My week with SIRS

I’ve been down for several days this week with influenza A, which is not shocking since this year’s vaccine (yes, I did receive it) has a whopping 51% effectiveness against the predominant circulating strain. You’ll have to find our prior posts on the horrible influenza vaccine on your own, myalgias prevent me from adding more links. 

Early into illness, I had a vivid dream in which I was being admitted to a hospital. A doctor who looked exactly like the Phillie Phanatic told me I met criteria for SIRS/sepsis, and started administering vancomycin and piperacillin-tazobactam by direct injection into my kidneys. 

But the only thing more boring than stories about people's self-limited viral infections are stories about their dreams, so I’ll stop now and retire quickly to my sofa (this, of course, is a really bad sepsis pun about the new qSOFA score). For while I did meet SIRS criteria, I never met qSOFA criteria (RR >= 22/min, altered mentation, or SBP <= 100 mm Hg), demonstrating with an N of 1 that qSOFA is more specific for identifying those likely to suffer "poor outcomes typical of sepsis".

Eli already linked to the Third International Consensus Definitions for sepsis, which are well worth a read. There is also an excellent piece in Slate about sepsis, by Dr. Jeremy Faust (an Emergency Medicine resident at Mt. Sinai in NYC), that accessibly covers the new definitions and the unintended adverse consequences of the CMS sepsis measure, including those that impact antibiotic stewardship. Finally, ECCMID is underway and I’ve already read tweets about a terrific session on sepsis there today—I’m assuming the content will be available at this link once the session is uploaded.

Should we track sepsis trends using administrative data?

A: Maybe, but only with extreme caution after adjusting for the influence of policy changes

One of the topics that our group at the University of Iowa is very interested in is the use of administrative databases for tracking the epidemiology of healthcare-associated infections, including those caused by resistant pathogens. Marin Schweitzer reported (open access) in 2011 that the ICD-9 code V09, which was commonly used for tracking MRSA trends, was a poor predictor of actual MRSA infection. More recently, Michi Goto completed a systematic review (free full text) that determined the accuracy of administrative data for surveillance of CAUTI, Clostridium difficile infection (CDI), CLABSI, VAP/VAE, postprocedure pneumonia, MRSA, and surgical site infections (SSIs). He found that administrative data detected CDI and SSI with moderate sensitivity and high specificity. For all other conditions, ICD-9 based algorithms had limited accuracy and utility.

Which brings us to a condition that we haven't much explored - sepsis. Sepsis has been in the news lately, since the Third International Consensus Definitions of Sepsis and Septic Shock (Sepsis-3) were published in February. I've included an image of a monument to a different Third International above for historical purposes. We would expect that these new definition might alter the incidence of sepsis as measured using administrative databases - but only time will tell.

Fortunately, Shruti Gohil and colleagues working with the CDC Prevention Epicenter program just published (free text in CID) an important evaluation of how previous changes in sepsis coding criteria, definitions and reimbursement might have altered sepsis rates. Using retrospective data (2000-2010) from California they determine the association between the release of CMS guidelines of sepsis coding in October 2003 along with the introduction in the MS-DRG reimbursement changes  for sepsis care in October 2007 and sepsis incidence. I've included two figures that showed (A) the change in incidence after each CMS change and (D) mortality per 1000 cases over the same period.

As appears obvious in the top figure, the marked increase in sepsis incidence, 3.6 fold over the study period, is temporally associated changes in CMS coding guidance and reimbursement. And fortunately, mortality appears to be decreasing. The authors suggest that some up-capture of less severely ill septic patients may be driving these findings. They also posit that background increases in sepsis, separate from those associated with CMS changes, could be driven by early recognition programs, such as Surviving Sepsis Campaign (2004), and improved diagnosis. The most important conclusion is this: "it is imperative that reported sepsis rates based on administrative data account for policy-related effects...interpretation of recent epidemiologic trends in sepsis based on administrative data should be approached with caution." 

More antibiotics NOT more better in sepsis

There is a meme in antibiotic therapy for all infectious disease clinical syndromes that earlier and more antibiotics lead to lower mortality. I'm not sure that this meme is supported by data from good studies, but it has been so effectively spread through the establishment that its very existence goes unnoticed (check this abstract's first sentence). I think this unproven belief threatens effective antimicrobial stewardship and is partially responsible for the emergence of antimicrobial resistant organisms, but I digress...

Published online in JAMA this week is a randomized trial of dual antibiotic vs monotherapy in sepsis funded through the German Sepsis Research Network (SepNet). The 2.5 year study in 44 German ICUs compared meropenem monotherapy (n=298) with meropenem+moxifloxacin (n=278) in patients with sepsis or septic shock. Patients were treated for 7 to 14 days or until discharge or death and duration was informed by a procalcitonin-guided treatment protocol on study days 7 and 10. The primary outcome was mean of daily total Sequential Organ Failure Assessment (SOFA) scores over 14-days with similar scores in both monotherapy (7.9 points) and dual therapy (8.3 points) patients, p=0.36. 28-day mortality was 22% in the mero and 24% in mero+moxi patients (p=0.58) and 90-day mortality was 32% in the mero and 35% in the mero+moxi patients (p=0.43).

Groups were similar and infections were predominately pneumonia, intra-abdominal and GU. Blood cultures were positive in 33% of patients with Escherichia coli and MSSA being the most commonly isolated, while 18 had MRSA from any source. 100% of cultures tested were susceptible to the mero+moxi combination while 94% of specimens were susceptible to meropenem monotherapy.

This is an important study and one that should make us question current empiric therapy dogma. However, it doesn't answer the question whether antibiotics overall made a difference and whether other therapeutic options including source control might be more important.  It's nice to see clinical ID slowly emerge into the modern evidence-based medicine era even if so few studies are completed in the US.

image source: http://abacaxihortela.blogspot.com/2011/09/only-1.html

Evidence-based Backlash: The Xigris eXample

Rich Savel, has a wonderful editorial in this month's issue of the American Journal of Critical Care (AJCC) discussing the importance and dangers of evidence-based medicine as currently practiced. He and co-author Cindy Munro use the rise and fall of Drotrecogin Alfa (Xigris, activated protein C) as an example for what can go wrong and why.

Rich Savel in the center

Their key conclusions:

1) "Though the results of a single, large RCT are important, they clearly are not sufficient for future agents to be rapidly integrated into national guidelines or consensus statements."

2) "Another important lesson is that pharmaceutical companies should stay as far removed as possible from development of guidelines promulgated by national medical societies. One of the most important things such a society has is its reputation, which it must be careful not to tarnish. Although this can often be a great challenge, it has become quite clear from the controversies surrounding APC that the relationship between pharmaceutical corporations on the one hand and academia and national medical societies on the other should be kept distinct and transparent."

3) and finally - “... the single most important lesson from the rise and fall of APC is that we should maintain skepticism: maintain it until the trial can be reproduced; maintain it in the face of trusted medical societies integrating recommendations for agents before sufficient evidence is presented; and maintain it until all potential conflicts of interest have been shared. EBM is not merely one way to practice; it is the only way. In addition to understanding all of the dynamic complexities and nuances of EBM, we must develop a healthy skepticism toward new research results and apply that approach liberally as the scientific method does its important job of confirming the validity of those results."

Full Disclosure: Rich and I were residents at NYH-Cornell back in the 1990s and we were also co-Assistant Chief Residents at Memorial Sloan Kettering under Kent Sepkowitz. Rich has gone on to great things as co-editor of the AJCC and medical directorship of the surgical intensive care unit at Montefiore Medical Center, Albert Einstein College of Medicine in NYC. Rich is also the editor and founder of the SCCM iCritical Care Podcast - which rocks.

Deus ex machina: duabus partibus (Part Two) - Tiny Magnets

With infectious diseases, there is always another miracle around the corner.  The problem is that the miracle typically stays around the corner. Come on down...The next contestants in the search for a miracle cure are..."tiny magnets."

Researchers in Switzerland are developing nanomagnets that could remove harmful compounds (e.g. bacteria) from the blood. The technology involves magnetized nanoparticles coated with carbon and pathogen-directed antibodies. The plan is that the antibodies attach to the pathogens and then the whole compound is removed from the blood with hemodialysis. Sounds pretty exciting. Probably exciting enough to hold off on further investments in infection prevention research, not!

Source: Technology Review (MIT): 11/28/2011

Conflicting Results in Clinical Trials: the APC Example

Dan posted last week on activated protein C (Xigris) being withdrawn from the market.  David Rind (Evidence in Medicine blog) has posted his thoughts on what might have been behind the initial positive study in 2001 and subsequent negative studies.  It is worth a read.

David Rind: APC and Conflicting Trials (10/29/2011)

Headline of the day

This is my favorite headline about the demise of drotrecogin alpha (a.k.a. activated protein C, Xigris), which was withdrawn from the market yesterday after the PROWESS-SHOCK study results revealed it to be no better than placebo in the treatment of severe sepsis. The headline, of course, implies that Xigris once was effective, it just isn’t any more…and from the quotes in this story, it appears that Lilly is arguing that improvements in sepsis management have now made it impossible to detect the incremental benefit that Xigris provided (you know, back when we were super-terrible at treating sepsis).

Fair enough, but that explanation ignores the controversial history of this drug and the role of Eli Lilly in the surviving sepsis campaign. It also ignores one of the most important lessons we should learn from this debacle: the perils of the subgroup analysis. Eli, our in-house methodologist, may wish to chime in, but you can start here with a nice review that points out why subgroup analyses of clinical trials should be treated with extreme caution, and used only to generate hypotheses, not for clinical decision making (or drug approval!).

Multiplex PCR and diagnosis of sepsis

Just came across a really nice paper in the Journal of Clinical Microbiology by Ephraim Tsalik, Chris Woods and others at Duke and the Durham VA. They tested whether multiplex real-time PCR can be a useful addition to blood culture in patients presenting with suspected sepsis to the ED of their two hospitals. Over an almost 6-year period they enrolled 306 patients with suspected sepsis (43 were eventually excluded for non-infectious etiology). Patients had blood samples taken within ~2-3 hours and a questionnaire administered to determine recent exposures and symptoms. Most of the confirmed etiologies were S. aureus (34%) and E. coli (23%).

Results showed that blood culture had a sensitivity of 25% vs. 20% for PCR, a similar negative predictive value (18% vs. 17%), and an area under the curve of 0.63 vs 0.60. Using blood culture as the gold standard, PCR had a sensitivity of 61%. Both PCR and culture detected organisms in 40 patients (38 were the same organism). As far as individual methods, there were 24 organisms only detected by PCR (largely E. coli and Klebsiella) and 52 only detected by blood culture (E. coli, S. pneumo, S. aureus and a large number of CoNS considered contaminants). Six species detected by culture were not in the PCR menu (e.g Listeria, Salmonella).

I think these results speak for themselves. Neither method is perfectly sensitive at this point suggesting that both methods should be used if possible to improve diagnosis. PCR can be quicker and detect additional organisms, but still missed a significant number. Interestingly, blood culture was more sensitive in detecting organisms from patients who had previously received antibiotics (P = 0.06). This is counter to what I would've suspected.

What I really liked about this paper is that it was completed in a way that was clinically useful since they enrolled patients as they presented to the ED and asked the question in the way a clinician would. This was not some convenient sample study which we so frequently see in diagnostic test comparisons. I also liked how they presented the information, giving the sensitivity/specificity, predictive values and AUC. It will be interesting to see if future studies can document a clinical benefit in terms of reduced mortality and length of stay when PCR is added to our diagnostic battery. Finally, I was impressed that this study was completed at all. Enrolling so many septic patients with questionnaires over such a long period of time is no small feat. The authors should be congratulated.