Lost Without a MAP: Blood Pressure Targets in Septic Shock

Another of the critical care articles published early online at www.nejm.org last week was this trial of High versus Low Blood-Pressure Target in Patients with Septic Shock.  In this multicenter, open-label trial, the authors enrolled 776 patients in France and randomized them to a target MAP (mean arterial pressure) of 65-70 mm Hg (low target) versus 80-85 (high target).  The hypothesis is that a higher pressure, achieved through vasopressor administration, will improve 28-day mortality.  If you don't already know the result, guess if the data from this trial support or confirm the hypothesis (the trial had 80% power to show a 10% absolute reduction in mortality).

Falling to Pieces: Hemolysis of the Hemoglobin Hypothesis

A paramount goal of this blog is to understand the evidence as it applies to the epistemology of medical knowledge, hypothesis testing, and overarching themes in the so-called evidence based medicine movement.  Swedberg et al report the results of a large[Amgen funded] randomized controlled trial of darbepoetin [to normalize hemoglobin values] in congestive heart failure (published online ahead of print this weekend) which affords us the opportunity to explore these themes afresh in the context of new and prior data.

The normalization heuristic, simply restated, is the tendency for all healthcare providers including nurses, respiratory therapists, nutritionists, physicians, and pharmacists among others, to believe intuitively or explicitly that values and variables that can be measured should be normalized if interventions to this avail are at their disposal.  As an extension, modifiable variables should be measured so that they can be normalized.  This general heuristic is deeply flawed, and indeed practically useless as a guide for clinical care.

Hemoglobin In Limbo: How Low Can [should] It Go?

In this post about transfusion thresholds in elderly patients undergoing surgery for hip fracture, I indulged in a rant about the irresistible but dodgy lure of transfusing hospitalized patients with anemia (which I attributed to the normalization heuristic) and the wastefullness and potential harms it entails.  But I also hedged my bets, stating that I could get by with transfusing only one unit of blood a month in non-acutely bleeding patients, while noting in a comment that a Cochrane review of this population was equivocal and the authors suggested an RCT of transfusion in acute upper gastrointestinal hemorrhage.  Little did I know at the time that just such a trial was nearing completion, and that 12 units of PRBCs could probably get me by for a year in just about all the patients I see.

In this article by Villanueva in the January 3, 2013 issue of the NEJM, Spanish investigators report the results of a trial of transfusion thresholds in patients with acute upper gastrointestinal hemorrhage.  After receiving one unit of PRBCs for initial stabalization, such patients were randomized to receive transfusions at a hemoglobin threshold of 7 versus 9 mg/dL.  And lo! - the probability of transfusion was reduced 35%, survival increased by 4%, rebleeding decreased by 4%, and adverse events decreased by 8% in the lower threshold group - all significant!  So it is becoming increasingly clear that the data belie the sophomoric logic of transfusion.

Fever, external cooling, biological precedent, and the epistemology of medical evidence

It is rare occasion that one article allows me to review so many aspects of the epistemology of medical evidence, but alas Schortgen et al afforded me that opportunity in the May 15th issue of AJRCCM.

The issues raised by this article are so numerous that I shall make subsections for each one. The authors of this RCT sought to determine the effect of external cooling of febrile septic patients on vasopressor requirements and mortality. Their conclusion was that "fever control using external cooling was safe and decreased vasopressor requirements and early mortality in septic shock." Let's explore the article and the issues it raises and see if this conclusion seems justified and how this study fits into current ICU practice.

PRIOR PROBABILITY, BIOLOGICAL PLAUSIBILITY, and BIOLOGICAL PRECEDENTS

These are related but distinct issues that are best considered both before a study is planned, and before its report is read. A clinical trial is in essence a diagnostic test of a hypothesis, and like a diagnostic test, its influence on what we already know depends not only on the characteristics of the test (sensitivity and specificity in a diagnostic test; alpha and power in the case of a clinical trial) but also on the strength of our prior beliefs. To quote Sagan [again], "extraordinary claims require extraordinary evidence." I like analogies of extremes: no trial result is sufficient to convince the skeptical observer that orange juice reduces mortality in sepsis by 30%; and no evidence, however cogently presented, is sufficient to convince him that the sun will not rise tomorrow. So when we read the title of this or any other study, we should pause to ask: What is my prior belief that external cooling will reduce mortality in septic shock? That it will reduce vasopressor requirements?