The Land of Irrelevance #3: The ASTER study

Acetaminophen for sepsis-related cardiovascular or respiratory failure? Things are going wild in America's mainstream research

“Ground control to ASTER study group…”

David Bowie would call, worried about space travelers who lost communication with Earth. Bowie’s genius inspired the third edition of The Land of Irrelevance, featuring a study with a starship-like name and an extraterrestrially odd hypothesis.

Space Oddity is the song that immediately reached my mind after reading the study’s title and abstract.¹ Another great opening to this post would be:

“These are the voyages of the starship Enterprise in its five-year mission… to boldly go where no man has gone before”

Well, they did. No one else on this planet spent millions to test whether acetaminophen improves organ dysfunction in septic patients with ventilatory or cardiovascular failure. And they were bold, undoubtedly. But I think Captain James T. Kirk’s crew is not a fair metaphor. I will stay with the “Lost in Space” Robinsons.

I was irresistibly drawn to pop culture “space” citations because ASTER immediately rang as an intentional reference to the word ASTEROID, and to make everything funnier, there was a failed Brazilian space mission named ASTER. It’s a multi-layered joke.

Just like the DEFENDER trial, which is also the name of an Atari spaceship videogame,² ASTER is lost in space because it is blind to the marginal utility of interventions. It is a fresh display of how sepsis undefinable definition leads investigators astray.

Let's break it down and see what's happening.

Title: Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis - The ASTER Randomized Clinical Trial

Scenario: Septic patients with cardiovascular or respiratory failure

Dominant Cause: “dysregulated” immune response to infection.

Dominant intervention: Infection treatment.

Hypothesis: Acetaminophen would increase the number of days alive and free of organ support to day 28 among critically ill patients with sepsis and respiratory or circulatory organ dysfunction.

Causal chain: (1) Acetaminophen is a reductant of cell-free hemoglobin, thus (2) preventing oxidation of lipids and other substrates, resulting in (3) fewer days of cardiovascular or respiratory failure. Just like that. Unfortunately, the paper didn't inform us how to fill the large causal gap between the premises, especially how they leaped from (2) to (3). For example, they could add a “how much” dimension to their reasoning. They could have stated how much of the cardiovascular/respiratory failure is due to free-hemoglobin oxidation of lipids and other substrates, how much oxidation is necessary to cause cardiovascular failure, and whether acetaminophen prevents enough of such oxidation. Now you see what I call a Half-Baked Hypothesis.

Case: Marginal Treatment/Cause.

“Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis…” is how the Robinsons’ paper states the biological plausibility. If you subscribe to this Substack, you know that when you are assessing biological plausibility “many” means “not even one".

Narrative:

As far as I know, no one ever died of the oxidant power of plasma cell-free hemoglobin. It is harsh but true. Truth is liberating, Robinsons!

The loose causal assumptions nevertheless appear to situate this study in the realm of redox. Back in the nineties, and even before, it was trendy to explain sepsis and shock using redox mechanisms. There were clinical trials, and of course, they failed. Bad priors! Sometimes it is revisited when someone gets more excited about methylene blue for shock and other similar interventions.³

The excessive oxidation hypothesis is indeed older and has been tested in many fields. We can trace it back to Linus Pauling's thesis that too much oxidation causes cancer. His thesis survives nowadays in the form of antioxidant supplements. Linus Pauling, however, ironically died of metastatic cancer despite taking a lot of antioxidants, mainly Vitamin C, the drug tested in the other arm of the ASTER study.

Anyway, although the ASTER study is hilariously lost in the translation from biological plausibility to clinical relevance, it is also a tragic account of the current state of critical care research. They played strictly by the book, collecting pre-clinical evidence, and small clinical trial results, to substantiate the hypothesis like building the layers of a pyramid. Pyramids don't collapse, as anyone knows. They stand forever. So, how could the ASTER pyramid collapse? Did they cherry-pick papers supporting the acetaminophen hypothesis, overlooking the unsupportive? Or did they fall prey to the pre-clinical research ubiquitous publication bias?

Well, it collapsed along with all the acetaminophen pre-clinical research because it was built over sepsis definitions. No one will ever find a treatment working inside a disease model that points to no specific dominant cause. If you work with sepsis, send a Thank You card to your closest Sepsis-3 panelist!

Hello American taxpayer! Your money should be spent on describing the disease, instead of clinical trialing Half-Baked Hypothesis like this one.

No amount of money or expertise could save our intrepid investigators/cosmonauts once they decide to engage in sepsis research. Sepsis-3 panelists, the super-villains I dubbed The Task Force, carefully prepared the trap for our gullible Robinsons. The Task Force is known to create disease models that fail to provide any actionable information for those engaged in sepsis research. Playing with ambivalence and incomplete formulations, they made implicit that immune response should be “regulated”, they taught you how to spot a septic patient, and then they let you float adrift forever in space by not giving you any hint of how to regulate the immune response.

Assuming there are hundreds of active pathways in response to infection, what is the probability of plasma cell-free hemoglobin being the dominant cause of ventilatory or circulatory dysfunction or both? The Robinsons are helplessly blind to the marginal utility of their intervention. It will NEVER work.

This is the sad ending of our story. The Task Force incited the ASTER study group to embark on the adventurous quest for sepsis treatment discovery. Once they entered the space capsule, The Task Force locked them inside, counted down, and sent their research project to outer space.

"Ground control to ASTER study group… please return to Earth! You are so needed down here!"

Thanks for reading!

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1. If you don’t know the song, please switch to your music streamer and return later.

2. I was a gifted Defender player forty years ago.

3. We must be acquainted with redox metabolism to treat methemoglobinemia and a few other conditions.