Hollow Hegemony: The Opportunity Costs of Overemphasizing Sepsis

Protocols are to make complex tasks simple, not simple tasks complex. - Scott K Aberegg

Yet here we find ourselves some 16 years after the inauguration of the Surviving Sepsis Campaign, and their influence continues to metastasize, even after the message has been hollowed out like a piece of fallen, old-growth timber.

Surviving sepsis was the brainchild of Eli Lilly, who, in the year after the ill-fated FDA approval of drotrecogin-alfa, worried that the drug would not sell well if clinicians did not have an increased awareness of sepsis. That aside, in those days, there were legitimate questions surrounding the adoption and implementation of several new therapies such as EGDT, corticosteroids for septic shock, Xigris for those with APACHE scores over 25, intensive insulin therapy, etc.

Those questions are mostly answered. Sepsis is now, quite simply, a complex of systemic manifestations of infection almost all of which will resolve with treatment of the infection and general supportive care. The concept of sepsis could vanish entirely, and nothing about the clinical care of the patient would change: an infection would be diagnosed, the cause/source identified and treated, and hemodynamics and laboratory dyscrasias supported meanwhile. There is nothing else to do (because lactic acidosis does not exist.)

But because of the hegemony of the sepsis juggernaut (the spawn of the almighty dollar), we are now threatened with a mandate to treat patients carrying the sepsis label (oftentimes assigned by a hospital coder after the fact) with antibiotics and a fluid bolus within one hour of triage in the ED. Based on what evidence?

Weak recommendation, "Best Practice Statement" and some strong recommendations based on low and moderate quality evidence.  So if we whittle it down to just moderate quality of evidence, what do we have?  Give antibiotics for infections, and give vasopressors if MAP less than 65.  But now we have to hurry up and do the whole kit and caboodle boiler plate style within 60 minutes?

Sepsis need not be treated any differently than a gastrointestinal hemorrhage, or for that matter, any other disease.  You make the diagnosis, determine and control the cause (source), give appropriate treatments, and support the physiology in the meantime, all while prioritizing the sickest patients.  But that counts for all diseases, not just sepsis, and there is only so much time in an hour.  When every little old lady with fever and a UTI suddenly rises atop the priorities of the physician, this creates an opportunity cost/loss for the poor bastard bleeding next door who doesn't have 2 large-bore IVs or a type and cross yet because grandma is being flogged with 2 liters of fluid, and in a hurry.  If only somebody had poured mega-bucks into increased recognition and swift treatment of GI bleeds....

Petition to retire the surviving sepsis campaign guidelines:

(Sign the Petition Here.)

Friends,

Concern regarding the Surviving Sepsis Campaign (SSC) guidelines dates back to their inception.  Guideline development was sponsored by Eli Lilly and Edwards Life Sciences as part of a commercial marketing campaign (1).  Throughout its history, the SSC has a track record of conflicts of interest, making strong recommendations based on weak evidence, and being poorly responsive to new evidence (2-6).

The original backbone of the guidelines was a single-center trial by Rivers defining a protocol for early goal-directed therapy (7).  Even after key elements of the Rivers protocol were disproven, the SSC continued to recommend them.  For example, SSC continued to recommend the use of central venous pressure and mixed venous oxygen saturation after the emergence of evidence that they were nonbeneficial (including the PROCESS and ARISE trials).  These interventions eventually fell out of favor, despite the slow response of SSC that delayed knowledge translation. 

SSC has been sponsored by Eli Lilly, manufacturer of Activated Protein C.  The guidelines continued recommending Activated Protein C until it was pulled from international markets in 2011.  For example, the 2008 Guidelines recommended this, despite ongoing controversy and the emergence of neutral trials at that time (8,9).  Notably, 11 of 24 guideline authors had financial conflicts of interest with Eli Lilly (10).

The Infectious Disease Society of America (IDSA) refused to endorse the SSC because of a suboptimal rating system and industry sponsorship (1).  The IDSA has enormous experience in treating infection and creating guidelines.  Septic patients deserve a set of guidelines that meet the IDSA standards.

Guidelines should summarize evidence and provide recommendations to clinicians.  Unfortunately, the SSC doesn’t seem to trust clinicians to exercise judgement.  The guidelines infantilize clinicians by prescribing a rigid set of bundles which mandate specific interventions within fixed time frames (example above)(10).  These recommendations are mostly arbitrary and unsupported by evidence (11,12).  Nonetheless, they have been adopted by the Centers for Medicare & Medicaid Services as a core measure (SEP-1).  This pressures physicians to administer treatments despite their best medical judgment (e.g. fluid bolus for a patient with clinically obvious volume overload).

We have attempted to discuss these issues with the SSC in a variety of forums, ranging from personal communications to formal publications (13-15).  We have tried to illuminate deficiencies in the SSC bundles and the consequent SEP-1 core measures.  Our arguments have fallen on deaf ears. 

We have waited patiently for years in hopes that the guidelines would improve, but they have not.  The 2018 SSC update is actually worse than prior guidelines, requiring the initiation of antibiotics and 30 cc/kg fluid bolus within merely sixty minutes of emergency department triage (16).  These recommendations are arbitrary and dangerous.  They will likely cause hasty management decisions, inappropriate fluid administration, and indiscriminate use of broad-spectrum antibiotics.  We have been down this path before with other guidelines that required antibiotics for pneumonia within four hours, a recommendation that harmed patients and was eventually withdrawn (17).

It is increasingly clear that the SSC guidelines are an impediment to providing the best possible care to our septic patients.  The rigid framework mandated by SSC doesn’t help experienced clinicians provide tailored therapy to their patients.  Furthermore, the hegemony of these guidelines prevents other societies from developing better guidelines.

We are therefore petitioning for the retirement of the SSC guidelines.  In its place, we would call for the development of separate sepsis guidelines by the United States, Europe, ANZICS, and likely other locales as well.  There has been a monopoly on sepsis guidelines for too long, leading to stagnation and dogmatism.  We would hope that these new guidelines are written by collaborations of the appropriate professional societies, based on the highest evidentiary standards.  The existence of several competing sepsis guidelines could promote a diversity of opinions, regional adaptation, and flexible thinking about different approaches to sepsis. 

We are disseminating an international petition that will allow clinicians to express their displeasure and concern over these guidelines.  If you believe that our septic patients deserve more evidence-based guidelines, please stand with us.  

Sincerely,

Scott Aberegg MD MPH

Jennifer Beck-Esmay MD

Steven Carroll DO MEd

Joshua Farkas MD

Jon-Emile Kenny MD

Alex Koyfman MD

Michelle Lin MD

Brit Long MD

Manu Malbrain MD PhD

Paul Marik MD

Ken Milne MD

Justin Morgenstern MD

Segun Olusanya MD

Salim Rezaie MD

Philippe Rola MD

Manpreet Singh MD

Rory Speigel MD

Reuben Strayer MD

Anand Swaminathan MD

Adam Thomas MD
Lauren Westafer DO MPH

Scott Weingart MD

References

1. Eichacker PQ, Natanson C, Danner RL.  Surviving Sepsis – Practice guidelines, marketing campaigns, and Eli Lilly.  New England Journal of Medicine  2006; 16: 1640-1642.
2. Pepper DJ, Jaswal D, Sun J, Welsch J, Natanson C, Eichacker PQ.  Evidence underpinning the Centers for Medicare & Medicaid Services’ Severe Sepsis and Septic Shock Management Bundle (SEP-1): A systematic review.  Annals of Internal Medicine 2018; 168:  558-568. 
3. Finfer S.  The Surviving Sepsis Campaign:  Robust evaluation and high-quality primary research is still needed.  Intensive Care Medicine  2010; 36:  187-189.
4. Salluh JIF, Bozza PT, Bozza FA.  Surviving sepsis campaign:  A critical reappraisal.  Shock 2008; 30: 70-72. 
5. Eichacker PQ, Natanson C, Danner RL.  Separating practice guidelines from pharmaceutical marketing.  Critical Care Medicine 2007; 35:  2877-2878. 
6. Hicks P, Cooper DJ, Webb S, Myburgh J, Sppelt I, Peake S, Joyce C, Stephens D, Turner A, French C, Hart G, Jenkins I, Burrell A.  The Surviving Sepsis Campaign:  International guidelines for management of severe sepsis and septic shock: 2008.  An assessment by the Australian and New Zealand Intensive Care Society.  Anaesthesia and Intensive Care 2008; 36: 149-151.
7. Rivers ME et al.  Early goal-directed therapy in the treatment of severe sepsis and septic shock.  New England Journal of Medicine 2001; 345: 1368-1377.
8. Wenzel RP, Edmond MB.  Septic shock – Evaluating another failed treatment.  New England Journal of Medicine 2012; 366:  2122-2124.  
9. Savel RH, Munro CL.  Evidence-based backlash:  The tale of drotrecogin alfa.  American Journal of Critical Care  2012; 21: 81-83. 
10. Dellinger RP, Levy MM, Carlet JM et al.  Surviving sepsis campaign:  International guidelines for management of severe sepsis and septic shock:  2008.  Intensive Care Medicine 2008; 34:  17-60. 
11. Allison MG, Schenkel SM.  SEP-1:  A sepsis measure in need of resuscitation?  Annals of Emergency Medicine 2018; 71: 18-20.
12. Barochia AV, Xizhong C, Eichacker PQ.  The Surviving Sepsis Campaign’s revised sepsis bundles.  Current Infectious Disease Reports 2013; 15:  385-393. 
13. Marik PE, Malbrain MLNG.  The SEP-1 quality mandate may be harmful: How to drown a patient with 30 ml per kg fluid!  Anesthesiology and Intensive Therapy 2017; 49(5) 323-328.
14. Faust JS, Weingart SD.  The past, present, and future of the centers for Medicare and Medicaid Services quality measure SEP-1:  The early management bundle for severe sepsis/septic shock.  Emergency Medicine Clinics of North America 2017; 35:  219-231.
15. Marik PE.  Surviving sepsis:  going beyond the guidelines.  Annals of Intensive Care 2011; 1: 17.
16. Levy MM, Evans LE, Rhodes A.  The surviving sepsis campaign bundle:  2018 update.  Intensive Care Medicine.  Electronic publication ahead of print, PMID 29675566.
17. Kanwar M, Brar N, Khatib R, Fakih MG.  Misdiagnosis of community-acquired pneumonia and inappropriate utilization of antibiotics: side effects of the 4-h antibiotic administration rule.  Chest 2007; 131: 1865-1869.

Early Mobility in the ICU: The Trial That Should Not Be

I learned via twitter yesterday that momentum is building to conduct a trial of early mobility in critically ill patients.  While I greatly respect many of the investigators headed down this path, forthwith I will tell you why this trial should not be done, based on principles of rational decision making.

A trial is a diagnostic test of a hypothesis, a complicated and costly test of a hypothesis, and one that entails risk.  Diagnostic tests should not be used indiscriminately.  That the RCT is a "Gold Standard" in the hierarchy of testing hypotheses does not mean that we should hold it sacrosanct, nor does it follow that we need a gold standard in all cases.  Just like in clinical medicine, we should be judicious in our ordering of diagnostic tests.

The first reason that we should not do a trial of early mobility (or any mobility) in the ICU is because in the opinion of this author, experts in critical care, and many others, early mobility works.  We have a strong prior probability that this is a beneficial thing to be doing (which is why prominent centers have been doing it for years, sans RCT evidence).  When the prior probability is high enough, additional testing has decreasing yield and risks false negative results if people are not attuned to the prior.  Here's my analogy - a 35 year old woman with polycystic kidney disease who is taking birth control presents to the ED after collapsing with syncope.  She had shortness of breath and chest pain for 12 hours prior to syncope.  Her chest x-ray is clear and bedside ultrasound shows a dilated right ventricle.  The prior probability of pulmonary embolism is high enough that we don't really need further testing, we give anticoagulants right away.  Even if a V/Q scan (creatnine precludes CT) is "low probability" for pulmonary embolism, we still think she has it because the prior probability is so high.  Indeed, the prior probability is so high that we're willing to make decisions without further testing, hence we gave heparin.  This process follows the very rational Threshold Approach to Decision Making approach proposed by Pauker and Kasirrer in the NEJM in 1980, which is basically a reformulation of VonNeumann and Morganstern's Expected Utility Theory to adapt it to medical decisions.  Distilled it states in essence, "when you get to a threshold probability of disease where the benefits of treatment exceed the risks, you treat."  And so let it be with early mobility.  We already think the benefits exceed the risks, which is why we're doing it.  We don't need a RCT.  As I used to ask the housestaff over and over until I was cyanotic: "How will the results of that test influence what you're going to do?"

Notice that this logical approach to clinical decision making shines a blinding light upon "evidence based medicine" and the entire enterprise of testing hypotheses with frequentist methods that are deaf to prior probabilities.  Can you imagine using V/Q scanning to test for PE without prior probabilities?  Can you imagine what a mess you would find yourself in with regard to false negatives and false positives?  You would be the neophyte medical student who thinks "test positive, disease present; test negative, disease absent."  So why do we continue ad nauseum in critical care medicine to dismiss prior probabilities and decision thresholds and blindly test hypotheses in a purist vacuum?

The next reasons this trial should not be conducted flow from the first.  The trial will not have a high enough likelihood ratio to sway the high prior below the decision threshold; if the trial is "positive" we will have spent millions of dollars to "prove" something we already knew at a threshold above our treatment threshold; if the trial is positive, some will squawk "It wasn't blinded" yada yada yada in an attempt to dismiss the results as false positives; if the trial is negative, some will, like the tyro medical student, declare that "there is no evidence for early mobility" and similar hoopla and poppycock; or the worst case:  the trial shows harm from early mobility, which will get the naysayers of early mobility very agitated.  But of course, our prior probability that early mobility is harmful is hopelessly low, making such a result highly likely to be spurious.  When we clamor about "evidence" we are in essence clamoring about "testing hypotheses with RCTs" and eschewing our responsibility to use clinical judgment, recognize the limits of testing, and practice in the face of uncertainty using our "untested" prior probabilities.

Consider a trial of exercise on cardiovascular outcomes in community dwelling adults - what good can possibly come of such a trial?  Don't we already know that exercise is good for you?  If so, a positive trial reinforces what we already know (but does little to convince sedentary folks to exercise, as they too already know they should exercise), but a negative trial risks sending the message to people that exercise is of no use to you, or that the number needed to treat is too small for you to worry about.

Or consider the recent trials of EGDT which "refuted" the Rivers trial from 14 years ago.  Now, everybody is saying, "Well, we know it works, maybe not the catheters and the ScVO2 and all those minutaie , but in general, rapid early resuscitation works.  And the trials show that we've already incorporated what works into general practice!"

I don't know the solutions to these difficult quandries that we repeatedly find ourselves in trial after trial in critical care medicine.  I'm confused too.  That's why I'm thinking very hard and very critically about the limits of our methods and our models and our routines.  But if we can anticipate not only the results of the trials, but also the community reaction to them, then we have guidance about how to proceed in the future.  Because what value does a mega-trial have, if not to guide care after its completion?  And even if that is not its goal, (maybe its goal is just to inform the science), can we turn a blind eye to the fact that it will guide practice after its completion, even if that guidance is premature?

It is my worry that, given the high prior probability that a trial in critical care medicine will be "negative", the most likely result is a negative trial which will embolden those who wish to dismiss the probable benefits of early mobility and give them an excuse to not do it.

Diagnostic tests have risks.  A false negative test is one such risk.

Is There a Baby in That Bathwater? Status Quo Bias in Evidence Appraisal in Critical Care

"But we are not here concerned with hopes and fears, only the truth so far as our reason allows us to discover it."  -  Charles Darwin, The Descent of Man

Status quo bias is a cognitive decision making bias that leads to decision makers' preference for the choice represented by the current status quo, even when the status quo is arbitrary or irrelevant.  Decision makers tend to perceive a change from the status quo as a loss and therefore their decisions are biased toward the status quo.  This can lead to preference reversals when the status quo reference frame is changed.  The status quo can be debiased using a reversal test, i.e., manipulating the status quo either experimentally or via thought experiment to consider a change in the opposite direction.  If reluctance to change from the status quo exists in both directions, status quo bias is likely to exist.

My collaborators Peter Terry, Hal Arkes and I reported in a study published in 2006 that physicians were far more likely to abandon a therapy that was status quo or standard therapy based on new evidence of harm than they were to adopt an identical therapy based on the same evidence of benefit from a fictitious RCT (randomized controlled trial) presented in the vignette.  These results suggested that there was an asymmetric status quo bias - physicians showed a strong preference for the status quo in the adoption of new therapies, but a strong preference for abandoning the status quo when a standard of care was shown to be harmful.  Two characteristics of the vignettes used in this intersubject study deserve attention.  First, the vignettes described a standard or status quo therapy that had no support from RCTs prior to the fictitious one described in the vignette.  Second, this study was driven in part by what I perceived at the time was a curious lack of adoption of drotrecogin-alfa (Xigris), with its then purported mortality benefit and associated bleeding risk.  Thus, our vignettes had very significant trade-offs in terms of side effects in both the adopt and abandon reference frames.  Our results seemed to explain s/low uptake of Xigris, and were also consistent with the relatively rapid abandonment of hormone replacement therapy (HRT) after publication of the WHI, the first RCT of HRT.

Sepsis Bungles: The Lessons of Early Goal Directed Therapy

On March 18th, the NEJM published early online three original trials of therapies for the critically ill that will serve as fodder for several posts.  Here, I focus on the ProCESS trial of protocol guided therapy for early septic shock.  This trial is in essence a multicenter version of the landmark 2001 trial of Early Goal Directed Therapy (EGDT) for severe sepsis by Rivers et al.  That trial showed a stunning 16% absolute reduction in mortality in sepsis attributed to the use of a protocol based on physiological goals for hemodynamic management.  That absolute reduction in mortality is perhaps the largest for any therapy in critical care medicine.  If such a reduction were confirmed, it would make EGDT the single most important therapy in the field.  If such reduction cannot be confirmed, there are several reasons why the Rivers results may have been misleading:

• As I have blogged in the case of intensive insulin therapy, Single center studies inflate treatment effects when compared to multicenter studies for reasons that are unclear, but which may be related to bias especially in unblinded studies.  (The revelation that Rivers was an investor in one of the devices used in the trial raised additional concerns about bias.)
• Regression to the mean may lead to reduced effect sizes when trials are repeated, especially when the index trial has a very large effect size.  In a similar vein, since large absolute mortality reductions are statistically unlikely in critical care medicine, Bayesian inference means that trials reporting large reductions are likely to represent type I statistical errors.

There were other concerns about the Rivers study and how it was later incorporated into practice, but I won't belabor them here.  The ProCESS trial randomized about 1350 patients among three groups, one simulating the original Rivers protocol, one to a modified Rivers protocol, and one representing "standard care" that is, care directed by the treating physician without a protocol.  The study had 80% power to demonstrate a mortality reduction of 6-7%.  Before you read further, please wager, will the trial show any statistically significant differences in outcome that favor EGDT or protocolized care?

Another [the final?] nail in the coffin of intensive insulin therapy (Leuven Protocol) - and redoubled scrutiny of single center studies

In the March 26th edition of the NEJM, the NICE-SUGAR study investigators publish the results of yet another study of intensive insulin therapy in critically ill patients: http://content.nejm.org/cgi/content/abstract/360/13/1283 .

This article is of great interest to critical care practitioners because intensive insulin therapy (Leuven Protocol) or some diluted or half-hearted version of it has become a de facto standard of care in ICUs across the nation and indeed worldwide; and because it is an incredibly well-designed and well-conducted study. My own interest derives also from my own [prescient] letter to the editor of the NEJM after the second Van den Berghe study (http://content.nejm.org/cgi/content/extract/354/19/2069 , the criticisms I levied against this therapy on this blog after another follow-up study recently showed negative results (http://medicalevidence.blogspot.com/2008/01/jumping-gun-with-intensive-insulin.html ), and in a recent paper railing against the "normalization heuristic" (http://www.medical-hypotheses.com/article/S0306-9877(09)00033-4/abstract ). The results of this study also add to the growing evidence that intensive control of hyperglycemia in other settings may not be beneficial (see the ACCORD and ADVANCE studies.)

The current study was designed to largely mirror the enrollment criteria and outcome definitions of the previous studies, had excellent follow-up, had well described and simple statistical analyses with ample power, and is well reported. Key differences between it and the original Van den Berghe study were the lack of high-calorie parenteral glucose infusions, and its multicenter design. This latter characteristic may be pivotal in understanding why the initially promising Leuven Protocol results have not panned out on subsequent study.

The results of this study can be summarized simply by saying that it appears that this therapy is of NO benefit and actually probably kills patients, in addition to markedly increasing the rate of very very severe hypoglycemia (6.3% increase, P<0.001). In contrast to Van den Berghe's second study in medical patients, there were no favorable trends towards reduction in ICU length of stay, time on the ventilator, or reduced organ failures. In short, this therapy appears to be a complete flop.

So why the difference? Why did this therapy, which in 2001 appeared to have such promise that it enjoyed rapid and widespread [and premature] adoption fail to withstand the basic test of science, namely, repeatability? I think that medical history will judge two factors to be responsible. Firstly, the massive dextrose infusions in the first study markedly jeporadized the external validity of the first (positive) Van den Berghe study - it's not that intensive insulin saves you from your illness, it saves you from the harmful caloric infusions used in the surgical patients in the first study.

Secondly, and this is related to the first, single center studies also compromise external validity. In a single center, local practice patterns may be uniform and idiosyncratic, so that the benefit of any therapy tested in such a center may also be idiosyncratic. Moreover, and I dare say, investigators at a single center may have more decisional latitude and control or influence over enrollment, ascentainment of outcomes, and clinical care of enrolled patients. The so-called "trial effect" whereby patients enrolled in a trial receive superior care and have superior outcomes may be more likely in single center studies. Such effects are of increased concern in trials whre total blinding/masking or treatment assignment is not possible. (Recall that in the Van den Berghe study, kan endocrinologist was consulted for insulin adjustments; in the current trial, a computerized algorithm controlled the adjustments.) Moreover still, for single center studies, investigators and the instutution itself may have more "riding on" the outcome of the study, and collective equipoise may not exist. As an "analogy of extremes", just for illustrative purposes, if you wanted to design a trial where you could subversively influence outcomes in a way that would not be apparent from the outside, would you design a single center study (at your own institution where your cronies were) or a large multicenter, multinational study? Which design would allow you to have more influence?

I LOVE the authors' concluding statement that "a clinical trial targeting a perceived risk factor is a test of a complex strategy that may have profound effects beyond its effect on the risk factor." This resonates beautifully with our conceptualization of the "normalization heuristic" and harkens to Ben Franklin's sage old saw that "He is the best physician who knows the worthlessness of the most medicines." I think that we now have more than ample data to assure us that intensive insulin therapy (i.e., targeting a blood sugar of 80-108) is a worthless medicine, and should be largely if not wholly abandoned.

Addendum 4/7/09: Also note the scrutiny of the only other "positive" study (with mortality as the primary endpoint) in critical care in the last decade: Rivers et al; see: http://online.wsj.com/article/SB121867179036438865.html .