You operate on appendicitis, right? Right?!

For the video version of this post, click here.

If Grey’s Anatomy has taught us anything, it’s that you have to operate on appendicitis. This fact is imbued in the cultural zeitgeist - it’s the first book of the Madeline series for crying out loud. But paradigms, even one as inertial as this one, can shift.

Appearing in the Journal of the American Medical Association, a clinical trial attempted to show that, for appendicitis, antibiotic treatment alone may be no worse than a surgical approach.

Finnish researchers, led by Paulina Salminen, took 530 individuals with uncomplicated appendicitis (no perforation or appendicolith, basically), and randomized them to go to the operating room, or to get antibiotics instead: 3 doses of ertapenem (a broad-spectrum, IV antibiotic) followed by a week of oral levofloxacin and flagyl.  After about a year of follow-up, the big question was how many people in the antibiotic group would have had to undergo surgery.

Of the 257 patients in the antibiotic group, 15 got operated on during the initial hospital stay. Another 40 would be operated on within the following year, a total of roughly 27% of the group.  This missed the pre-specified non-inferiority target, but there are still some interesting numbers to look at.

First of all, let’s consider why there was a surgical group at all. The only reason, really, is to look at the complication rate so we can see what antibiotics might help us avoid.  Of the 273 people in the surgical group, 20% had complications, about half of which were surgical site infections and the remainder were due to pain and abdominal complications. Surgery has risk - and avoiding those risks, even in just 73% of cases, might be worthwhile.

But major caveat here: Almost all of these appendectomies were performed using an open technique, not laparoscopically. This is sort of crazy.  Laparoscopic appendectomies lead to fewer infections, fewer abdominal complications, and a shorter length of stay. In speaking with some surgeons, I was told that the only reason they’d consider an open technique is for cases of complicated appendicitis, cases which were specifically excluded from this trial.

The authors write that they encouraged open appendectomies since resource-poor areas of the world might not have laparoscopic equipment, but this really ends up stacking the deck against surgery. If I were given the choice of a quick laparoscopic appendectomy with guaranteed results versus a 25% recurrence rate with antibiotics, I might take the surgery.  But if my only choice was open surgery - with a risk of adhesions, obstruction, infection - well, antibiotics might just make the cut.

Heroes wanted: Will cardiac-arrest alerts come to your town?

For the video version of this post, click here.

If you suffer an out-of-hospital cardiac arrest, your chance of surviving is only around 10%. But you can improve those odds dramatically if a bystander initiates CPR before EMS arrives.  Boosting the rates of bystander-initiated CPR, then, has become a major public health focus. But, typically, the means to increase the rate have been simple: train more people. While laudable, training can only reach a small fraction of the community, and the chance that someone in your immediate vicinity has been adequately trained remains small.

But what if we could expand your immediate vicinity?  What if every CPR-trained person within, say, half-a-kilometer, got a text message when an individual may have suffered a cardiac arrest.

This idea, which, I’m just gonna say, is totally awesome, is the subject of a paper appearing in the New England Journal of Medicine. Here are the details:

Swedish researchers, led by Leif Svennson, created a system leveraging the power of our modern mobile communications infrastructure.  For about a year and a half, in Stockholm, when EMS was called for a patient with suspected cardiac arrest, an electronic system would be activated that A) identified where the patient was, and B) identified if one of around 6000 volunteers were within 0.5km.

Major kudos to the research team for making this a randomized trial. Based on a computer-based coin flip, the nearby-provider would either be alerted or not. You can imagine that there would have been some push-back about that; the system knew there was a trained provider nearby, but, in half the cases, would do absolutely nothing.

But I think this was exactly the right thing to do. These types of interventions, which seem to be all upside, can often have unforeseen consequences.  They need to be rigorously studied.

As it turns out, this idea worked. The rate of bystander-initiated CPR was 62% in the intervention group and only 48% in the control group, a dramatic (and statistically significant) difference.  Now, the alerts didn’t appear to increase survival, but the study was under-powered for that outcome. The pragmatic researcher would argue that a much larger trial is needed.

But I don’t have to be pragmatic - this is opinion-based commentary. These are dramatic results that may save lives. I think we can all learn from this system, and hopefully build out these types of targeted response systems more broadly.

I mean, after all, our cell phones are tracking our every move anyway.  Might as well get some benefit independent of targeted advertisements and government surveillance.

Antidepressants During Pregnancy and a Rare, Fatal Disease in Newborns

For the video version of this post, click here.

There’s a reason why so few medications are recommended during pregnancy, and for the most part it’s not because we have evidence that they cause fetal harm. No, the reason so few drugs are recommended in pregnancy is because they’ve never been tested in pregnant women.  With the exception of a few medications explicitly designed for pregnancy, pregnant women are almost universally excluded from clinical trials.

So to determine if a drug may be harmful in pregnancy, we have to use observational data, and that means adjustment.  This week, we can use a study appearing in the Journal of the American Medical Association as a perfect example.

Do anti-depressants, when used in pregnancy, increase the risk of persistent pulmonary hypertension of the newborn?  PPHN is a very rare, but highly morbid condition whereby the fetal circulation persists after birth, leading to hypoxia, respiratory failure, and in about 10% of cases, death.

To determine if anti-depressants increase the risk of PPHN, a group of Harvard researchers used data from the Medicaid eXtract database, comprising almost 4 million pregnant women. Of those 4 million, about 130,000 had filled a prescription for an anti-depressant towards the end of pregnancy, mostly SSRIs. The rate of PPHN was 20 out of 10,000 births among those not taking anti-depressants, and 30 out of 10,000 births among those who did.  Case closed?

Well, no. These women weren’t randomized to take anti-depressants, they took them for a reason, and lots of factors play into this: depression, obviously, but also personal beliefs, access to care, and any number of other confounders.

Enter adjustment. The authors worked very hard to identify a slew of confounders, and after accounting for them, the relationship between anti-depressants and PPHN went away. So it would seem that women who are more prone to take anti-depressants are more prone to have a child with PPHN, but the medications are not causal.

Unless...there was over-adjustment.  Over-adjustment occurs when you statistically account for something that lies on the causal pathway between the exposure and outcome of interest.  As an example, what if anti-depressants increase the risk of premature birth, which increases the risk of PPHN.  Adjusting for prematurity would make it look like the medications were safe, when in fact they weren’t.

It can be hard to tease out.  But there’s a really important fact that we shouldn’t forget here. All medications have risks, and all medications have benefits. Depression in a mother is a much, much greater risk to a newborn than PPHN.

Personally, I think the signal of harm is small enough to essentially be insignificant. For women with depression, these medications may, in fact, dramatically benefit both mother and baby.

The Risk of Venous Clots Differ Depending on Which Oral Contraceptive You Take

 

For the video version of this post, click here.

At any given time, there are around 11 million women in the US who are actively taking combined oral contraceptive pills. The first case-report describing a blood-clot in a woman taking the pill was published in 1961, and large epidemiologic studies have since confirmed that the pill increases clot risk, particularly in those who smoke or are above age 35.

But different formulations of oral contraceptives may affect clot risk differently. And here’s where the data gets more interesting. Progrestin-only pills don’t seem to increase clot risk very much, but combined estrogen / progestin pills do. So estrogen seems to be the culprit. Strangely, though, the clot risk seems to differ depending on which progesterone analogue is mixed with the estrogen.

Trying to quantify these risks is really hard.  Many women will use many formulations  over their lifetime, and may go on and off the pill sporadically.

So to study this, you need a really good database. Ideally, an electronic system that is tracking every prescription women get, and all the relevant outcomes. A study appearing in the British Medical Journal uses just that - two large, primary care databases to track the link between various pill formulations and venous thromboembolism.

This was a case-control study.  Identify the cases of VTE, match to controls who didn’t have VTE, and examine how the risk factors differ.

But the devil is in the details. The best way to mess up a case control study is to choose the wrong controls.  The strangest quirk of the BMJ study is that the controls had some different inclusion criteria than the cases.  Potential cases, identified at the time of VTE, were excluded if they had received anticoagulant therapy in the past 42 days.  The controls were excluded if they had EVER received anticoagulant therapy.  This choice would lead to higher-risk people being in the case group, and that could bias the final results.

What the final results showed is that more modern formulations of the pill, so-called 3rd and 4th generation OCPs, had higher risk of VTE than older formulations. Being on one of the older pills increased the risk of VTE by about 2.5 times.  Being on a newer pill upped that risk to around 4 - 5 fold.

Is this effect real? Maybe. It is possible that docs who prescribe newer generation OCPs are more vigilant about VTE symptoms, leading to increased diagnosis.  But regardless, it bears noting that the absolute risk here remains very small. Out of 10,000 women on an older generation pill, 7 will be diagnosed with a VTE compared to 14 on a newer generation pill.

A reasonable strategy may be to prescribe 2nd generation OCPs to women who are concerned about these risks.  Of course, for women who smoke or have significant VTE risk factors, another method of contraception may be easier to swallow.

Is a Firm Handshake the New Fountain of Youth?

 

For the video version of this article, click here.

Normally, in 150 seconds, I give a synopsis of a breaking study – something that just hit the news.  Today, we’re taking a different angle, and tackling a study that has had time to breathe for a while.

The Prospective Urban Rural Epidemiology, or “PURE” study, published in the Lancet reports on the association between grip strength and a variety of bad outcomes ranging from diabetes to cardiovascular disease, to death.

It’s a big study, involving nearly 150,000 people across 17 countries. The headline-grabbing finding was an association between weaker grip strength and subsequent all-cause mortality.  The take-home, for every 5 kg less grip strength you have, there’s a 16% increased risk of death.

But once the study moved from the peer-reviewed and venerable pages of The Lancet into the press, things got a bit messy. So I want to apply some much-needed context.

Let’s get one thing out of the way first.  Grip strength is NOT the same as handshake strength.  This is a grip strength dynamometer, used to precisely measure the maximum force the hand can generate, which is a product of a variety of factors including muscle mass and the length of the forearm:

A handshake is a social construct, and has nothing to do with anything.  This was not a study about forceful handshakes.

Second – this study describes an association.  It is very probable that a strong grip says something about your overall health.  It is NOT probable that grip strength is directly tied to outcomes.  The article in no way implies that hand strengthening should be a public health intervention.

But the real issue here is applicability.  With a study of almost 150,000 people, it’s not hard to find significant associations.  The clinical question is: Can measuring grip strength help me risk stratify patients?  Put another way, if I had two random patients in front of me, how often would the person with more grip strength live longer? If the answer is 50%, that’s chance, and the test is useless. If the stronger person always lives longer, it’s a perfect test and we should be doing it on everyone all the time.  The truth, of course, is somewhere in the middle.

But here’s the letdown. The authors don’t report their full, multivariable model, so we don’t know how well grip strength categorizes risk, only that there is an association there. Based on the authors’ comparison with blood pressure as a risk factor, I suspect that accounting for grip strength would address some of the randomness in figuring out who dies when, but only a small amount, probably around 2-5%.

So what’s impressive about this study isn’t the results.  That stronger people live longer is not particularly exciting.  What’s impressive is the logistics.  150,000 people, 17 countries, prospectively collected outcomes. This is good, if not revolutionary work. So despite the flaws of the reporting in the press, we can still hand it to the researchers.

Will EVOO Really Keep Dementia at Bay? Randomized Trial Results Just In.

For the video version of this post, click here.

We’ve talked a lot about diet studies here on 150 Seconds. I like to complain about them because most are observational.  People who eat healthy diets are healthier. Randomized trials are better, but unless you’re preparing every meal for the participant, you can never be 100% sure what they are getting.

Today we’re talking about a randomized diet trial that takes a somewhat unique approach to the issue.  In fact, I think the methodology in this study is more interesting than the results. In an article appearing in JAMA internal medicine, a group of Spanish researchers report on the relationship between a Mediterranean style diet and cognition in a group of around 450 individuals at higher risk of cardiovascular disease.

Mediterranean diets are characterized by fresh fruits and vegetables, fish, nuts, and olive oil. Micronutrient-wise, we’re basically talking about higher amounts of mono- and polyunsaturated fats, which, in the lab at least, seem to have antioxidant and anti-inflammatory properties.  In terms of cognitive decline, which may be partly a vascular process, tamping down these things could be beneficial.

There were 3 groups in the study.  A control “low-fat” diet group, and two Mediterranean diet groups: 1 supplemented with nuts, one with olive oil.  Here’s where it got interesting. The participants cooked all their own food - basically, the intervention was just some education and a weekly food “gift” of either 1 liter of olive oil or 1 cup of nuts.

Despite the lack of rigorous dietary control, the intervention groups did change their eating habits. Caloric intake didn’t change much, but carbohydrate intake went down and polyunsaturated fat intake went up in both mediterranean diet groups compared to the controls.

As for the primary results?  I wouldn't call them sizzling. Cognitive function declined a bit more in the control group than either of the Mediterranean diet groups, but changes were mild overall.

The trial itself had a few blemishes.  One is that, at first, the control group wasn’t treated very similarly to the intervention groups.  Controls had fewer visits, and didn’t get weekly “gifts” from the study.  This was remedied about halfway through the trial, but some damage had probably been done and it’s conceivable that controls who didn’t feel as invested in the study wouldn’t have performed as well on cognitive testing.

The second issue is a somewhat high dropout rate, around 25%, that was differential among the groups.  Neither of these are killer, but when you combine a couple of flaws like this with relatively mild results overall, you’re left wondering what to take home from this?

For me, it’s not the primary results. I’m just impressed that the simple act of giving people healthy food, giving people olive oil, changed their eating habits. That’s pretty slick if you ask me.

The Obesity Paradox is Neither Obesity nor a Paradox.... Discuss.

 

Want to go right to the video version?  Click here.

It’s called “the obesity paradox”.  Basically, it’s the observation that in many chronic disease states, people who are heavier seem to live longer than those who are lighter.

This is a finding that is ripe for jumping to conclusions, and headlines often imply that years of your physician telling you to lose a little weight can now be safely ignored.

A large study in the Annals of Internal Medicine examines the relationship between BMI and overall mortality in a population of type 2 diabetics with the title “The Obesity Paradox in Type 2 Diabetes Mellitus”.

This terminology, in my opinion, is a bit of a disservice to some of the great paradoxes like dividing by 0 and “this sentence is a lie”. Here’s the deal:

This was a large prospective, English cohort of around 10,000 patients.  The authors assigned the participants into the classic BMI categories at their first visit (underweight, normal weight, overweight, and obese) and then followed them for about 10 years.  It turned out that survival was lowest in the underweight group, and kept right on improving as weight increased.

Now, after adjustment for the things you’d want to adjust for (age, sex, smoking, chronic diseases, duration of diabetes, etc), it turned out that, compared to those of normal weight, the overweight people lived longer, the underweight people lived shorter.  The obese people turned out to have similar adjusted rates as the normal weight people.

There are two things going on here that may explain these results, and neither is a paradox.

The first has to do with the one-time measurement of weight. Put simply, it’s very likely that change in weight is more important than what the weight actually is. Imagine a train hurtling down the tracks towards a ravine – we might care just as much about the speed of travel as its position.

Has the individual been gaining weight?  Losing weight?  At what rate?  These factors may tell us much more about the health of the individual than what the weight actually is.

The second issue is that type 2 diabetes is a disease that is caused by overweight and obesity.  An otherwise healthy diabetic will be an overweight diabetic. That’s simply who gets diabetes. In the general population, it’s relatively clear that overweight and obesity are associated with higher mortality.  In diabetics, we’d expect that curve to shift to the right.  In other words, a survival benefit of being overweight is exactly what we’d expect to see in a disease that is caused by being overweight.  No paradox, and importantly, NO suggestion that gaining weight would benefit the type 2 diabetic with a normal BMI. But of course, if you want to avoid paradoxes, you’ll be fine if you don’t go crossing your own timestream.

Reducing C-sections, by any means necessary.

Canadian researchers performed a large, cluster-randomized trial to try to reduce C-section rates in Quebec. The intervention was multi-faceted, ranging from education to auditing with physician feedback.  A great example of a trial with a statistically significant, yet very discouraging results.  The original article appears in the NEJM.

My take in 150 Seconds can be found here.

Possible link between maternal diabetes and autism spectrum disorders

An article appearing online now in JAMA used the huge Kaiser-Permanente database to determine that maternal diabetes increases the risk of autism spectrum disorders by almost a factor of 2.  My take below, in 150 seconds.

Analysis in 150 Seconds: Maternal Diabetes and Autism | Medpage Today.

Arts, Crafts, and Dementia in the Elderly - Is timing everything?

 

This week in 150Seconds, I take on a recent study in the journal of Neurology that examined the effects of Arts, Crafts, and Computer use on the development of mild cognitive impairment in the elderly.  It's a nice study, but an error in the interpretation of subgroup analyses is one I see frequently, and decided to discuss in the following video:

MedPage Today: 150 Seconds - MCI