Septic Shock

This study is not neonatal at all, not even pediatric, but I think it is really important.

Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. Drotrecogin Alfa (Activated) in Adults with Septic Shock. N Engl J Med. 2012;0(0):null. Epub 2012/05/24.

There is a complicated history behind this study.

Previous studies were contradictory, but suggested that maybe there was a minor effect of activated protein C (Drotrecognin)  in the treatment of the sickest adults with sepsis. It was known that abnormalities of coagulation are common in septic adults, and the idea that correcting these abnormalities with activated protein C might improve outcomes was not crazy.

A very contentious decision by the FDA to approve the sale of Drotrecognin, after the initial suggestive trials, has been widely criticized, largely because of a perception that the decision was not adequately supported by the clinical data, and that it was tainted by conflicts of interest, and serious pressure from commercial interests.

The FDA made it clear that they wanted further confirmatory studies, and the result of that is the new study by Ranieri and colleagues. Nearly 1700 critically ill adults with septic shock were randomized to either Drotrecognin or placebo.

There was no benefit in any measurable outcome from the intervention.

This result is striking, the study has sufficient power to eliminate any important benefit of the drug in adults with severe sepsis. (A negative pediatric study has already been published). Drotrecognin now joins a long list of interventions which do not improve outcomes in severe sepsis. These include: high dose steroids; antagonists to TNF, IL-1 , platelet-activating factor, bradykinin, and cyclooxygenase; immunoglobulins; anti-lipopolysaccharide interventions; and so on.  Suffredini AF, Munford RS. Novel Therapies for Septic Shock Over the Past 4 Decades. JAMA: The Journal of the American Medical Association. 2011;306(2):194-9.

My interpretation of this is that we need to be super careful.

Many of the physiologic changes which occur in severe sepsis, which we think are part of the problem, are probably adaptive and part of a normal response. So attempting to interrupt what we think are excessive or harmful responses will not necessarily be beneficial.

This actually also applies to things which are much more low tech than recombinant activated protein C. Such as fluid boluses.

In what I think is one of the most important studies in the history of scientific medicine Kathryn Maitland and her collaborators showed that fluid boluses, given to african children with early septic shock, actually increased mortality, rather than the expected decrease. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483-95. Epub 2011/05/28

So why are these studies so important?

They show firstly that studies in critically ill patients can be performed, if there is enough will to do so. They are very difficult, and there are all sorts of roadblocks and inhibitions, but they are possible.

They shows secondly that haemodynamic, metabolic, and biochemical changes in severe shock may be helpful and adaptive rather than maladaptive.

What are the implications for neonatal sepsis?

To my knowledge there has never been a substantial controlled trial in neonatal severe sepsis. This is even though a major cause of mortality and long term morbidity in newborn infants is sepsis. Our commonly used interventions have to be studied.

Even interventions which have not yet been proven ineffective may be ineffective, such as low dose steroids. They need to be investigated in newborn infants. I think the major preliminary questions to be addressed are the following:

What are the hemodynamic changes that usually occur during septic shock in the newborn? are they different to older patients? are they different between gram negative and gram positive infections? Are newborns truly effectively hypovolemic during sepsis? Do babies benefit from low dose steroids? Should we give steroids early or only after failure to respond to the usual inotropes? Is one inotrope better than any other?

To answer these questions will require clinical trials networks committed to performing these difficult trials. However, one thing I do not think we need to study in newborn infants is activated protein C!

About Keith Barrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , . Bookmark the permalink.

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