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.

Trial of Extubation: An Informed Empiricist’s Approach to Ventilator Weaning

“The only way of discovering the limits of the possible is to venture a little way past them into the impossible.”    –Clark’s Second Law

In the first blog post, Dr. Manthous invited Drs. Ely, Brochard, and Esteban to respond to a simple vignette about a patient undergoing weaning from mechanical ventilation.  Each responded with his own variation of a cogent, evidence based, and well-referenced/supported approach.  I trained with experts of similar ilk using the same developing evidence base, but my current approach has evolved to be something of a different animal altogether.  It could best be described as a “trial of extubation”.  This approach recently allowed me to successfully extubate a patient 15 minutes into a trial of spontaneous breathing, not following commands, on CPAP 5, PS 5, FiO2 0.5 with the vital parameters in the image accompanying this post (respiratory rate 38, tidal volume 350, heart rate 129, SpO2 88%, temperature 100.8).  I think that any account of the “best” approach to extubation should offer an explanation as to how I can routinely extubate patients similar to this one, who would fail most or all of the conventional prediction tests, with a very high success rate.

A large part of the problem lies in shortcomings of the data upon which conventional prediction tests rely.  For example, in the landmark Yang and Tobin report and many reports that followed, sensitivity and specificity were calculated considering physicians’ “failure to extubate” a patient as equivalent to an “extubation failure”.  This conflation of two very different endpoints makes estimates of sensitivity and specificity unreliable.  Unless every patient with a prediction test is extubated, the sensitivity of a test for successful extubation is going to be an overestimate, as suggested by Epstein in 1995.   Furthermore, all studies have exclusion criteria for entry, with the implicit assumption that excluded patients would not be extubatable with the same effect of increasing the apparent sensitivity of the tests.

Even if we had reliable estimates of sensitivity and specificity of prediction tests, the utility calculus has traditionally been skewed towards favoring specificity for extubation success, largely on the basis of a single 20-year old observational study suggesting that patients who fail extubation have a higher odds of mortality.  I do not doubt that if patients are allowed to “flail” after it becomes clear that they will not sustain unassisted ventilation, untoward outcomes are likely.  However, in my experience and estimation, this concern can be obviated by bedside vigilance by nurses and physicians in the several hours immediately following extubation (with the caveat that a highly skilled airway manager is present or available to reintubate if necessary).  Furthermore, this period of observation provides invaluable information about the cause of failure in the event failure ensues.  There need be no further guesswork about whether the patient can protect her airway, clear her secretions, maintain her saturations, or handle the work of breathing.  With the tube removed, what would otherwise be a prediction about these abilities becomes an observation, a datapoint that can be applied directly to the management plan for any subsequent attempt at extubation should she fail – that is, the true weak link in the system can be pinpointed after extubation.

The specificity-heavy utility calculus, as I have opined before, will fail patients if I am correct that an expeditious reintubation is not harmful, but each additional day spent on the ventilator confers incremental harm.  Why don’t I think reintubations are harmful?  Because when my patients fail, I am diligent about rapid recognition, I reintubate without observing complications, and often I can extubate successfully the next day, as I did a few months ago in a patient with severe ARDS.  She had marginal performance (i.e., she failed all prediction tests) and was extubated, failed, was reintubated, then successfully extubated the next day.  (I admit that it was psychologically agonizing to extubate her the next day.  They say that a cat that walks across a hot stove will never do so again.  It also will not walk on a cold stove again.  This psychology deserves a post of its own.)

When I tweeted the image attached to this post announcing that the patient (and many like her) had been successfully extubated, there was less incredulity than I expected, but an astute follower asked – “Well, then, how do you decide whom and when to extubate?”  I admit that I do not have an algorithmic answer to this question.  Experts in opposing camps of decision psychology such as Kahneman and his adherents in the heuristics and biases camp and Gary Klein, Gird Gigerenzer and others in the expert intuition camp could have a heyday here, and perhaps some investigation is in order.  I can summarize by saying that it has been an evolution over the past 10 or so years.  I use everything I learned from the conventional, physiologic, algorithmic, protocolized, data-driven, evidence-based approach to evaluate a patient.  But I have gravitated to being more sensitive, to capture those patients that the predictors say should fail, and I give them a chance – a “trial of extubation.”  If they fail, I reintubate quickly.  I pay careful attention to respiratory parameters, mental status, and especially neuromuscular weakness, but I integrate this information into my mental map of the natural history of the disease and the specific patient’s position along that course to judge whether they have even a reasonable modicum of a chance of success.  If they do, I “bite the bullet and pull it.”

I do not eschew data, I love data.  But I am quick to recognize their limitations.  Data are generated for many reasons and have different values to different people with different prerogatives.  From the clinician’s and the patient’s perspective, the data are valuable if they reduce the burden of illness.  I worry that the current data and the protocols predicated on them are failing to capture many patients who are able to breathe spontaneously but are not being given the chance.  Hard core evidence based medicine proponents and investigators need not worry though, because I have outlined a testable hypothesis:  that a “trial of extubation” in the face of uncertainty is superior to the use of prediction tests and protocols.  The difficult part will be determining the inclusion and exclusion criteria, and no matter what compromise is made uncertainty will remain, reminding us that science is an iterative, evolving enterprise, with conclusions that are always tentative.