Sepsis Update: Lactate, Antibiotics, and Procalcitonin


Sepsis is one of the decade’s most heavily debated topics in emergency medicine and intensive care and is among one of the most prevalent reasons for admission to intensive care units (ICUs). Many of the current articles on sepsis estimate as many as 750,000 cases a year of which 225,000 resulted in mortality.1,2

In 2002 the Society of Critical Care Medicine, the European Society of Intensive Care and the International Sepsis Forum collaborated under the sponsorship of Eli Lilly and Edwards Lifesciences3 to form 52 recommendations in an attempt to improve outcomes in this high-risk disease process.4 These recommendations were based primarily on grade E evidence that was predominantly derived out of one single center study.5 This protocol obligates physicians to be quick to perform invasive procedures such as central and arterial line placement and also calls for other treatments like administering early empiric antibiotics, pressors, and blood products which all carry risk.

While the improvement in mortality in some studies that utilized these “bundles” is staggering, some have questioned exactly which parts of the bundle are beneficial, which parts are not, and which parts may be causing harm.6,7,8 The purpose of this update is to focus on what some consider the evidence-based medicine cornerstones of sepsis management as well as some new data that should lead us all to question our current practices.9


  • The current working diagnosis for sepsis is two systemic inflammatory response syndrome (SIRS) criteria and a suspected infection, but how do we separate the sick from the lame and lazy?
    • Severe sepsis: Includes end-organ damage
    • Septic shock: Hypotension despite fluid resuscitation
  • Early antibiotics have been shown to improve mortality
    • Low threshold to give empiric antibiotics

What’s New


Many time-sensitive conditions have clearly defined tests to screen for and diagnose these conditions. For example, every patient with chest pain gets an EKG so an ST-Elevation Myocardial Infarction (STEMI) is not missed because “time is heart.” Every patient with symptoms concerning for stroke is risk-stratified with the Cincinnati stroke scale and immediately undergoes a head CT because “time is brain.” However currently, there is not a universally accepted “sepsis lab” that shows positive or negative for sepsis, nor is there imaging that shows the “sepsis sign.” Because of this we need to look for surrogate markers of sepsis, such as the SIRS criteria, and stratify the severity based on organ dysfunction, hypotension, and hyperlactatemia.

Lactate has become the best screening tool, not only to screen for sepsis but it can also be used as a marker of severity. Trending the lactate level as a treatment marker early in the disease process is now routine practice. Most emergency department (ED) sepsis screening tools utilize the SIRS criteria as a trigger to pull any variety of screening labs. Studies have shown that a lactate of >4 has a significantly higher mortality than a level <2.10 Lactate levels have shown a linear and proportional correlation with mortality.11 One study used lactate and hypotension as a marker for septic shock. Physicians have classically used hypotension to stratify a patient’s degree of morbidity, but it is vitally important that we realize the dangers of relying on hypotension alone to clinch this diagnosis. Approximately one half of the patients with a lactate of >4 had a systolic blood pressure of >90. Patients with elevated lactate and normal or high blood pressures had the same mortality as the patients with hypotension alone.5

What’s new: We should absolutely be utilizing lactate screening in patients with suspected sepsis. An elevated lactate should be treated as at least an equivalent to hypotension, if not a more concerning predictor of mortality.

Antibiotic Use

Patients along the sepsis spectrum receive early antibiotics per the guidelines4 in spite of controversial data concerning empiric antibiotic use in ED.12,13 While studies do report improvement in survival rates with early antibiotic use in patients along the sepsis spectrum14,15,16 there is also concern for antibiotic misuse and overuse.17,18

To illustrate an example, a young healthy patient could present to an ED complaining of a cough.  This patient has temperature of 100.5 F, a heart rate of 91 and is tachypneic to 22 breaths per minute and will likely get early empiric antibiotics. This is due to the fact that The Joint Commission (TJC) and the Center for Medicare & Medicaid Services (CMS) have set forth guidelines to meet a 4 hour antibiotic window and if a clinician does not give this well-appearing patient IV antibiotics, it may be reported publicly as a quality measure and could result in a “ding” on the hospital’s core competencies.19,20

It does stand to reason that if a patient is suffering the sepsis clinical syndrome that a bacterial infection is likely to be the cause. In res ipsa loquitur fashion, an appropriate antibiotic aimed at the specific bacteria in a timely fashion should improve outcomes. This is reminiscent of the 2003 British Medical Journal article on whether or not the utilization of parachutes will prevent major trauma related to a “gravitational challenge.”21 However, empiric antibiotics for all patients that trigger the sepsis criteria may lead to misuse and overuse.

What’s new: While it is very likely that early antibiotics in the severe sepsis or septic shock patient probably leads to improved survival and outcomes, the data is not so clear on patients that merely meet SIRS criteria with suspected infection. We may actually be harming these patients and creating resistant strains of bacteria. Because of this, we may see changes in the future regarding which patients should get antibiotics and which should not, and what time is an adequate “time to antibiotics.”


For ethical reasons, it is very difficult to construct a worthwhile study that would definitively describe which patients should get antibiotics and when. There is concern that antibiotic misuse and overuse can lead to inappropriate administration to patients who don’t need them, on the other hand, worrying too much about this could also lead to a delay in treating patients that would benefit from treatment. While it may be difficult to limit antibiotic use up-front in the ED, it may be worthwhile to explore a marker utilized to indicate when to stop antibiotics. Procalcitonin may be the answer to this dilemma.

Procalcitonin (PCT) is a biologically active precursor to the calcium-modulating hormone calcitonin.22 It has been shown to be associated with bacterial infections and correlate with the degree of infection.23,24,25 One small study showed that procalcitonin measurements in specific patients may decrease the duration of antibiotics while concurrently shortening the patient’s ICU stay.26 Currently, procalcitonin is used in academic centers and is often a “send out” lab that may take days to get results from, this unavoidable delay results in decreased real-time clinical decision making. Much of the new data written on the use of PCT and ongoing trials are aiming to further elucidate its utility in critically ill patients. If PCT becomes a test that can be ordered and resulted in a timely fashion in community hospitals it may become a routinely ordered lab on patients with suspected sepsis.

One study showed that PCT may be superior to the currently accepted markers that we use to diagnose infection such as the white blood cell count and C-reactive protein.27 A new meta-analysis in the Lancet Infectious Disease journal showed that PCT may be utilized as a screening biomarker for the early diagnosis of sepsis.28 However not all of the data hails PCT as the answer to all sepsis related questions. Some new and preliminary data raise questions as to the utility of procalcitonin at all. One study, the PROcalcitonin to Reduce Antibiotic Treatment in Acute-Ill Patients (PRORATA) trial, showed promise to further elucidate these questions, but was stopped due to slow enrollment.29 Likewise, the Procalcitonin and Survival Study (PASS) study also did not show favorable outcomes in a randomized controlled trial in which one arm used PCT measurements to escalate and de-escalate antibiotics.30

What’s new: Procalcitonin may be used in the future of sepsis, but currently its utility is not certain. There has been some conflicting data as to whether or not PCT can be used as a screening biomarker in the ED or whether it may be used to streamline antibiotic use in the intensive care unit setting.

Bottom Line/Pearls & Pitfalls

  • The recognition of sepsis should be viewed as the first step in management.
  • Lactate may be a better predictor of “badness” in our ED patients even if they have an adequate blood pressure and “look good.”
  • Early antibiotics are probably beneficial for the septic patient, but using “time-to-antibiotics” as a quality control measure may lead to inappropriate antibiotic administration.
  • Procalcitonin is probably not ready for prime-time in emergency departments, but may be a test that we will utilize in the future.

Further Reading / References

  1. Angus D, Linde-Zwirble W, Lidicker J, Clermont G, Carcillo J, Pinsky M. Epidemiology of severe sepsis in the United State: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303-10.
  2. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546-54.
  3. Eichacker PQ, Natanson C, Danner RL. Surviving sepsis–practice guideline, marketing campaigns, and Eli Lilly. N Engl J Med 2006;355:1640-2.
  4. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004; 32:858-73.
  5. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.
  6. Barochia AV, Cui X, Virberg D, Suffredini AF, O’Grady NP, Banks SM, Minneci P, Kern SJ, Danner RL, Natanson C, Eichacker PQ. Crit Care MEd 2010;38(2):668-78.
  7. Chamberlain DJ, Willis EM, Bersten AB. Aust Crit Care 2011; 24(4):229-43.
  8. Jones AE, Brown MD, Trzeciak S, Shapiro NI, Garrett JS, Heffner AC, Kline JA. Crit Care Med 2008;26(10):2734-9.
  9. Marik PE. Ann Intensive Care 2011;1(1):17.
  10. Shapiro NI, Howell MD, Talmor D, et al. Serum lactate as a predictor of mortality in emergency department patients with infection. Ann Emerg Med 2005;45:524-8.
  11. Birnbaumer DM. Lactate level correlates with prognosis in patients with suspected infection. Acad Emerg Med 2012;19:983.
  12. Mandell L.A. Wunderink R.G., Anzueto A., et al:  Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;(Suppl 2)44:S27-S72.
  13. Thompson D. The pneumonia controversy: hospitals grapple with 4-hour benchmark.  Ann Emerg Med 2006;47:259-261.
  14. Rivers E., Nguyen B., Havstad S., et al:  Early goal-directed therapy in the treatment of severe sepsis and septic shock.  N Engl J Med 2001;345:1368-1377.
  15. Trzeciak S., Dellinger R.P., Abate N.L., et al:  Translating research to clinical practice: a 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department. Chest 2006;129:225-232.
  16. Shapiro N.I., Howell M.D., Talmor D., et al:  Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol. Crit Care Med 2006;34:1025-1032.
  17. Pines J.M.:  Measuring antibiotic timing for pneumonia in the emergency department: another nail in the coffin. Ann Emerg Med 2007;49:561-563.
  18. Pines J.M.:  Profiles in patient safety: antibiotic timing in pneumonia and pay for performance. Acad Emerg Med 2006;13:787-790.
  19. Pines JM. Timing of antibiotics for acute, severe infections. Emerg Med Clin of N Am 2008;26:245-257.
  20. The Joint Commission for the Accreditation of Hospitals and Organization Specification Manual. Available at:
  21. Smith G, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ 2003;327:1459-61.
  22. Meisner M. Pathobiochemistry and clinical use of procalcitonin. Clin Chim Acta. 2002;323:17–29.
  23. Al Nawas B, Krammer I, Shah PM. Procalcitonin in diagnosis of severe infections. Eur J Med Res 1996;1:331–333.
  24. Castelli GP, Pognani C, Meisner M, Stuani A, Bellomi D, Sgarbi L. Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction. Crit Care. 2004;8:R234–R242.
  25. Brunkhorst FM, Wegscheider K, Forycki ZF, Brunkhorst R. Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock. Intensive Care Med.2000;26(Suppl 2):S148–S152.
  26. Simon P, Milbrandt EB, Emlet LL. Procalcitonin-guided antibiotics in severe sepsis. Crit Care 2008;12(6):309.
  27. Wanner GA, Keel M, Steckholzer U, Beier W, Stocker R, Ertel W. Relationship between procalcitonin plasma levels and severity of injury, sepsis, organ failure, and mortality in injured patients. Crit Care Med. 2000;28:950–957.
  28. Wacker C, Prnko A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis 2013;13(5):426-35.
  29. Clinical Trials Website which can be found at:
  30. Jensen JU et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med 2011;39(9):2048-58.
Edited by Alex Koyfman

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