Out to Lunch: Nutrition and Supplementation in Critical Illness

A study in week's issue of the NEJM (Heyland et al, Glutamine in Critical Illness, April 18th, 2013) left me titillated in consideration of how new evidence demonstrates underlying misconceptions, shortcomings, and biases in our understanding of, and general approach to, disease and its pathophysiology.  Before you read on, try to predict:  Will supplemental glutamine and anti-oxidants influence the course of critical illness?

The Canadian Critical Care Trials group has continued the effort to determine the causal role of macro- and micronutrients and their deficiency and supplementation in critical (and other) illness.  The results are discouraging (glutamine and anti-oxidants don't work), but only if we consider RCTs to be a tool for the assessment of the therapeutic value of putative molecules and their manipulation in disease states.  RCTs are such a tool, but only if we happen to be fortunate enough to be pursuing a causal pathway.  In the absence of this good fortune, RCTs remain valuable but only to help us understand that the associations we have labored to delineate are not causal associations, and that we should direct our focus to other, potentially more fruitful, investigations.  As I articulated in the last post, this dual role of RCTs represents a paradox which can be the source of great cognitive dissonance (and misunderstanding).  The (properly conducted and adequately powered) RCT is a method for determining if observational associations are causal associations, but the promise of confirming causal associations in an RCT by manipulating dependent variables with a potential therapeutic agents carries with it the possibility of proving the efficacy of a disease treatment.   During this protracted scientific process, there is a tendency to get carried away, such that our hypothesis mutates into a premise that we are studying a causal factor and the RCT is the last hurdle to confirming that we have advanced not only the science of causation, but also clinical therapeutics.  Alas, the historical record shows that we are far better at advancing our understanding (if we are willing to accept the results for what they are) than we are at finding new treatments for disease, because most of the associations we are investigating turn out not to be causal.

A Centrum a Day Keeps the Cancer at Bay?

Alerted as usual by the lay press to the provocative results of a non-provocative study, I read with interest the article in the October 17th JAMA by Gaziano and colleagues: Multivitamins in the Prevention of Cancer in Men. From the lay press descriptions (see: NYT summary and a less sanguine NYT article published a few days later,) I knew only that it was a positive (statistically significant) study, that the reduction in cancer observed was 8%, that a multivitamin (Centrum Silver) was used, and the study population included 14,000 male physicians.

Needless to say, in spite of a dormant hope something so simple could prevent cancer, I was skeptical. Despite decades, perhaps eons of enthusiasm for the use of vitamins, minerals, and herbal remedies, there is, to my knowledge (please, dear reader, direct me to the data if this is an omission) no credible evidence of a durable health benefit from taking such supplements in the absence of deficiency. But supplements have a lure that can beguile even the geniuses among us (see: Linus Pauling). So before I read the abstract and methods to check for the level of statistical significance, the primary endpoint, the number of endpoints, and sources of bias, I asked myself: "What is the probability that taking a simple commercially available multivitamin can prevent cancer?" and "what kind of P-value or level of statistical significance would I require to believe the result?" Indeed, if you have not yet seen the study, you can ask yourself those same questions now.