopard form. [Credit: Tambako the Jaguar, CC 2.0]

Here is my reaction in snow leopard form. [Credit: Tambako the Jaguar, CC 2.0]

Why the snarl?

There’s a particular section of that report that really did it. It’s around the point where the lead author quoted comes up with this:
He said: “For a long time it has been a discussion on the periphery. This is real. We need to understand it and tackle it.”

I get it. You run a big and impressive study. You want to get word out there. It’s a chance to say something. It’s hard not to try and make it sound that little bit more seductive. After all, you wouldn’t want to get trumped by surfing dogs on the news. It’s so tempting to make sure the release sounds that little bit more sensational.

Then you end up with a whole lot of misrepresentation.

The thing is, awareness is not at all a peripheral topic in anaesthesia. Generations of anaesthetists have sweated over it. It is a core part of what anaesthetists offer patients when they deliver general anaesthesia. It’s a topic that has been researched extensively (both the protocol and summary paper under discussion have more than 40 references at the back, though not every one is specific to awareness). There are a variety of monitors that have been trialled as a means of preventing awareness. Sounds like the sort of behaviour of those trying to ignore the whole thing, right? (It’s even inspired blog posts from obscure people.)

Read that report and you’d think the profession hadn’t realised this was a thing that was a thing. After the opening we hear about a string of things that have been “recognised officially for the first time”. Apparently patients can be aware (not news). Some patients are traumatised and some are not (not news). Having medicine on board that prevents you moving increases your risk (not news). Drug errors are implicated (not news).

It’s hardly the first time there’s been a bit of the sensational in a bit of coverage on something related to anaesthesia. It certainly isn’t as extreme as this special effort from 2005, where one of the commonly used co-agents was fingered as somewhere between cyanide and arsenic. A few years later the follow-up study showed that all the earlier stuff claimed was actually not an issue.

Excellent. The self-correcting virtuous circle of research strikes again, right? Slight pity about the impact on all the doctors and patients in between times of course.

Why the mankini?

So why try to dress it up as something memorable? Maybe they were misrepresented and really just wanted to stress that it is a problem that needs addressing (it is). Maybe they wanted to be able to say “I” just a few extra times.

The thing is there’s lots of interesting stuff in the study they could have focussed on. They sampled a period including nearly 3 million anaesthetics, utilising 296 local site co-ordinators with a 100% response rate. That’s a pretty astonishing effort and makes it about as big as you could hope for when it comes to sample size.

They chose to include only self-reported cases of possible awareness which is a slightly different method to that frequently used in other awareness research. Often an interview technique is used where patients are specifically quizzed over a bit of time which might well influence people’s recall of events. This may partly explain the overall lower reported incidence of awareness here, which for this study is around 1 in 20 000 anaesthetics (down from the oft quoted 1-2 per 1000). Even on a pessimistic interpretation, you’d only have a rate of about 1 in 6000 anaesthetics.

They confirmed that having an anaesthetic to deliver a baby or for heart surgery can still be considered high risk situations, but kids having surgery were a lower risk group using this study methodology. All of these things are worth a chat. So why make it sound like no researchers came before and anaesthetists didn’t really give a damn?

It’s not just sleepy doctors

Maybe there are bigger issues here. A recent excellent piece on the risks of blowing your own trumpet in research appeared over at The Conversation. It covers a bit on BICEP 2 and improbably fast neutrinos (there’s a whole series on Understanding Research at The Conversation which is well worth a read). It makes the very fair point that a bit of circumspection can save a lot of confusion for all.  A bit more reserve might have other benefits.

The temptations to claim big results are obvious. In an environment where funding is hard to come by and it is easy to feel your work is invisible there is a push on at many levels to make a big splash whenever possible. The problem is that framing all research findings as bold new discoveries is a disservice to the public we’re trying to inform. Surely the story of research is one of small revelations not sudden bolts of lightning. Isn’t it more honest to let the public know that research tends to be a lot of work to reveal sometimes obscure details in a complex picture?

Then maybe when we try to explain that new knowledge takes decades to fully understand, or that making the step from first insight to clever thing that changes your life is actually thousands of shuffles it would make more sense. The argument that science needs a long-term strategic plan with consistent commitment from supporters would be more obvious. The need to have lots of different people looking at a puzzle from a variety of angles would be far easier to explain too.

Whether it’s a case of “I” disease, or a desire to bring sexy back to (or even just to) your patch of research it might just be time to communicate a bit more honestly. If there is a time and place to put on a mankini, I’m pretty sure it doesn’t involve researchers.*

 

 

* In the spirit of logical consistency, it should probably be said that the time and place for a mankini cannot involve researchers because there is no time and place that should involve a mankini.

 

Splatter, Puny Humans and Space Surgery

Most shows in space suffer from some fundamental flaws. The monochromatic fashion choices. The humanoid template of 98% of interplanetary lifeforms. The flexible relationship with physics. One of the things that bugs me is the lack of focus on the mundane stuff. I never see anyone in orbit clipping their toenails. There’s always some multi-hearted warrior alien in the way of the boring.

The bit that I struggle the most with is the fact that everyone is just walking around like gravity is still in charge. Shouldn’t everyone be pulling the big somersaults in mid-air as they talk over the latest threat to internationally coordinated space uniforms?  How could you possibly create a miniature pocket of Earth-equivalent gravity? (My pondering here may be a result of my ignorance on the topic of miniature gravity pockets.)

Nowhere is this more apparent than in the deep space practice of medicine. The reality of medicine doesn’t include ‘Tricorder’ electronic reiki devices or holograms acting as medical professionals. It is a much trickier problem that is scrabbling for good solutions in an age where we’re inching ever closer to spending long periods orbiting or heading off to Mars. Once you include people in a situation, you guarantee periods of ill health or fortune. And mostly not big dramatic accidents. Ingrown toenails, styes and mouth ulcers will crop up. Cancer too.

Just recently there’s been a few stories describing different approaches to solving the problems of surgery in space. Unsurprisingly, the anaesthetic isn’t mentioned in all of the focus on the technology of doing the surgery. Unless the aim is to make any space surgery as traumatic as giving unwelcome birth to alien spawn, then the anaesthetic bit is worth a look to round out the story.

 

Can’t we just make illness take a break?

Well, no. NASA estimates it takes about 68 months of combined person time before you’ll need emergency evacuation. It’ll take at least 7 months to get out to Mars. We’ve already seen examples of self-surgery on the frontier before (see here and here). Disease doesn’t tend to respect our life plans. We’ll just be adding the challenge of weightlessness.

As you’d expect our bodies are more adapted to the experience of gravity than the absence of it. Leaving its steadying hand induces changes in every body system in ways designed to trip up the naive anaesthetist. As a first example part of the lining of all your blood vessels, the endothelium, functions differently. This changes the normal maintenance of blood pressure and the balance of substances passing out into the tissues. Kidney impairment can result from associated changes in blood flow.

It doesn’t stop there. There is a shift of the fluid in your body so that your head is actually more ‘wet’. The heart of an astronaut decreases in muscle mass and becomes more spherical. This contributes to heart dysfunction, particularly in the phase of the cardiac cycle where the heart is relaxing. There’s also some evidence of heart rhythm disturbances and development of coronary artery disease. Your blood volume decreases and specifically has less red blood cells available to carry around oxygen. Your respiratory system actually does pretty well out of it, although some congestion of the  nasal passage might occur (all that fluid).

For the budding space anaesthetist there’s also alterations in the way the body interacts with drugs. This is not only due to changes in metabolism and clearance from the liver and kidneys. The receptors on which some drugs act will also change in number and sensitivity. That all adds up to lots of adaptations for the medico, and we haven’t even got to the practicalities of the surgery.

Blood is Thicker than Water

Many of the demonstrations so far for surgical techniques in space have occurred while undertaking brief weightless flight in very high planes (those undertaking parabolic flight arcs). There has already been demonstrations of keyhole surgery in zero gravity although the organs floating buoyantly around inside the abdomen can be a little obstructive.

The other challenge that immediately comes to mind is what happens if there is bleeding? If you need to visualise that a little more,  consider this demonstration of the behaviour of fluids in space by Commander Chris Hadfield. Now imagine you’re not dealing with a little floating globule of water. Imagine there’s arterial blood spurting out under pressure and you’re trying to operate. It won’t be long before the space you’re working in looks like you handed a toddler a particularly gruesome paint gun. Quite apart from the blobs of blood floating in front of you. It would be enough to make a blood splatter expert combust.

Solving this problem has driven a variety of responses. One previous attempt involved effectively placing a clear box over the patient – but it didn’t take long for that to turn into a monochromatic blood-hued box. More recently a team described the use of domes that would get laid over a bleeding area then filled with fluid to provide hydrostatic compression. Such a system has already been tested and appears to offer an early prototype to help control bleeding while modifications should allow ongoing operating.

An alternative approach is to use the assistance of robots such as  this prototype that would be released inside the patient and work away on the inside. Testing of this system is not that far away. Of course, the greatest technology we have will still need someone to do the driving and that’s part of what makes things interesting.

Many skills are needed to be an astronaut. [via www.themirror.co.uk]

Many skills are needed to be an astronaut. [via http://www.themirror.co.uk]

The Right Stuff

Who will you call when faced with an angry appendix 4 months out into space? There’s two obvious options – train medical types to become astronauts or train astronauts to pick up scalpels. The latter seems to be the current approach for missions heading way out there (although I’m not sure I’d expect much given the description for the Mars One program). Part of the idea here might be to support the initial training by communication with experts on the ground. Unfortunately for emergencies there’s a bit of a communication lag (up to 22 minutes one way for a chat) and I’m not sure WhatsApp is likely to take off as a surgical trainer any time soon.

So maybe the more sensible thing is to look for people from medicine who might meet the profile of someone who’d be useful in space. Maybe someone with training in a critical care specialty. Or who has some experience in doing medicine in unusual or difficult environments. Or even mid-flight.

It’s all the sort of mundane stuff that is actually more interesting than phasers at 12 paces. It’s even inspired me to order a new shirt.

Coming soon to a shirt and life plan near me. [via snorgtees.com]

Coming soon to a shirt and life plan near me. [via snorgtees.com]

After a bit more reading?

One of the better recent reviews I found came out of South Africa:

Van der Walt J, Ernst AH. The anaesthetic management of microgravity-exposed individuals. South Afr J Anaesth Analg 2013;19(5):243-7.

 

What if my job is to give kids poison?

When I’m trying to explain to kids and families my job, I have a standard set of lines. Like,

“I’m the sleepy doctor and I look after the being comfy and being safe part of the operation” or,

“The surgeon is going to look after that little bit of you, I’ll be looking after the rest of you”.

And yet, for most of my (relatively short) kids’ anaesthetics career, there’s been a lingering question – what if when I’m doing the  helping, I’m actually providing kids with a very particular kind of poison?

Not that sort - then I'd have to be reported. [via hairbangersradio.ning.com]

Not that sort – then I’d have to be reported. [via hairbangersradio.ning.com]

Anaesthesia and Delicate Kids

It is quite hard to fathom now, but it’s relatively recently that general anaesthesia has been offered routinely to really small kids having surgery. In fact, you don’t even have to look that far back to find review articles trying to persuade the medical community that newborns actually do feel pain.

But these days we provide general anaesthesia for the sort of procedures previously thought off limits by anaesthetists. A win all round, right? Well, of course. However, over the last decade there has been an increasing interest in exploring the potential extra effects of those anaesthetics. The ones beyond the implantation of gnarly dream states with flying pink marmosets into tiny minds.

What has emerged is the possibility that the same anaesthetic agents that give the kind of controlled sleep parents could only dream of at home may cause damage to neurones in the rapidly developing nervous system. The sort of rapidly developing nervous system that you might find, say, in a newborn suddenly assailed with all the stimuli of a big new world, with the additional need to start getting on with surviving. You can see why that would not be thrilling news for a paediatric anaesthetist.

The Animals Speak … Confusingly

Unsurprisingly, this information comes from animal research. Studies have shown that exposure of rodents to common anaesthetic agents during the period where their little synapses are being created at neck-snapping speed seems to result in the process of programmed cell death, called apoptosis, being kicked into action. In rodent, and now primate models, this apoptosis is widespread and is also associated with less growth of nerve cells.

This isn’t enough to leap in and change everything we do. There are still uncertainties with all of this. The first big area of the debate is whether the animal models even match the newborn human brain and spinal cord. Rodent studies are classically done at about day 7 of furry critter life. While there’s some who would say that’s perfect as kids’ brains are rapidly developing to the age of 2, there are others loudly proclaiming that this correlates with the young human at about 24 weeks along during the pregnancy. That would be an extremely premature delivery.

Then there’s the anaesthetic. The animals are often given an anaesthetic for up to a day. A day of life in a rodent whose period of synaptogenesis over a week or so correlates with 3 months of a pregnancy equates to a very, very long anaesthetic. Sometimes in the animal research, the anaesthetic dose given would be enough for you and your next 10 neighbours. What we need is someone to look at what happens in actual people.

Trying to Bring it Back to Real People

Enter the Danes. Research recently released by a group in Denmark (I’ve provided the paper at the end) provides a little reassurance for any parents trying to stake a claim at a selective pre-school. They’ve followed up kids who had a general anaesthetic for a relatively small operation that gets done in kids under the age of 3 months. It’s an operation called a pyloromyotomy, and it’s what you do when a young whippersnapper turns up vomiting because the exit of their stomach has an overgrown bit that needs some surgical relief. It’s less than an hour through theatres, and involves minimal discomfort afterwards.

Pyloric stenosis in picture form. Someone should do an operation or something. [via www.pedsurg.ucsf.edu]

Pyloric stenosis in picture form. Someone should do an operation or something. [via http://www.pedsurg.ucsf.edu]

It turns out that the Danes have an impressive background in maintaining databases about their people, pre-dating anything the NSA got going with the aid of your local digital behemoth. The researchers tracked down every single kid born in Denmark between the years of 1986-1990 who had this operation, a total of 779 kids (whittled down to 748 with a few exclusions). They then used the database to provide a sampling of 5% of the general population, giving 13,723 kids for comparison. Then they compared standardised education scores that are obtained by pretty much all Danish kids at the age of 15-16 years.

What they found was that the average test scores were similar between the two groups. In fact, when adjusting for the potential confounders of gender, birth weight, parental age and parental education, the estimated mean in the group who had anaesthesia was 0.01 below the control group who hadn’t had the operation and anaesthetic before 3 months of age.

Phew! Well, actually there’s still more to the story. The exposed group did have a higher rate of “non-attainment” of testing scores. Non-attainment may be the result of kids having some form of special need that stops them doing the standard ninth grade curriculum. It can also just be because kids drop out and some go to schools that don’t do the testing. It is possible thought that there is a group experiencing some form of neurocognitive effects that are being missed from this follow-up.

Sleep Easy Then

Well yes, and no. There’s still enough here to say that we’re raising more questions than we’re answering. This is one of the biggest papers looking at long-term outcomes in kids. And it tries to deal with some of the confounders that plague the area. Often babies having surgery are getting that surgery precisely because they are very ill to start with, and they therefore have lots of other reasons to potentially have neurological changes later. The confounders make it really hard to be definitive about much though.

There is also a small problem with the long time frame for sampling. The kids in this study got a great anaesthetic no doubt. Up to 27 years ago. 27 years ago Michael Jordan, the guy on so many shoes, hadn’t won a basketball championship. Not only have the drugs got better, but the monitors have got better and the surgery has evolved. The constant looking back to outdated practices will continue to be a research challenge in this area. It also potentially highlights that we need to look just as carefully at how we give the anaesthetic, not just at what we give in the anaesthetic.

What we can definitely say is that more work needs to be done. This is news only to the garden gnome hiding in the old wing of the hospital and the FDA has partnered up with the International Anesthesia Research Society to support this sort of work (and provide good resources for families). The animal research definitely shows anaesthetic agents can induce changes to nerve cells. What we still need to figure out is whether this correlates with meaningful impacts on kids. What we definitely know is that anaesthesia has provided safe surgery for little kids for many years with little in the way of evidence to suggest big effects. It remains a question to be explored through. Unlike the sound of one hand clapping – that’s sorted.

So the recommendation for surgery for now is not to do surgery in kids under 2 unless they really need it. Of course, we do that anyway. The other thing we really need is more research on better ways to do the general conduct of anaesthesia.

This whole topic is a good reminder that the introduction of any excellent advance requires constant surveillance to look for potential issues. And I’d absolutely back anaesthesia as way less scarring than the soft rock from the band in the first picture.

(Here’s The Danish Paper)

Jerry Seinfeld – Research Mentor

For a couple of annoying years I did the wedding MC circuit. Always the MC, never the embarrassing interloper. This is not something I enjoy. The MC gig is the one you get when you’re not so important to the couple that they want you involved for the truly meaningful bits, but they know you well enough to be fairly certain you’ll stick to the rules. You know not too dark, not too insulting, light on the nudity. I’ve recited bits of self-written sonnetry and memorised bits of foreign language diatribes. And in my pursuit of the level of “drawing an occasional smirk and no walk outs” I’ve come to greatly respect actual comedians. Be they improv superstars or super scripted performers, I stand in awe of all. And I have come to this conclusion:

Everything I need to know about my work, I can learn from Jerry Seinfeld.

Building Cricket Cages

He’s not everyone’s cup of herbal strained foliage dregs, but I’ve been a fan since the early days of the sitcom. A while back I came across this profile from the NY Times Magazine (bit of a longread). The thing I found most interesting is not just that he keeps bashing away at it to feed an obsession. The fascinating element is his obsession with approaching perfection, be it in the door mechanism of a 1957 Porsche or continual whittling away to create the perfect bit. Seinfeld crafts his jokes over more than just a couple of sessions – he keeps at it over years. Take as an example the joke about the marriage game of chess with the board made of flowing water and the pieces made of smoke. The key to the joke delivering was drawing a board in the air. Some years after he started performing it.

It turns out that he’s describing pretty much the process of being an anaesthetist (alright, there’s a bunch of really easy gags to make right about there, so I’m just going to wait patiently while you run through them…

… done? OK, moving on).

I’m not talking so much about the patter most of us work on to try and win the patient over. We only have a few brief minutes before patients, in a place of exquisite vulnerability, put their trust in a stranger. The routine for kids can be particularly challenging and confronting to hopes of retaining dignity in the workplace. Of course, most comedians probably don’t have the option of turning up the sleepy gas to make the heckling stop.

The real similarity is in the pursuit of ever incremental steps towards the perfect anaesthetic. Anaesthetists can obsess over the smallest detail of every element of what they do to try and produce the perfect parameters. A discussion of taping in a cannula can take up a leisurely lunch on a day off. It’ s a slow march towards small moments of perfection. To build the cricket cages that Mr Seinfeld reveres.

Actually, it's really impressive, but I'd just let the bug go and be a bug.

Actually, it’s really impressive, but I’d just let the bug go and be a bug.

Building Perfect Research for the Side of the Road

I had another MC gig a while back. This time at a conference (a whole different type of angry after that one, but that’s for another day). One of the speakers in the session was the principal investigator for a trial of an automatic chest compression machine for giving CPR to patients suffering cardiac arrest. What followed was a seriously impressive presentation of how to strive for the cricket cage when doing prehospital research.

The prehospital environment is by its nature messy. It isn’t a pristine lab where elements are easy (well, easier) to try and control. There’s often a bit of dodging the stuff that’s flying while trying to get the job done. Trying to manage this is a big challenge for a researcher trying to perform high quality work in a place defined by chaos.

The investigators for this study, the CIRC trial, published their study design a while back in Resuscitation.

CIRC Design

A big flaw they’d identified in previous research comparing the machines with people doing CPR was the possibility that those getting compressions hadn’t received good quality CPR, particularly as measured by amount of time actually receiving the vital compressions. So they set about addressing it. Across the 3 participating countries, they put more than 5000 prehospital providers through a standardised 4 hours training program. They then had them undertake exams to prove they were up to scratch. Then each centre had a period where their ability to deliver on the protocol was assessed before they were allowed to recruit. Follow-up assessments of quality and regular re-training were also part of the script. It’s not in here, but in the presentation the good Dr Wik also mentioned that every included patient had the duration of time and depth of CPR measured directly (including by transthoracic impedance).

The result – more than 80% of the time that patients were being treated in either the machine or manual compression group, they were receiving effective compressions. As compressions are vital to success of CPR, this is really important. And it’s around 20% more efficient than any equivalent prehospital study in the area has ever demonstrated. It’s staggering. It’s the sort of result anyone prior would have said was impossible.

I’m actually not going to get into the results (basically equivalent between the two groups, with lots of reasons given). The standout feature was the level of effort required to overcome the challenges of the setting. If we want to build an excellent research project, looking cool in flight suits doesn’t remove the need to be absolutely rigorous in getting the data.

So now we’re building our cricket cages, or examining the door of the Porsche. Before we even get going we know we need to simulate our jobs on ovals and in upturned cars, design our education plans and test our ability to collect the data reliably. It couldn’t be more vital to a good idea to get our script right, to test it out and whittle away to make it astounding. We might not reach perfection, but we should at least aim to make the Norwegian guy jealous. And if anyone feels like chipping in a 1957 Porsche Speedster for the simulations, we will make good use of it.

Wake up!

Confession time. Each way when I go to work, I don’t entirely know what I’m doing. Yes, that’s right, when I’m doing that whole “helping kids sleep through their surgery” thing there’s a big black hole at the centre of my practice. Now, before anyone contacts the Tele so they can place a screeching headline at the top of their website (“BLACK HOLES IN THE OPERATING THEATRE”; “BEST GUESS: DOCTORS TESTING DRUGS ON KIDS”), that’s actually the reality of where we’re up to with anaesthesia.

After more than a decade of training, I am well qualified to assess a patient’s clinical condition, figure out what options are available to keep them comfortable and safe through the operative period and administer a combination of medicines to induce a level of unconsciousness so the patient isn’t aware of what is going on. That in itself feels like magic. Each work day I deliver anaesthesia to patients and it quite literally feels like seeing a miraculous phenomenon take place time after time.

What I’m struggling with is the exact mechanism of how the medicines induce that anaesthetised state. That’s not because it was one of those factoids I learnt for a period of 20 minutes around the exam and promptly let fall on the pavement outside (I refer to those factoids as “statistics”). It’s also not because no one can be bothered looking. People have proposed various mechanisms, such as specific receptors being the target for anaesthetic agents, or that they change the composition of cell membranes, thereby altering how key cells within particular brain pathways work. The problem has been that not all anaesthetic medications interact with the same receptors or pathways, which is disappointing if you’re the type of person who yearns for the certainty of a single unifying theory for any concept up for discussion.

So if you’re a gas geek, this week was particularly exciting. A group combining bright sparks from the University of Michigan and Asan Medical Centre, South Korea have published a paper which brings us a big step closer to knowing how anaesthetic agents produce their magic. It’s big news for anaesthesia, but I sort of think for our broader understanding of consciousness itself.

Anaesthesia has been around for a pretty decent amount of time now. Although there are earlier reports of anaesthetic use, modern inhalational anaesthesia is generally described as originating with the demonstrations of William Thomas Morton (a dentist probably quite happy showing his face in any media format). Having performed a painless tooth extraction on September 30, 1846 he was invited to perform a demonstration in the operating theatre at the Massachusetts General Hospital. This allowed Dr John Collins Warren to painlessly remove a neck tumour on October 16, 1846 after which he famously declared “Gentlemen, this is no humbug”.

Since then, anaesthesia has become a vital component of interventional medicine. While I’m obviously biased, it is one of the most important discoveries in medicine over the last couple of centuries, allowing progress in surgical science, whole new fields of treatment and the injection of a whole bunch of humanity into perioperative care. (I should point out that I am not suggesting that anaesthetics don’t have their side effects or bad bits, but this is the glass half full post.) Of course, anaesthesia is so well accepted as part of the furniture, there are plenty of people who aren’t entirely sure that anaesthetists are medically trained (we are), or assume that we got into it so we could avoid interaction with normal awake humans (mostly untrue) or that we spend most of our time doing crosswords (please, we have tablets now).

Now, to this discovery and a bit of background (stick with me, it won’t be that rough). One of the reasons that previous proposed mechanisms have faltered is that there are agents that work in distinctly different fashions. Many of the agents that produce anaesthesia potentiate the action of a particular neurotransmitter called gabba-aminobutyric acid (GABA). This has always made intuitive sense because, when binding with certain receptors, GABA produces neurones that are less able to get excited. Less excited equals less active equals more sleepy, right?

The problem is that some other agents in use, particularly ketamine, don’t do this at all. Ketamine (yep, Special K) is the classic example of a drug that interacts with N-methyl-D-aspartate (NMDA) receptors. So if you do an electroencephalogram (EEG) to monitor electrical activity in the cortex of the brain, unlike the GABA drugs, ketamine leaves you with a cortex that still looks busy.  Hmmm …

Now, a little about the brain. You probably know that jobs of the brains are associated in particular areas. Well, information flows between these areas. Information travelling from the frontal cortex to other bits of the cortex is sometimes called “feedback” or recurrent processing (at least in the anaesthetic literature). This feedback is thought to mediate conscious experience. Information flow from the posterior to anterior direction is thought to be key in sensory processing.

Now, the same group releasing their work this week previously showed that in a conscious person, the information flowing from the frontal lobe back to the parietal lobe dominates the information heading in the other direction. They also showed that this dominance is decreased by the anaesthetic agents that interact with GABA receptors. What they have now demonstrated is that this information flow is altered in the same way by ketamine. So the cortex might look busy, but the flow of information between the two areas is still disrupted. (I’m hyperventilating a little here, it’s really exciting.)

This story is great for a few reasons. One is that from the point of view of a purist, the application of a different form of analysis (Normalised Symbolic Transfer Entropy) to evaluate this association is interesting all on its own (although I’m not going to pretend all of the details have immediately washed in). It’s also a great example of the long, quiet pursuit for an answer finally coming a little closer to reality.

More broadly though, I quite like the idea that the consciousness of the individual is predicated on the flow of talk from one part of the brain to another, in the same way that our collective understanding of the world is so profoundly dependent on the way information flows from one group to another.

In the meantime, I can stop worrying quite so much about that black hole.