Brain Damage
Should our Thought Leaders take Vitamin C?
WEEKS AGO, I found a gem of unskilled translational research on Vitamin C from Australia, and, unable to deal with its uncomfortable bullshitness, I had to let it sink into unconsciousness, waiting for a connection that would draw it back from the inconceivable. Then it happened. A subscriber called me out on X to show me a study of Vitamin C for cardiac arrest, performed in the Netherlands, with the noble pursuit of saving brains.
I love the Vitamin C issue.
Years ago, Dr Paul Marik, a former intensivist/professor/researcher I used to respect for his sharp views on physiology and evidence-based critical care (!), started shouting on the internet that he had discovered sepsis is actually scurvy. Bold claim!
I read his rationale and found it clever. Although his claims on clinical effect were exaggerated, it was enough for me to try his HAT protocol on a few patients. I remember that an old lady with septic shock benefited remarkably. From that day on, I focused my attention on the “Vitamin C Affair”.
What followed was really impressive. First, the rationale. Vit C is an essential vitamin, which means that our bodies don’t produce it. We must ingest it in the final form. Sepsis and other physiological stressors deplete our reserves. However, Vit C is necessary for the synthesis of catecholamines, such as epinephrine and norepinephrine. Moreover, it is an antioxidant, and many fear the horrible, yet unproven, clinical effects of oxidants. In fact, if you dig deeper, you’ll find many other potentially helpful effects. The Vitamin C hypothesis is a great example of how translational researchers fail to weigh dominance/marginally.
Well, setting Marik's clumsiness aside, the Vit C hypothesis is actually better than tight glycemic control and the endless chloride case. At least, it shows some approximation with human physiology. However, something different happened with Marik’s naive hypothesis. After he made the news with grandiose announcements of a miracle treatment, the field attacked him virulently.
I was shocked by the reaction. As an outsider from a developing country, I couldn’t understand what was going on. I had to travel to a Latin American Sepsis Institute meeting in São Paulo to look at American and local pundits in the face while they discussed Marik’s protocol.
That was the final piece. I witnessed an ugly mix of despair and contempt, and an urge to make it clear to the audience that no one should ever prescribe Marik's protocol. They even staged a pro-con session, where the pro contender said he had nothing to support the use of Vit C in sepsis.
Wow. The social forces of critical care were there, shaping the discussion. That was eye-opening. This Substack's verve owes a lot to that afternoon in São Paulo. The critical care establishment is about sitting in the right tables, like in High School Musical.
In the following years, Marik’s vitamins protocol walked the hype-oblivion arch that many miraculous therapies do. Later, Marik himself became something less than an internist/intensivist.
The genie, however, was out of the bottle.
Today, we will discuss The Great Paradox, or why many therapies appear effective in preclinical settings but fail in subsequent clinical studies. I will present two studies to illustrate the point. One is that deliciously deliriant review paper from Australia, based on the hypothesis that sodium ascorbate (a Vitamin C salt) is more effective against sepsis (and everything else) than Vitamin C, and the other is the recent brain-damaged study from the Netherlands, comparing low or high Vitamin C for survivors of cardiac arrest.
The Great Paradox, explained
Take a look at any issue of the Shock Journal. The journal usually has a session devoted to clinical research and one devoted to basic science. Articles on basic science try to emulate clinical diseases in the laboratory to study the effect of an intervention. Informed by a disease model that explains how the disease develops, researchers will try to model the disease in bench or in vivo studies.
Only that it doesn't happen. Never.