Tuesday, November 21, 2017

Trying to navigate the MDI and adolescence maze (and failing…)

Since Max does not want to use a pump, we are on Multiple Daily Injections. On the quick acting insulin side, we have always been using Novorapid pens. We are fairly happy with Novo, assuming it is pre-injected to match the carb absorption curve as much as possible. On the slow acting side, we switched from Lantus to Levemir because we couldn’t avoid a systematic low trend when Lantus picked up. Then, for a few months, Max expressed the desire to switch back to Lantus (I have absolutely no idea why he wanted to do that, but since it is HIS diabetes, he gets to choose…). After a few months, we switched back to Levemir, as the “pickup lows” resurfaced. Those aren’t completely avoided with Levemir, but they are less severe.
As far as the schema and doses are concerned, we have two peculiarities:
  • we use a single evening dose of Levemir in the evening (around 10 units) in contrast with the standard two doses 12 hours apart schema.
  • we tend to have low total insulin requirements, in the 0.25 to 0.50 U per day/kg. At times, after sports, Max can actually skip fast acting doses and have a meal. We did get a few periods (months) where a very low (<0.25U/kg.day) TDD was used. Max had an ACTH stimulation test to exclude Addison’s disease which turned out to be normal (along with insulin dosing).
As far as dosing is concerned, Max typically guesstimates his doses (teens…) without severe consequences: only one trip to the hospital for a post-sport hypo that scared the school (a slight over-reaction, but better safe than sorry), zero glucagon injection required, and 4 and 1/2 year of sub 6 HbA1c.

I you are beginning to think we have an easy ride, you are wrong…

“What hath night to do with sleep?”

(John Milton, Paradise Lost)

The biggest problem we have is that there is a huge chasm between the basal insulin theory and the practice, at least in teens. Regardless of the care we put into the injections, variability is kind. Our site rotation plan is quite decent. So is Max’s injection technique. Storage is what it should be. Doses are adapted depending on the exercise of the day. Trends are corrected the next day, etc…

Still, too often, the results seem to be a lottery.

One of the questions on my mind was to double check if we could correlate poor outcomes with injection sites. (Well, to be honest, there are many questions on my mind but I will focus on that one in this post).

Site rotation


We use the standard “front of leg” site for basal insulin. We usually plan a site sequence for the week. Unless a mistake is made, we do not use sites two days in a row and, in the worst case scenario, sites are re-used after a week. Now and then, we reset the sites rotation we use. I am aware that some app can help, but in most cases, apps are a burden and we tend to stay away from them. Max two legs are divided in three height zones (upper, middle, lower) and three sides (internal, middle and external) giving us a total of 18 injection sites to rotate through.

Outcome classification and scoring


Outcome are defined – subjectively – by examination of CGM traces as follows.

STB is a stable night, regardless of the level (we of course would correct stable low or stable high levels). This is the usual archetype of a “good basal rate”
TL and TH are nights with mild trends that you would typically associate with a slightly excessive or insufficient basal rate.

ER, MR, LR are the rises. Early in the night (before 24:00), in the middle of the night (between 00:00 and 3:00) or late in the night (between 3:00 and 6:30). These rises are characterized by a sudden relatively quick increase, steeper than trends but not as steep as meals, they are typically at the rate of roughly 30 mg/dL.hour. Obviously, as soon as the increase is confirmed (example, starts at 90 mg/dL is at 150 mg/dL after two hours) corrective measures are taken. (for example: a 30 mg/dL trend would be corrected by x units to bring the 150 mg/dL back to around 100 mg/dL plus x units to compensate the trend for the next 3 hours). That basic algorithm has never failed us on the low side (no hypo caused) but is sometimes insufficient and is typically reassessed  after 2.5 to 3 hours. Late rises are a pain, especially if they are combined with a dawn phenomenon. As a caregiver, you either have to go to sleep extremely late or wake up extremely early. Setting up CGM alarms is a no go. They aren’t flexible enough to help. 150 md/dL at 6 AM is OK, we aren’t going to be able to correct it anyway, but it would be nice to have one at 1AM in the same conditions and rising.

HYP are the severe low trends which require multiple and frequent corrections. They typically rear their ugly heads after intense sport sessions. We do of course correct those actively. While we do reduce basal in obvious situations and adapt the evening meals after such sport sessions, we never totally got rid of it.

That classification is therefore somewhat subjective and can’t be directly derived by nightly averages.

DAWN the dawn phenomenon is treated separately. It shows up in random clusters. The dawn phenomenon’s classification is again somewhat subjective. That being said, it is quite obvious when it shows up, kicking a LR into high gear above 300 mg/dL, pushing a TL situation into a TH one, etc…

Scoring is even more arbitrary (even though it is normalized for more sophisticated analysis). STB is worth 10 points, that is the ideal situation. Trends are given 6 points, they are extremely easy to assess. Early Rises are not that bad, easy to correct at a decent hour, they are worth 5 points, Middle of the night rises are still manageable and worth 4 points. Late rises are basically uncorrectable: you would have to disrupt the kid’s sleep way too early for a correction, and you might be ending up with stacking issues at breakfast. They only get 3 points. Hypo is the worst case scenario and is worth a single point. ND stands for the few nights the Dexcom wasn’t operational (we cover with the Libre) and are given a “neutral” 6 score.
def outcometoscore(outcome):
    if outcome == 'STB':
        return 10
    if outcome == 'TL':
        return 6
    if outcome == 'MR':
        return 4
    if outcome == 'ER':
        return 5
    if outcome == 'LR':
        return 3
    if outcome == 'TH':
        return 6
    if outcome == 'HYP':
        return 1
    if outcome == 'ND':
        return 6

Results


Here  is a visualization of our actual rotation (approx 300 shots) – the diameter of each circle proportional to the number of shots (ok, the area would be better, but the differences wouldn’t be as visible)

image
Here is the numerical view
image
Comment: the human mind is not very good at generating truly random series even if it intends to. Remember that there is always a week before a site is reused though.

We favor the lower zones, possibly because they are easier to reach.
image

our leg distribution is quite good
image
So is our side randomization
image
Now, let’s look at outcomes
image
As you can see, we have less than a third stable nights, quite a few “trending low” nights (easy to fix with a few dextrose tablets when the trend is established), about 40% of sudden unexplained increases and a relatively low number of severe hypos (more about them later). Regardless of what you know, of how careful you are, the variability of nights is a pain.
image
We observe a fair number of dawn phenomenons, in around 25% of the cases.

Outcomes


Is any site really bad?
image
It seems there are some differences indeed. However, given the arbitrary scoring system, the small sample size for some sites and confounding factors (more below), a random distribution can’t be excluded.

image

Height doesn’t seem to be much of a factor either. The lower part of the leg seems to lead to very slightly better outcomes, but that is only, strictly speaking, statistically borderline significant.
image
Legs are equivalent. That’s a certainty.
image
The external side of the leg seems to lead to better outcomes (which are heavily weighed towards stable nights).
Another interesting thing to look at is the average score per week day. Saturday is clearly the worst day and that can be explained by the fact that it is often Max’s most intensive tennis day (2.5 hours) where delayed hypos are more frequent. Wednesday is also a “sport day”, with PE in the morning and tennis in the afternoon. That Saturday turns out to also be a significant confounding factor as far as the injection site is concerned: given our weekly rotation basis, the same site may end up being used frequently on Saturdays…
image

Conclusions


The impact of the exact injection site is limited in the absence of lipodystrophy.
A good site rotation prevents the appearance of lipodystrophies.
Non computer generated site rotation sequences are not optimal.
That type of basic analysis is interesting, but not tremendously helpful in the absences of lipodystrophies. I suspect that they would however be revealed by careful site tracking.
Other approaches yield slightly more interesting results, at the risk of non statistical significance. Some more informed approaches are quite interesting (post sport night sequences). We may get to that in another blog post.

Even with the best effort, in patients who have been able to maintain sub six HbA1c values for 4 1/2 year, who benefit from a favorable environment (dual CGM, reasonably informed dad on duty) T1D teen nights are highly variable.

What? no dosing info?


You may be surprised by the lack of dosing information/analysis. In practice, insulin sensitivity varies tremendously from one individual to an other. We dose “as best as we can”, following all the standard guidelines. The point of this post was simply to look at the possible impact of sites, assess our site rotation.

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