Friday, January 11, 2008

Corticosteroids in septic shock-the wheel keeps turning

I remember forty years ago as a house office that we used steroids in patients with septic shock. We also used antibiotics,fluids and vasopressors. There were no large randomized clinical trials (RCT) whose results formed the basis of our treatment plans. The age of evidence based medicine (EBM) had not yet arrived.

Since then we have had RCTs that demonstrated the benefit of high dose steroids followed by larger trials that showed no benefit. Was that the end of steroid use ?No it was not. The stage shifted to the use of low dose or so-called physiological dose steroids.It seemed we were giving too much and perhaps we were not selective enough . Enter the phase of testing for adrenal function in spesis patients.

A trial by Annane et al published in JAMA in 2002 used a corticotrophin stimulation test to divide sepsis patient into those who responded with a cortisol increase to some decided upon cut off and those who did not. The latter group appeared to benefit from corticosteroid treatment.This was not the only trial suggesting the value of low dose steroid and testing for adrenal function,there were several others but the Annane number may have determined the meta-analysis outcome.

RCTS work best in studying treatment effects in a relatively homogeneous,relatively clinically stable conditions where there are not be-deviling co morbidities and a rapidly changing clinical picture in which the timing of various intervention may be determinative. In sepsis small clinical trials and reliance on adding up those trials which may vary in critical ways and calling it a meta-analysis may well lead to recommendations that are faulty because of all the reasons we learn in epidemiology 101 that cause clinical studies to be misleading.

RCTs are often small and fail to capture the perplexing diversity of relevant variables (known and unknown) that lurk in complex, hospitalized patients. It is the sickest patients that simplistic rules formulated by committees harm the most and in whom the pathophysiological diversity is likely to overwhelm premature generalizations and an overly eager rush to mandate treatment rules.

Now the evidence wheel is turning back over to the " no significant difference" marking regarding the use of low dose steroids. This "negative study" appears in the Jan 10,2008 issue of the New England Journal of Medicine. This study, the Corticus study, gives results markedly different from the Annane trial. See here for a discussion of the trial. A brief review of the discussion section informs us that there were major differences in the two trials.These included difference in entry requirements, duration of therapy and a major difference in the survival rate in the placebo group to name a few of those factors discussed in the article. As if that were not enough to muddy the waters the authors tell us about the "lack of adequate power" and say further:

On the basis of the current data,however, the likelihood of seeing any differences in outcomes between the two study group was unlikely.


(Apparently the trial was stopped because they ran out of money and they are telling us they did not round up enough patients to show a difference if one really existed. Is there something wrong here?

So we are told the Corticus trial was quite different from the Annane trial in a number of possibly important procedural matters and it was too underpowered to show a difference.
The authors are not deterred from making a recommendation anyway-at least in sort of a negative way. They say that "hydrocortisone cannot be recommended as a general adjuvant therapy for septic shock nor can corticotrophin testing be recommended." However, they admit hydrocortisone may have role if given early to patients in whom the administration of high dose pressors does not raise the blood pressure. Isn't evidence based medicine great? I think that is what we did forty years.

Another important point was mentioned in the companion editorial by Dr. Simon Finfer. Apparently one of the problems in recruiting patients for the trial was the fact that earlier guidelines had already enshrined the used of steroids in septic shock. Finfer said:

...apparently authoritative guidelines may make the conduct of important confirmatory trials more difficult.

So it looks like small clinical trials may give apparent positive results that then may get incorporated into guidelines whose controlling effect on clinical practice may inhibit or even foreclose on larger trials that might correct the earlier faulty false positive trials.

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