Whenever anyone reads this, there is a good chance I’ll be drinking coffee. Either that or I’ll be just after a coffee. Or thinking about my next coffee. I start the day with it. I have it way after bedtime. Every now and then I even stop to enjoy videos of naked filters in action (mmm … naked filter). And although it’s mostly about the taste, I wouldn’t pretend I don’t get the familiar caffeine buzz.
There is one thing that I sometimes think about when I’m having my coffee that might reflect my niche professional interests though. Coffee makes me thinks about kids. Or more specifically that we need to experiment on kids more.
I’m not suggesting an experiment comparing to other known stimulants like red cordial. It’s more that marvellous little caffeine molecules remind me that kids are unique little creatures and that extends to the medicines we use. Now doctors are paid to know stuff like that. One of the frustrations when trying to deploy clever drugs in kids though is that sometimes there isn’t as much information out there on using particular agents in paediatric patients. Those patients are effectively a niche group and far less gets invested in studying new products on them.
However, kids aren’t always just little adults. The way we use caffeine is about the best example I can give. That’s because just this week, I gave a baby who would fit in your cupped hands about 10 shots of coffee. And it was deliberate.
Breathing is Mostly Good For You
To make sense of this you need to start picturing a really small kid in your head. Now make them a little smaller. This newborn actually came a little earlier than intended and they’ve just made it to 3 kg. They’re entire circulating blood volume is about the same size as a can of soft drink.
Newborns, particularly the premature ones, have a lot of things to get right. One of those is breathing. They have an annoying habit of occasionally forgetting that breathing is a thing that you are required to do and they just stop. It can be of variable length and generally their slightly immature regulation systems eventually kick in and they get going again. These apnoeas are more common in premature babies. They are also made more common by the agents we use in anaesthesia, which is why this is of interest to me.
One of the accepted treatments to prevent this is to give caffeine. Caffeine is in a family of drugs called the methylxanthines. These block an inhibitory action driven by adenosine binding to receptors in locations including the respiratory centre. So giving caffeine fires up the drive to breathe.
The surprise is in the dose we use. Depending on what you read, your average cup of coffee handed over by a surly barista has about 70-80 mg of caffeine. If you’re the mythical 70 kg physiological male model, that’s about 1 mg/kg. When that baby comes to their operation, we infuse 20 mg/kg of caffeine citrate into their vein (which works out as about 10 mg/kg in the base form). It really is like pouring 10 espressos down that little person’s throat. No wonder they are a little more switched on to this whole breathing adventure. I’m sure they can practically see unicorns by the end of it.
There’s evidence to back this approach with caffeine up. That’s probably just as well, because you wouldn’t necessarily guess at that dose if you were trying to make do without good research in kids. In this case, someone saw a particular problem in kids and then made what was an obvious link to that little premature baby wearing organic-farmed clothes and throwing a short black past a hipster beard. And it works.
Unfortunately, kids often suffer from our lack of experimentation on them. Particularly when it comes to treatments that bear some relationship to adult conditions. Which brings us to the pancreas. In cows.
Dodgy Research to Make you Bleed
There are lots of drugs we use that are derived from unexpected sources. During a cardiac procedure, it would be quite common to use things derived from both cow’s lungs and salmon sperm. There’s another drug that was pretty popular early in my training too. It’s called aprotinin and was first derived from the pancreas of bovine heroes.
When you place a patient on cardiac bypass (aka ‘the heart-lung machine’) a bunch of changes happen that lead to increased potential for bleeding later on. One way to try to decrease this bleeding is to use a particular class of drugs called anti-fibrinolytics. A fibrinolytic would be something that dissolves blood clot and too much of this can be an issue after bypass. So you can see why the “anti-” bit has some advantages.
For a long time aprotinin was a popular choice to send on this mission, partly because it also seems to have some anti-inflammatory actions. Then around 2006 research got released suggesting that adult patients getting really high doses of this stuff might have more issues with their kidneys not working after the operation. The panic that ensued wasn’t quite in the “this global traveller has a fever they must have Ebola” league, but it was serious enough that spots all over the world took aprotinin off the books.
Further follow-up studies seemed initially to support this idea, particularly in a study known as the BART Study (a high water mark in edited acronyms, seeing as that stands for Blood Conservation Using Antifibrinolytics in a Randomized Trial or BCUART). This randomised trial was stopped early because of concerns the aprotinin was associated with more deaths. Then people looked a bit closer and flaws became obvious. There were unexplained exclusions, large numbers of reclassifications, blood thinning agents were used inconsistently and monitoring of blood clotting wasn’t quite right. It all ended up being non-reproducible. So 5 years later, aprotinin started returning (there’s a good summary here) because the benefits of less bleeding are felt to outweigh any other weakly suggested risks. At least it self-corrected I guess.
Won’t someone think of the children?
In the meantime, there was much less evidence available for whether aprotinin was an issue in kids which is a pity because small kids have plenty of reasons to be more at risk from bleeding when they have one of these bypass operations. Aprotinin was generally used mostly for those having more complex operations but it was in use. Except of course that suddenly it got taken away.
What evidence was available suggested that it didn’t cause kidney issues, although longer, harder operations did. There was some studies suggesting that it did the best job reducing bleeding and the need to give blood back (which would be a good feature, because transfusions have significant long-term issues). There were some that said it wasn’t helpful. There were some that didn’t get enough patients to say much, and at least some of the time this was because research halted once fears in adults were raised. Kids aren’t always little adults though.
This is the crux of the problem. Those working in paediatric areas are too often left to try and figure out what to make of adult research in the context of that kid with a blood volume filling a soft drink can. Then when we respond to adult safety research, we may deny kids a treatment that could really make a difference in this unique patient group.
I’m not saying being cautious isn’t the best response when fears are raised. It’s just the only real answer is to make a point of doing more research in kids, with all the challenges and fears that step brings. Otherwise, using treatments on the basis of mostly adult information becomes a bit like an experiment itself.
So we need more research in kids. It’s something to think about over your next coffee. Or I guess you could leap in with the red cordial comparison.
If you’d like to spend more time reading about aprotinin in little kids having heart surgery, here’s a selection of the papers I looked at:
Székeley A, Sápi E, Breuer T, et al. Aprotinin and renal dysfunction after pediatric cardiac surgery. Pediatr Anesth. 2008;18:151-9.
Williams GD, Ramamoorthy C, Pentcheva K et al. A randomised, controlled trial of aprotinin in neonates undergoing open-heart surgery. Pediatr Anesth. 2008;18:812-9.
Bojan M, Boulat C, Peperstraete H and Pouard P. High-dose aprotinin, blood product transfusions, and short-term outcome in neonates and infants: a pediatric cardiac surgery center experience. Pediatr Anesth 2012;22:818-25.
Fan Y, Lin R, Yang L et al. Retrospective cohort analysis of a single dose of aprotinin use in children undergoing cardiac surgery: a single-center experience. Pediatr Anesth 2013;23:242-9.