Sepsis: Untangling Bundles, Goals, Measures

Probably one of the of the most paradigm-changing papers in the fields of emergency medicine, critical care medicine, and infectious disease was Rivers, Nguyen and colleagues early goal directed therapy for sepsis paper published in The New England Journal of Medicine in 2001. 

Sepsis, the common final pathway for infectious syndromes and what your grandma called "blood poisoning", is a dysregulated immune response to infection that causes organ dysfunction.  Severe sepsis carries a mortality rate of approximately 25% and is a cause or contributor to many deaths. 

The EGDT paper, with its spectacular results showing a 16% mortality reduction, spurred the development of international consensus guidelines, the Surviving Sepsis campaign, and elevated sepsis to the medical emergency that it is. The bundle of interventions included in EGDT (aggressive fluid resuscitation, prompt antibiotic administration, vasoactive medication administration, blood transfusions)  has quickly come to be regarded as the standard of care.

However, there has been growing concern regarding just how powerful the bundle is and which components are essential and which have less importance. The ARISE, ProCESS, and ProMISe trials failed to replicate the results of the initial trial and there is a strong argument that sepsis care has advanced so much, because of EGDT, that "usual" care incorporates much more than it did in 2001 (because of the results of the initial trial) and later trial patients got many of the interventions of EGDT before randomization. As quality measures and reporting increasingly hone in on the bundle, it is essential to unpack the bundle and not grade providers and facilities negatively if not all components of the bundle contribute positively.

A pair of new papers provide some insight that may help to disentangle the various component of the bundles. The first, by Khalil and colleagues, was published in Critical Care Medicine and is focused on explaining the discordant results between Rivers's study and observational studies that support EGDT and the three negative randomized trials. The conclusion reached was that in the observational studies time to antibiotic administration was substantially faster in the EGDT arms and in the randomized trials very similar arguing that timing of antibiotics explained the discordant results. Interestingly, they also noted increased mortality with EGDT in the sickest group of patients.

The second paper is a patient level meta-analysis of the ARISE, ProCESS, and ProMISe trials. This type of analysis adds increased power to detect effects. The results again show no effect of EGDT on mortality and in subgroup analyses controlling for how aggressive a given center is in resuscitation -- addressing the "usual care" conjecture -- no difference was found. The investigators did find EGDT being associated with higher costs, however. 

So what to make of all this ? A few thoughts:

• The bundle needs to be unbundled: as third-party payors have focused on bundle compliance as a quality measure that may influence payment it will be crucial to make sure they are measuring something that unequivocally matters
• Antimicrobials are of paramount importance: sepsis is a response to infection and taming the infection with antibacterials, antivirals, antifungals, and/or antiparasitic medications as quickly as possible may make the biggest difference (even the order in which one gives antibiotics may matter, depending on the inciting organism)
• As the PRISM investigators note, individualized sepsis care based on variables particular to the patient being treated, rather than a one-size-fits-all approach, is likely the correct manner to treat sepsis

Sepsis is an important diagnosis to make and aggressive care, even if non-formulaic, should be the norm. The Rivers trial was pathbreaking and changed the dialogue regarding this condition. I am sure that these latest salvos in the medical literature will be answered and more elucidation will be forthcoming,

Can I Check Your Inflammatory Reflex?

The realms of infectious disease and critical care medicine intersect at a place called sepsis. Sepsis is what our grandmothers called "blood poisoning" and what our ancestors before that believed was caused by evil "humors" in the body. As one of about 113 physicians with dual training in both infectious disease and critical care medicine, this disease entity is one I find extremely fascinating for obvious reasons. A good way to think of sepsis, is as the final common pathway for many infections as they increase in severity. 

Sepsis recently underwent a notable change in definition that improved the utility of the concept by reflecting state-of-the-art scientific principles. The fundamental basic definition of sepsis is dsyregulated host response to infection. When I first saw the new definition, which I found to have much more clarity than prior versions, I didn't parse every word out. However, after reading Clifford Deutschman's analysis, I am reminded of how important definitions are both for what they include and also for what they exclude.

The definition of sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. What Deutschman's piece highlights is the fact that the definition stipulates only a host response -- not which part of the host. Most people, rightly, think of the dysregulated response as largely immunologic but, like many physiological phenomenon, there's more to the story. He also goes on to point to the answer to the question of what other systems are involved. 

Tracking down his references one finds that it is the nervous system that is involved. A tantalizing aspect of this involvement is something known as "the inflammatory reflex" (sounds like a media term for an attribute of Donald Trump) as elucidated by Kevin Tracey.

This reflex involves the vagus nerve directly communicating with the immune system. This communication is two way with infection triggering "sickness behavior" such as anorexia, social withdrawal, and sleepiness. On the other side, T-cells of the immune system are influenced in order to diminish inflammation, which though essential can sometimes be overwhelming. 

The details of this interaction are endlessley fascinating and open up whole areas for intervention. Equally fascinating is understanding the evolutionary role of this pathway, which predates the immune system proper as it is present in the simple organism C.elegans which does not have immune cells. Sickness behavior is interesting in its own right and one can see how such behavior might delimit contagion and conserve metabolic resources needed to weather the infectious storm--a really cool thing to contemplate.

What Do Vibrators & Sepsis Have in Common?

Answer: The movie Hysteria and very little else (but exceptions unfortunately exist). 

I can't resist commenting on mentions of infectious diseases in popular media. As I've written before, these mentions often give a snapshot of how the general public views a particular topic whether it is HIV, Ebola, or influenza.

Hysteria is a somewhat fictional account of the invention of the vibrator in 19th century England as well aa a critique of the diagnosing of hysteria--a nebulous term that, when applied to a woman, horrifically could led to a hysterectomy for no reason. The film accurately depicts hysteria as akin to blood-letting, leeches (which do have a few legitimate medicinal uses), and the "laudable pus" that emanated from infected wounds.

In the movie Dr. Mortimer Granville, the real inventor of the vibrator, is portrayed as an innovative, evidence-based, and modern physician railing against treatments that are ineffective or do harm. In one of the opening scenes, Dr. Granville has an important exchange with a nurse instructing her to remove dirty bandages from wounds because of the risk of sepsis, a word derived from the Greek term for "to make rotten".

As an infectious disease and critical care medicine physician, sepsis--a systemic inflammatory state induced by infection with microorganisms--is something I can't avoid seeing upon setting foot in the hospital but the concept was completely foreign to medicine until the germ theory was developed and accepted. No embrace of antisepsis and sterility could really occur if there was no realization that microbes could cause disease. "I don't think I have those," the patient in the scene remarks and indeed it would be impossible for a person without the context of the germ theory to imagine invisible organisms as being responsible for a state of disease.

The senior physician remarks that "germ theory is poppycock" to which Dr. Granville retorts "Lister has proved it."

Today that microorganism can cause disease is not even greeting with disbelief from children, who rush to have Band-Aids applied to the slightest abrasion. In the end, germ theory--the development of which I hope to write a lot more about--was not poppycock but the result of the synthesis and integration of many facts by the likes of Lister, Pasteur, Koch, Semmelweis, Leeuwenhoek, and others. 

This small vignette from a movie largely unrelated to the topic gives a brief glimpse into what those heroic individuals had to overcome in order to usher in an era of vaccines, antibiotics, the entire medical speciality of infectious diseases, and ever increasing life spans.

Sepsis: ProCESS shows Progress

The treatment of severe sepsis, colloquially known as blood poisoning, has underwent a real revolution in the last 10+ years largely on the basis of a seminal paper by Emanuel Rivers.

The Rivers study, conducted at one center, demonstrated impressive morality reductions when septic patients were treated to reach specific physiologic goals (that were essentially set to reflect normal physiology). The study protocol required the insertion of a central venous catheter.

Since that paper, early goal-directed therapy (EGDT) has become the paradigm and is the cornerstone to the sepsis management bundle. 

However, some debate has occurred over which goals are most important to achieve and whether the bundle can be de-bundled.

A major study on this topic, known as ProCESS and led by Pitt, was recently published in The New England Journal of Medicine.

The aim of this study was to determine whether EGDT with or without a central venous catheter for sepsis in emergency departments was superior to routine care. The results of the study, somewhat surprisingly, did not demonstrate any difference in mortality amongst the groups. 

The implication, to me, of this study is that early recognition and prompt treatment of severe sepsis is the key step that must be performed. I think part of this result is explained by the widespread diffusion of the general principles exemplified in the Rivers trial. Whether or not a formal protocol or central venous catheter is in place does not matter if one is treating severe sepsis appropriately. However, not everyone can function without a protocol so smaller hospitals may still fare better under a protocol-driven approach--as the accompanying editorial notes.