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Persistence of Memory

I have steadily endeavored to keep my mind free so as to give up any hypothesis, however much beloved (and I cannot resist forming one on every subject), as soon as the facts are shown to be opposed to it.
— Charles R. Darwin

I’m getting old: 50, almost 51, and that’s over 350 in dog years. As a result of my advancing age there are things I do not get: tattoo’s, hip hop, visible undergarments, and those rectangular, square plastic glasses that seem so popular and look hideous on everyone. It gets harder to change.

I have been able to stick MD after my name for almost a quarter century now (175 dog years for those keeping track), and it does give a sense of perspective to the ebb and flow of medical therapies. Medicine for the last hundred years has been all about change. Dogma from last century is nonsense this century, all due to that damn science. It gets so tiresome having to learn something new.

Last month’s New England Journal of Medicine was another in a seemingly endless series of plus ça change, plus c’est la même chose moments.4 They published the results of the CORTICUS study, a trial that looked at the use of corticosteroids in septic shock. For background, septic shock occurs when a severe infection shuts down most important organs and the patient cannot maintain their blood pressure. Mortality is high and, depending on the patient, the infection and the infecting organism, mortality ranges from 30 to 110%. People can die several times during their admission and be temporarily brought back, at least from the sloppy definitions of the near death experience proponents (shameless plug for Quackcast 23). Sepsis is a Bad Disease. Patients in septic shock often have lower levels of cortisol in their blood than they should. So maybe giving replacement cortisol, in the form of hydrocortisone or prednisone, would decrease the death rates.

The results of the CORTICUS (I so want to be involved in a study that has an obscene acronym) suggests steroids are not effective. When compared to placebo, physiologic hydrocortisone (i.e. giving enough hydrocortisone to replace the deficit) was no better at preventing mortality. It didn’t work. Or didn’t it. Or did it? Which one?

I remember back when I was a resident back last century. We had to walk to the hospital barefoot in the snow, uphill, even in August. Made our own penicillin in the basement from moldy cheese. We took call every day and loved it. The sun was warmer, the sky bluer, water was wetter. Good times. It was also when the first study of sepsis and steroids was published. In that study they used relatively large doses and had an improved outcome.5

So everyone got steroids for sepsis.

Then another, better study, was published that demonstrated no change in mortality, but the patients who received steroids had more secondary infections. Bummer. More data. I have to change my practice. Damn. I hate it when that happens.

So the use of steroids faded. In medicine every therapy returns in a new way. I am waiting for the resurgence in the use of theophylline, for example. It’s going to happen.

Then it was noted that septic patients were relatively cortisol deficient. When tested their cortisol levels were lower than it should be in sepsis and that their adrenal function, the source of cortisol, was suppressed. Perhaps if patients received physiologic, replacement doses of steroids, they would do better.

Early studies looked promising, several small trials were done and several meta analyses suggested that there was a sweet spot for steroids, that indeed a lot was dangerous but a little was of benefit in decreasing mortality.

Although meta analyses are often subsequently disproved, it was compelling information. So steroids came back in vogue. Damn. Have to change practice again. Given that my mind is mostly filled with the lyrics of 1970’s rock music, it better not happen again. There is just so much I can learn.

Until the CORTICUS study. Now what. Do we give steroids? Or not? Or in a subgroup of patients? Damned if I know. My Critical Care colleagues tell me that they may yet be a role in patients with refractory sepsis since cortisone made them better faster, and generally the quicker you get out of a septic state the better you do (although not demonstrated in the CORTICUS study, it was not set up to determine outcome in this subgroup so the issue is still open to debate).

So over the last 25 years its yes and no and yes and mostly no when it comes to the treatment of sepsis.

This ebb and flow of medical knowledge is a standard feature of the practice of medicine and is, to the best of my knowledge, never a feature of sectarian or unscientific medicine (so-called Complementary and Alternative or Integrative Medicine).

I often wish I could practice unscientific medicine. Learn one all encompassing myth and never have to change again. CAM proponents often point to the changing interventions of medicine as a flaw. Look, they say, these guys don’t know what they are doing. One day its yes, next day its no, then its yes again. Do you know why a doctor’s mind is so clean and pure? Because she is always changing it.

Part of the problem is that in medicine we learn and practice evolves as the science behind the practice changes, and as an ever moving target, we are always refining practice. It is a strength of medicine, but leads to a degree of doubt and uncertainty and one thing people hate is doubt and uncertainty. Better a firm conviction about nonsense than a doubt about reality.

The other issue this study raises, and it is an important one when reading in clinical study, is sample size and its influence on the ability to determine differences in study groups. The smaller the study size, the more difficult it is to find a difference and the more likely it is that differences are due to noise. This concept is expressed as the power of a study.

The power of a study can be calculated in advance. In the accompanying editorial they note, given a 35% mortality rate, that to demonstrate a 15% decrease in relative risk of mortality would require 2600 patients. The CORTICUS study had 499 patients and would not be able to accurately determine small differences between the groups.

Note that to find a 15% difference, you need to study 2600 patients.

This is an issue in most clinical studies in both science-based medicine and in studies of sectarian modalities: the sample size is so small that “statistically significant” results are more likely due to background variation. If you have a small difference that is statistically significant between small groups, it is probably meaningless.

Look at the recent acupuncture and heartburn study:2 15 patients in each group. Even if the difference in the two groups were 100% and the end point was death i.e. 15 lived and 15 died, the results would still be meaningless, regardless of the statistical significance. Not enough patients.

Most studies, especially in the CAM literature, suffer from this issue. Most are simply extended case series. It’s the old joke.

One patient with a disease: “In my experience…”

Two patients with a disease: “In many patients…”

Three cases with a disease: “In case after case after case…”

BTW. Read Prior Probability: The Dirty Little Secret of “Evidence-Based Alternative Medicine” on this blog. Makes me feel like M.J. GUMBY: “Oh I have a piece of brain stuck in my head… oh my head hurts!” It’s what all statistics do to me. But it is a key concept in reading any medical literature, CAM or not.

Unfortunately, the problem with information, good, bad, or indifferent, is once it gets in the literature it stays. There are a lot of myths in the practice of medicine: normal temperature is 98.6, atelectasis causes fever, you have to double cover Pseudomonas, antibiotics are strong or powerful. The problem can be that with any strongly held opinion, it is hard to change your mind. Human psychology is such that people look for facts that confirm pre existing beliefs and ignore those that contradict them. Medicine is no different and it is interesting how misinformation persists when it is contradicted by good data.

The Journal of the American Medical Association published an article last month entitled “Persistence of Contradicted Claims in the Literature.”3

They looked at data that was initially based on observational epidemiology that were later contradicted by randomized clinical trials. In this case they looked at Vitamin E and cardiovascular benefits and Beta Carotene and Alzheimer’s.

Epidemiological studies suggested benefit from each, later clinical trials said, nope, sorry, we were mistaken.

It seems that despite excellent clinical trials, people cannot bring themselves to refute the older epidemiologic data and persist on citing the literature in support of these interventions that don’t work.

What is also interesting is the rationales for not believing the controlled trials, ranging from quibbles bout bias, differing populations, pharmacokinetics, confounding variables to poor endpoints.

So I suppose steroids will continue to be used in sepsis, depending on the patient and how the doc understands a complex and changing literature.

This article also brings some insight into all medicine, real or “alternative.” If you are convinced, for whatever reason, that you can treat a disease with water or needles or even, heaven forbid, steroids, it may be difficult to change your mind even if the contradicting data is good. It is how people are.

This brings home the issue as to how difficult it is to do convincing clinical trials: even the best trials can be unconvincing if you are unable to discount earlier, poorly designed or less powerful, studies. Bad trials, like those found in sectarian practices, crumble under the slightest touch. Once you read past the self aggrandizing abstract (most do not) you see that, like Oakland, there is no there, there.

In sectarian medicine, early trials, which tend to have positive results, are also the more poorly designed, biased trials. Once published, they persist in supporting unscientific modalities even after better trials demonstrate the lack of efficacy. The arc of publishing studies related to sectarian modalities is increasingly well done studies with decreasing efficacy until an excellent study shows no effect. But the early studies continue to pollute the intellectual waters. I wonder if there is such a thing as intellectual primacy: the first thing you learn, regardless of subsequent contradictory information, sticks better in the brain solely because it was the first learned.

It must be nice to be a CAM provider, or some MD’s I know: immune from ever having to learn or change.

Take home?

Medicine is hard, confusing, contradictory and always changing. Real docs may share more commonalities with CAM practitioners than they would like. Change is hard, especially for old fogey’s like me.

Makes we wish I were a homeopath.

Footnotes

  1. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. PMID: 18184957 Return to text
  2. Aliment Pharmacol Ther. 2007 Nov 15;26(10):1333-44. Epub 2007 Sep 17. Clinical trial: acupuncture vs. doubling the proton pump inhibitor dose in refractory heartburn.
    Dickman R, Schiff E, Holland A, Wright C, Sarela SR, Han B, Fass R. Return to text
  3. JAMA. 2007 Dec 5;298(21):2517-26. Persistence of contradicted claims in the literature. Tatsioni A, Bonitsis NG, Ioannidis JP. Return to text
  4. The more things change, the more things stay the same. Barbarian. Return to text
  5. A meta analysis: http://www.annals.org/cgi/content/full/141/1/47. A structured review: http://www.bmj.com/cgi/content/full/bmj;329/7464/480. Return to text

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