Jan 012013

It started with a friendly pro/con debate in the December 2011 Chest, about whether lactate clearance or mixed venous oxygen saturation is a better "goal" for early goal-directed therapy in severe sepsis and septic shock. It ended with Alan Jones reviving rumors and innuendo that have swirled around Emanuel Rivers's 2001 sepsis trial, and by extension his entire body of work.

Continuous central venous oxygenation saturation monitoring, used in Rivers's 2001 NEJM landmark trial, requires a proprietary catheter (such as the one made by Edwards Lifesciences). Intermittently-obtained central venous oxygen saturation correlates well with mixed or continuous central venous oxygen saturation, and is considered a proper substitute for continuous central venous O2 saturation. Most intensivists use the less onerous intermittently collected central venous oxygen saturation.

The randomized LACTATES trial compared early goal directed therapy using lactate clearance (change in lactate / original lactate / time elapsed) against a strategy using ScvO2, and showed equivalent outcomes (mortality) in the two groups. Alan Jones (PI of LACTATES) squares off against the threesome of Emanuel Rivers, Ronald Elkin and Chad Cannon to make the case that lactate clearance is more useful and should replace SvO2 in EGDT.

Jones's most compelling point is that either central or mixed venous O2 sats can be normal or high in severe sepsis, even in the presence of severe organ hypoperfusion, because if oxygen extraction varies throughout the body (as it does during sepsis), the mixed blood can "average out" to a misleadingly normal/high value. Therefore, following ScvO2 results in mismanagement. Also, lactate clearance has repeatedly been shown to independently predict survival from sepsis, whereas ScvO2 (as a single variable) has not. 

Rivers and friends counter that ScvO2 is more sensitive as an early-warning system in sepsis than lactate (based on their own data), that lactate kinetics are too complex and variable between patients to use it as a standard, that lactate levels often don't rise even in life threatening sepsis, and that using percent lactate clearance is oversimplified (e.g., it considers a lactate going from 10 to 9 as being the same as one from 4 to 3.6: both are a 10% clearance). They also bemoan the fact that people have interpreted Jones's LACTATES to mean central lines are not needed at all in severe sepsis (although of course they are under current practice standards, to measure central venous pressures).

But in the rebuttals, things heated up.

In response to criticism of LACTATES's methodology, Jones raises suspicions about Dr. Rivers's original single center trial, even casting aspersions on the care delivered at Henry Ford, noting Rivers's original control group mortality was "20% higher than any septic shock mortality reported in the recent literature." Jones also suggests peculiarity of Dr. Rivers's data collected between 1997 and 2000, calling it "markedly different than any other septic shock population reported in the world’s literature" and wondering if "systematic selection bias was a significant problem in the their study." Ouch.

As reported in the Wall Street Journal, other prominent academics have wondered publicly about the dramatic benefit seen in Dr. Rivers's original study. According to the WSJ piece, a medical resident at Henry Ford doing a follow-up study raised a red flag as to the integrity of the original data, suggesting there were 25 patients who should have been included and had they been, would have reduced or eliminated the trial's findings. The hospital performed its own internal analysis of the data, and publicly announced everything was proper -- but declined to share the primary data with anyone on the outside, the WSJ story says. Since Rivers and his hospital had (at one time) some kind of relationship with Edwards Lifesciences, makers of a central venous monitoring catheter, the whole thing is redolent with intrigue.

I saw Dr. Rivers speak once. He gave a great presentation. The main thing I remember about it, though, was that he announced "nothing to disclose" and then showed several videos of his septic shock patients, during which he kept zooming in for tight shots on the Edwards Lifesciences logo on the ScvO2 monitor, holding focus for several suspenseful, brand-building seconds. (Wouldn't you know it, there was a 0% mortality for those three patients! I felt like I should be getting a free lunch, at least.)

EDIT/UPDATE:  There is a document that looks like an unsigned, unpublished letter to the WSJ in response to that piece, which you can (at this writing) read on Scott Weingart's EMCrit blog. It is signed only "The Department of Emergency Medicine - Henry Ford Hospital". I have not verified its authorship or authenticity. The document describes the internal review that was conducted and denies the assertions made in the WSJ piece about potential mishandling of data leading to a false positive result for EGDT:

Click to access Henry-Ford-Hospital-Reply-to-WSJ-10.27.2008.pdf

Clinical Takeaway: All the combatants agree that ScvO2 and lactate provide complementary information. I'll keep checking both, and hope the forthcoming ProCESS study lights our way.

Jones AE. Point: Should Lactate Clearance Be Substituted for Central Venous Oxygen Saturation as Goals of Early Severe Sepsis and Septic Shock Therapy? Yes. CHEST 2011;140:1406-1408.

Rivers EP et al. Counterpoint: Should Lactate Clearance Be Substituted for Central Venous Oxygen Saturation as Goals of Early Severe Sepsis and Septic Shock Therapy? No. CHEST 2011;140:1408-1413. 

Rebuttal from Alan Jones

Rebuttal from Manny Rivers

Thomas M. Burton, "New Therapy for Sepsis Infections Raises Hope but Many Questions," The Wall Street Journal, August 14, 2008.

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Should lactate clearance replace ScvO2 in sepsis protocols?