I've been asked to talk about studies of glucose control, and the suggestion is that we have
had the wrong target.
And I think we have had the wrong target.
I have no financial conflicts of interest in this subject.
The original data rapidly accumulated to eight, large scale English language RCTs, and many,
many other RCTs studying intensive insulin therapy in adults.
And the key study -- the progenitor study of all this, the study that drove the interest,
and all of the succeeding enthusiasm -- was a study by the Leuven Group, Dr. Van den Berghe
was the PI, and published in the New England in 2001.
Published in the same issue of The New England Journal as the Rivers, et al. study.
Quite an issue that was.
I would say that there are perhaps several wrong targets.
I would say that the first wrong target is the surfeit of RCTs.
Here we have a very large number of RCTs, and except for the Leuven one, surgical ICU,
essentially in terms of their primary outcome, primary analysis on mortality, they almost
uniformly show that tight glucose control does not impact mortality, and that tight
glucose control causes variable degrees of hypoglycemia.
This all stopped, in the adult world at least, with the NICE-SUGAR study.
And in the NICE-SUGAR study, there were over 6,000 patients in several countries -- an
enormous undertaking -- and mixed ICUs.
So, our last speaker spoke about the importance of treating each patient individually -- it's
a key issue -- but if you're going to recommend a therapy, like aspirin for example, that's
going to be used for everybody, then in those cases you need to have studied it in everybody.
Otherwise you don't have generalizability.
So whilst you lack specificity, and you lack insight, from this study, what you absolutely
gain is generalizability.
Unfortunately the generalizability was that, in general, it causes harm.
Does it cause much harm?
Well, you know, not a whole lot of harm, I suppose, except if you're one of the people
who did badly.
As a population level, the excess mortality was 2.6%.
It's 2.6% of that study population.
People in critical care are a little US focused.
Well, it's a big country.
You know, it's a good starting point.
If you imagine 5 million patients in ICUs in the US, if you imagine 20% of them are
mechanically ventilated in adult ICUs.
Now in other countries -- in Canada, and Australia, and the UK, and Europe -- the percent of ventilated
patients is infinitely higher than that -- more like 85%.
It's hard to get into an ICU in other countries, but the US is very different.
Nonetheless, that means if tight glucose control is truly generalizable to all medical surgical
ICU patients who are ventilated, then the adoption of that practice caused, or would
have caused, excess mortality of about 2.6% among those patients.
How big a number is that?
That's 20% of 5 million, that's 1 million, so 2.6% of 1 million.
I'm very leery of extrapolating with any kind of precision.
We've heard about the 100,000 Lives Saved, and the 5 Million Lives Saved Campaign, and
all those.
When you look at the math behind those, they're: take your mother's age and multiply it by
your father's height, and divide by the height of your dog, or something, and these are random
numbers.
But what you do know is, if the NICE-SUGAR study is true, implementation of tight glucose
control caused, or would have caused, many hundreds of thousands of lives to be lost.
Here's a list of all of the randomized trials, and Griesdale and colleagues published these
medical, surgical, mixed and what not.
And essentially, it's flatly negative.
What were the consequences of the original study?
There were two consequences.
The first was a profusion of randomized trials trying to replicate the Leuven results.
Some people think the more randomized trials, the better.
You know, if you have a good question, and it's worth asking, then it's a good thing
to do.
However, the study was based on very dubious rationale.
The studies were consistently negative.
And the studies-- I'm not sure if I'm going to explode, or something right now -- if somebody
doesn't like me.
But, certainly it's not my phone.
No, it's I don't know.
It doesn't matter, I'll shout above it.
--and there was a consistent signal of hypoglycemia.
And we'll talk about whether this is a good thing or not, in children.
The next consequence was one of guidelines, and we'll talk about them a little later.
I said that the first wrong target, I thought, was multiple, multiple trials trying to replicate
it.
And the second wrong target, was the immediate adoption of guidelines enforcing the practice.
They were parallelling the trials that were seeing whether the practice was good or not.
Neither, in, I think, reasonable people's opinion, were actually valid.
And the trials were mandated by the vast bulk of the agencies involved in guideline and
mandates, such as the JCO, the IHI, Surviving Sepsis Campaign, the American Thoracic Society,
Veterans Administration Cooperative, and you name it.
And all of the underground societies.
And indeed, physicians, and clinicians, and hospitals, were held to a standard of care,
based on the single study from Leuven.
And this is despite study, after study, after study failing to replicate it.
The next target, and all that was very nicely put in, in the revised talk.
But there you go.
See, I saved a lot of bother.
The third wrong target, I think, is nutrition.
While the studies focused on glucose, that was the primary intervention, co-interventions,
proper nutrition, seemed to be, in fact, a whole lot more important.
Is that true?
Look here at total non-protein calories.
The Van den Berghe study was way over 1,600, per 24 hours.
And in the NICE-SUGAR -- it's practiced across Australasia and Canada -- far less than that,
1,200.
What about enteral versus parenteral calories?
On day four in the Van den Berghe study, about 20% of calories were enteral, whereas about
80% of calories that the patients were going to get were enteral in the NICE-SUGAR study.
What about the rate of introduction of nutrition?
In the Van den Berghe study, see here, that on day two, about 75% of the maximum rate
had been achieved, whereas in the NICE-SUGAR study, on day two, about 60% of the maximum
rate had been achieved.
The wrong target number four, the fourth wrong target, I think, is the control group.
The control group is a really important issue.
You can make a study look very good or very bad by having a very good or bad intervention,
or having a control group that simply is very different from the intervention.
And so, independent of how good or bad the control or the intervention is, the study
may well be internally valid.
Well that's a necessity for you to make progress, but the external validity is primarily anchored
to the control group.
If the control group care is kind of like your care, and the control group outcomes
are kind of like your outcomes, and the intervention makes the patients a whole lot better, that's
an intervention that you should take very seriously.
If, on the other hand, the control group interventions or the control group outcomes are nothing
like your basic care, then probably the study is simply not relevant to your patient population.
Because the cardiac surgical group was the prime mover of the first Leuven study, it's
appropriate to look at the control group in that study, and see how do they compare to
the rest of the world.
We go here to the Northeast of England.
That's an underprivileged part of England.
I hope there's nobody here from the Northeast of England.
You probably, or maybe you don't -- well, never mind.
The minister for health at the time said that the reason there was so much coronary disease
in the Northeast of England, was they ate too much fish and chips.
And she might have been right.
It's an underprivileged part of the world.
It's National Health Service, which is very good, but it's not well resourced, and the
rates of endemic disease -- preventable disease -- are high.
So in the Northeast of England, how do cardiac surgical centers perform?
Here we have dots.
Mortality on the y-axis and size of number of patients on the x-axis.
And each little red square represents a hospital.
So here are the worst performers, in an underprivileged part of the world.
The worst performer, here, has a mortality of 3.8%.
The average mortality in the Northeast of England is 1.7%.
The Leuven group, the best outcome, with the intervention intensive insulin therapy, was
2% mortality.
But their control group mortality was 5%.
Dr. Van den Berghe has explained to me that this is unfair because they had very high
euroSCOREs and they were sick.
And indeed, they were very sick.
In Toronto General Hospital, over a five year period, which is a quaternary referral center
like nothing else -- only deals with high risk cases.
Duminda Wijeysundera published a review showing that the five year mortality for all comers
for cardiac surgery was 1.1%.
So, that's the rest of the world.
So, if your mortality and your population mirror the Leuven group, then tight glucose
control might have been good for you.
If they do not, you have no business subjecting your patients to that therapy, and I submit
you do not have much business subjecting your patients to an RCT.
We'll randomize you to something that is completely irrelevant.
The next wrong target, I think, is children.
There are two key studies.
One does not look at tight glucose control per se, but gives very, very important lessons.
That's the "Early Insulin Therapy in Very-Low-Birth-Weight Infants."
This is a study of premature infants who are on a feed and grow regimen.
And, of course, when you try to feed and grow in neonates, they get hyperglycemia.
And it's not associated with good outcomes.
And a sensible study, in my mind, tried to maintain the calorie intake but prevent the
adverse hyperglycemia.
Their metabolism is simply not mature enough.
Dr. Troster will explain that to us later.
And what that showed, here, was that they didn't exactly achieve severe hypoglycemia,
they just managed to lower the level modestly.
And that, unfortunately, was associated with adversity.
The conclusions in the abstract were that early insulin therapy offers little clinical
benefit and may increase hypoglycemia.
What they didn't add in the abstract, which is all anybody ever reads, is that it also
doubled mortality.
In one way, it's kind of a snicker; in another way, it's a really serious thing.
You may think, well, I can manage hypoglycemia, but I can't manage dead kids.
You know, that's a big, big deal.
The second is the study by Dirk Vlasselaers and Dr. Van den Berghe from Leuven.
It's an important study, published in The Lancet.
The reason, I believe, that children are a bad target for studies trying to replicate
the Leuven one study, are as follows: the mortality in pediatric ICUs is far lower than
it is in adults.
So no matter what, even if you've got a really good therapy, it's going to be so hard to
show it.
The second reason is, you have to wonder, what would be the mechanism of benefit.
It could only benefit mortality if the mode of death was one that would be plausibly interrupted
by glucose control.
If a truck runs over your head, and you're brought in brain dead, no amount of glucose
control is going to save that child.
If the child has some developmental problem, and is palliated, no amount of glucose control
is going to protect that child.
So, those are reasons why, unlike in the adult population, where you may think intercurrent
sepsis, et cetera, could've caused excess death, could be ameliorated with tight glucose
control.
Here, we had the worrisome instance of hypoglycemia, which was 25% for what they call "modest,"
and 5% of the kids had severe hypoglycemia.
They followed up that study with a paper in JAMA, and it was editorialized by Rob Tasker.
They suggested, in fact, that there was no worsening in neurological outcome.
And it is true, they did not detect a worsening in neurologic outcome.
Dr. Van den Berghe wrote a letter to The New England Journal criticizing an editorial I
wrote on the topic, and suggesting that, in fact, her study had proven that this was safe.
The JAMA study just got by the reviewers, I guess.
It proved nothing of the sort.
The randomization in that study was clearly not equal.
The adjusted and the unadjusted rates were very, very different -- a sure sign of confounders.
And so we responded, and that's that.
Nobody with any experience of pediatric intensive care would reasonably ignore hypoglycemia.
And if any group is good at treating it effectively, it would be the Leuven group.
You could not hope to manage their skill, because this is one thing they do very well.
Well, you can't expect -- they manage, I believe this, I believe they control glucose extremely
well.
They're extremely practiced.
You cannot expect nursing units in other parts of the world, where they maybe have two patients
to one nurse, quite unlike Leuven, to replicate that degree of intensity of care.
The second reason this is a problematic paper is it's simply not plausible.
You ask: is it relevant?
You look at the causes of death in your PICU, and you say, are they plausibly prevented
by glucose control?
And what you have here is what's called neurological complications and deterioration, or intractable
ARDS, or terminal weaning failure.
I'm sorry, but we review our deaths very, very carefully, and we could not plausibly
relate deaths in our ICU to inadequate glucose control.
In summary, I'd say there is an uncertain target, which should be how we should practice.
And I think what we get from that, at least in the adult's contexts -- mirror this in
the children, maybe -- is a byproduct -- not an intended product, but a byproduct -- of
the NICE-SUGAR study because the control group in that study had excellent outcomes.
They had gradual, and enteral, and low sugar-containing feeds.
But this is, in fact, modest control, and maybe that's recommended.
It's not zero control; it's not ignoring glucose.
We suggest taking care with glucose sampling, if you're going to do it, recognizing accuracies
of your technique, and using ranges that ensure that you are not aiming for very tight control.
So, I would suggest that there are several targets that were missed in the whole glucose
control experiment.
Number one, the effect size was implausible.
Number two, far too many randomized trials tried to reproduce it, and I would say, with
a very dubious basis, particularly given the irrelevancy of the control group in the first
paper.
The second issue, I think, is the guidelines that were targeted.
What you'll notice when you go on the IHI website and the JCO website, is that there
is no trace of those old guidelines.
At least with Surviving Sepsis, they are published in print.
So at least there's an issue of integrity there.
But to hold people accountable to guidelines, that then disappear without a trace, that's
dodgy.
I think children are a very poor target for this.
And that's not to say that studies, such as Dr. Nadkarni's intraoperative protection for
specific indications, but for death prevention from all causes, it makes no sense in children.
Thank you.