Tag Archives: procalcitonin

Sepsis Biomarkers: What’s New?

Author: Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

A 43-year-old female presents with cough, congestion, wheezing, fever, and myalgias. She has a history of hypertension and recurrent UTI. She tried to overcome her symptoms with acetaminophen and oral fluids, but her symptoms have worsened. Her vital signs include RR 23, HR 102, BP 102/63, T 101.2, and Saturation 94% on RA. She has right-sided crackles on exam and appears ill, with dry mucosa. You start one liter of LR, while ordering CBC, renal panel, lactate, urinalysis, and chest Xray. Her chest Xray and urinalysis are negative, but after 1L LR, she still appears ill. The lactate returns at 4.2, and you start IV antibiotics with concern for septic shock. Your medical student on shift asks about using procalcitonin to rule out a bacterial cause of sepsis. You know about lactate, but are there other markers you can use in sepsis?

Sepsis is common in the ED and a major cause of morbidity and mortality. The body’s response to an infectious source in sepsis often results in dysregulated immune response, and current diagnosis relies on physiologic criteria and suspicion for a source of infection with laboratory and imaging studies. The host response triggered by the infection can be measured using several biomarkers.1-4

Biomarkers are defined by laboratory assessments used to detect and characterize disease, and they may be used to improve clinical decision-making. Through the years, complete blood cell count (CBC), troponin, creatine kinase (CK), lactate, C-reactive protein (CRP), ESR, and myoglobin have been advocated as biomarkers for a long list of conditions. However, what do biomarkers offer in sepsis? Some argue these biomarkers lack sufficient sensitivity outside of history and exam, while others state these markers can drastically improve medical decision making. In sepsis, diagnosis may not be easy, and a reliable biomarker may be able to improve early diagnosis, risk stratification, assessment of resuscitation, and evaluation.4-8

The post will evaluate several key biomarkers including lactate, procalcitonin, troponin, and novel lab assessments.


Lactate can be used in sepsis for resuscitation and severity stratification. It is normally produced in tissues due to pyruvate and NADH metabolism. There are several causes of lactate elevation, and not all are due to shock. Excess beta activity, inflammatory mediators, and liver disease may increase lactate.8-13  The table below demonstrates types and sources of lactate production.

Type A Type B1

Associated with disease

Type B2

Drugs and Toxins

Type B3

Associated with inborn errors of metabolism

Tissue Hypoperfusion


Anaerobic muscular activity


Reduced tissue oxygen delivery







Thiamine deficiency




Hepatic or renal failure


Short bowel syndrome







Lactate-based dialysate fluid



Alcohols: Methanol, Ethylene Glycol







Anti-retroviral agents

Pyruvate carboxylase deficiency


Glucose-6-phosphatase deficiency


Fructose-1,6-bisphosphatase deficiencies


Oxidative phosphorylation enzyme defects


The Surviving Sepsis Campaign recommends lactate for screening.1 Point of care (POC) lactate can be used for this screen, with specificity of 82% for lactate > 2 mmol/L. However, POC lactate has sensitivity of 30-40%, thus physicians must consider the clinical picture and patient appearance.11-16 Arterial blood is not required for this screening, and a venous blood gas (VBG) is fast and easily obtainable. As long as analysis occurs within 15 minutes of sampling, no effect from tourniquet or room temperature is observed.16,17 Lactate is not as reliable if the sample is run over 30 minutes from the time the sample is obtained.


As lactate elevates, mortality increases. In patients with lactate greater than 2.1 mml/L, mortality approximates 14-16%. If lactate reaches 20 mmol/L, mortality approximates 40% or higher.20 Lactate is an independent marker for mortality, no matter the patient’s hemodynamic status. Lactate greater than 4 mmol/L meets criteria for septic shock, and levels greater than 2 mmol/L are associated with increased mortality and morbidity.1,21-26

What about cryptic shock?

Cryptic shock is defined by sepsis in the patient with normal vital signs. A patient who is hemodynamically stable but with elevated lactate is at increased risk for mortality, as end organ damage occurs soon after lactate production. Thus, lactate serves as an early marker for shock and provides valuable diagnostic information. 9,11,20,21

What to do with the intermediate lactate level…

Lactate > 4 is associated with high mortality, but intermediate levels are as well (2.0-3.9 mmol/L).1,20-26 In fact, levels in this range meets Centers for Medicare and Medicaid Services (CMS) criteria for severe sepsis following SSC guidelines.Importantly, mortality can reach 16.4% for patients in this range, and ¼ of these patients with an intermediate level progress to clinical shock.22 Lactate levels greater than 2 warrant close monitoring and aggressive treatment with IV fluids and antimicrobials. The table below provides recommendations based on lactate level.

Lactate Level CMS Measure Resuscitation Recommendation
< 2 mmol/L None Lactate levels may be negative in over half of patients with sepsis. Clinical gestalt takes precedence over markers.
2-4 mmol/L Severe Sepsis Resuscitation with intravenous fluids, antimicrobials and reassessment of lactate within 60 minutes.
> 4 mmol/L Septic Shock Aggressive resuscitation warranted regardless of vital signs.


Lactate clearance is an important target in sepsis resuscitation. Many target a clearance of 10%, as early lactate clearance is associated with improved outcomes. Arnold et al. found 10% clearance to strongly predict improved outcomes.28 Delayed or no clearance is associated with high mortality, some studies showing 60% mortality rates.28-21 Lactate can be substituted for ScvO2, which requires invasive, specialized equipment.4,28-31


Lactate does not always elevate in sepsis, as 45% of patients with vasopressor-dependent septic shock demonstrate a lactate level of 2.4 mmol/L.32 Hernandez et al. suggested 34% of patients with septic shock did not have elevated lactate, though patients with no lactate elevation had a mortality of 7.7%, while those with lactate elevation 42.9% mortality.33 Lactate should not be used in isolation for assessing presence of shock or as a marker for clinical improvement. Rather, other measures such as mental status, heart rate, urine output, blood pressure, and distal perfusion in combination with lactate is advised.5-7,11



A great deal of literature has evaluated procalcitonin, a calcitonin propeptide produced by the thyroid, GI tract, and lungs with bacterial infection. This biomarker is released in the setting of toxins and proinflammatory mediators, while viral infections inhibit PCT through interferon-gamma production. These levels increase by 3 hours and peak at 6-22 hours, and with infection resolution, levels fall by 50% per day.5-7,34-40 This biomarker can be specific for bacterial infection, decreases with infection control, and is not impaired in the setting of immunosuppressive states (such as steroid use or neutropenia). However, other states including surgery, paraneoplastic states, autoimmune diseases, prolonged shock states, chronic parasitic diseases (such as malaria), certain immunomodulatory medications, and major trauma can increase PCT levels.34-37

Antibiotic Stewardship

Most of the literature evaluating PCT has been published in ICU studies for lower respiratory tract infections (LRTI) and sepsis. The literature suggests algorithms guided by PCT may be able to reduce antibiotic exposure and treatment cost, though with little to no effect on outcomes.37-49

In COPD and bronchitis, it can be difficult to differentiate viral versus bacterial infection. PCT may hold promise in assisting in this differentiation. The ProResp trial randomized patients to two arms, one guided by PCT and the other not.40 If PCT levels were greater than 0.25 mcg/L, antibiotics were given. Ultimately, the group based on PCT demonstrated less antibiotic use (44% in the PCT group, versus 83%), but no difference in length of stay or mortality.40 The ProHOSP trial was a similar trial with the same cutoff. This trial found similar results to the ProResp trial.41


PCT may be useful in sepsis diagnosis, but ultimately, the clinical context and picture must be considered.43-47 Source of infection, illness severity, and likelihood of bacterial infection should take precedence over a lab marker such as PCT, which may not return while the patient is in the ED. If concerned for sepsis, antimicrobials and resuscitation should be started.

 PCT can identify culture positive sepsis and may help in prognostication. Bacterial load may also correlate with level of PCT.34-47 PCT levels of < 0.25 mcg/L indicate that bacterial infection is unlikely, with levels greater than 0.25-0.50 mcg/L indicating bacterial source.38,45-49 However, sensitivity in one meta-analysis was 77%, with specificity of 79%.45

The PRORATA trial evaluated ICU patients admitted with sepsis.48 In this trial, antibiotic use was guided by PCT levels of 0.5 mcg/L. Similar to the prior studies discussed, decreased antibiotic use was found, but the all-important patient mortality benefit was not found. This level of 0.5 mcg/L was recommended as the cutoff for bacterial sepsis diagnosis in a 2015 meta-analysis.49  The following table depicts the PCT levels used in two key studies.

ProHOSP and PRORATA trial PCT Use41,48

Antibiotic Use PCT Level
< 0.1 mcg/L 0.1-0.25 mcg/L 0.25-0.5mcg/L 0.5-1mcg/L > 1.0 mcg/L
ProHOSP antibiotic use (respiratory infection only) No No Yes Yes Yes
PRORATA antibiotic use (sepsis patients in ICU) No No No Yes Yes

Ultimately, PCT should not influence provider decision to diagnose, resuscitate, and manage patients with criteria for sepsis.50,51 This lab may assist ICU providers, specifically when to discontinue antimicrobial therapy. Levels of 0.5 mcg/L strongly suggest bacterial sepsis. Providers in the ICU may be able to trend PCT levels in regards to decision of when to discontinue antimicrobials.  If the clinical picture suggests bacterial source, severe local infection (osteomyelitis, endocarditis, etc.), patient hemodynamic instability, PCT greater than 0.5 mcg/L, or no change in PCT level while on therapy, antimicrobial therapy should continue.37-49


Yep, that’s right, troponin. Troponin is most commonly used to diagnose acute MI, with the AHA stating elevation above the 99th percentile in healthy population meets criteria for ACS.50,51 Troponin can also be used to risk stratify patients entered into the HEART pathway, and high sensitivity troponin can increase sensitivity.50-54 Cardiac troponin consists of two forms: I and T (these are regulatory proteins). Injury of cardiac tissue results in these proteins entering the bloodstream. However, troponin can elevate in multiple settings, shown below.55-59

Cardiac Causes Noncardiac Causes
Acute and Chronic Heart Failure

Acute Inflammatory Myocarditis Endocarditis/Pericarditis

Aortic Dissection

Aortic Valve Disease

Apical Ballooning Syndrome

Bradyarrhythmia, Heart Block

Intervention (endomyocardial biopsy, surgery)


Direct Myocardial Trauma

Hypertrophic Cardiomyopathy


Acute Noncardiac Critical Illness

Acute Pulmonary Edema

Acute PE

Cardiotoxic Drugs

Stroke, Subarachnoid hemorrhage

Chronic Obstructive Pulmonary Disease

Chronic renal failure

Extensive Burns

Infiltrative Disease (amyloidosis)

Rhabdomyolysis with Myocyte Necrosis


Severe Pulmonary Hypertension

Strenuous Exercise/Extreme Exertion

Risk Stratification

Troponin elevation is associated in worse patient outcomes, particularly mortality, as well as increased length of stay. In sepsis, anywhere from 36-85% of patients may demonstrate troponin elevation. 58-68  This elevation is associated with septic shock and mortality, with almost two times the risk of death.58-64,69 Troponin elevation may be due to several factors including demand ischemia, direct myocardial endotoxin damage, cytokine and oxygen free radical damage, and poor cardiac oxygen supply due to microcirculatory dysfunction. 57,60,61,63,65,69 LV diastolic and RV systolic dysfunction are also associated with increased troponin and mortality.64

Troponin elevation in sepsis allows for prognostication and predicts a patient who is sicker. Resuscitation is essential with elevated troponin in sepsis. However, troponin’s role in resuscitation, the assay used, and the cut-off level need to be determined. If an elevation occurs, an ECG should be obtained, along with bedside echo to evaluate for wall motion abnormalities. Sepsis cardiomyopathy can cause diffuse hypokinesis, but focal wall abnormalities require emergent cardiology consultation.56-61


Novel Biomarkers

Sepsis has a complex pathophysiology, which results in a multitude of biomarkers released. These biomarkers are currently under study, and we will discuss several here.5-8

Endothelial Markers

Sepsis results in endothelial changes, associated with modifications in hemostatic balance, change in microcirculation, leukocyte trafficking, vascular permeability, and inflammation.

Measuring this endothelial dysfunction may allow earlier diagnosis of sepsis, as well as prognostication. These include vascular cell adhesion molecule (VCAM-1), soluble intercellular adhesion molecule (ICAM-1), sE-selectin, plasminogen activator inhibitor (PAI-1), and soluble fms-like tyrosine kinase (sFlt-1).5-8,70-73

Proadrenomedullin (ProADM)

This is a precursor for adrenomedullin, a calcitonin peptide. It likely functions in a similar fashion as PCT in the setting of acute cytokine release with bacterial infection. This peptide works as a vasodilator, though it has immune modulating and metabolic effects as well, and it is elevated in renal failure, heart disease, and cancer. ProADM may be able to risk stratify patients with sepsis and pneumonia into different categories based on level.73-79

One study evaluated an algorithm utilizing CURB-65 and ProADM levels.79 CURB-65 is a validated prognostic score for community-acquired pneumonia that consists of BUN > 19 mg/dL (>7 mmol/L), respiratory rate > 30, systolic blood pressure < 90 mm Hg or diastolic blood pressure  < 60 mm Hg, and age > 65 years.80 The algorithm combining CURB-65 and ProADM did not change patient outcome, though it did decrease patient length of stay.79 This marker could assist in prognostication and early discharge, but further study in the ED is needed.

Acute-Phase Reactants

Cytokines are released in response to inflammation, especially sepsis. There are multiple markers including IL-6, IL-8, IL-10, sTREM01, suPAR, CD-64 index, Lipopolysaccharide-binding protein (LBP), ICAM-1, and pentraxins. The greater the elevation in these markers, the worse the prognosis. However, these require further study before regular use can be recommended.8,81

Cardiac Biomarkers

Commonly utilized for heart failure and coronary disease, NT-proBNP and BNP may be associated with worse outcomes in sepsis. Higher levels can predict longer hospital stay and mortality. Obtaining these biomarkers may help predict cardiac dysfunction in sepsis and the need for inotropic medications, though these require further study.67,82-86 Providers must remember that NT-proBNP and BNP lack specificity, as valvular heart disease, Afib, PE, COPD, and hyperthyroidism can elevated these markers, while obesity may decrease levels. 81-85


Key Points:

  • Biomarkers cannot replace the bedside clinician, but they may assist clinical decision making, risk stratification, and prognostication. Lactate has the best evidence in sepsis.
  • Lactate is useful for assessing severity, screening, and resuscitation. However, it is not always elevated in sepsis. Venous POC levels are recommended.
  • Procalcitonin is a marker of bacterial versus viral It is not associated with mortality benefit, but may reduce antibiotic usage. PCT requires further study in the ED.
  • Troponin can be elevated in many conditions and is associated with worse prognosis in sepsis. Sepsis cardiomyopathy is more common than many providers realize.
  • Biomarkers on the horizon include endothelial activators, acute-phase reactants, BNP/NT-proBNP, and proadrenomedullin.


References/Further Reading

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  11. Shapiro NI, Schuetz P, Yano K, et al. The association of endothelial cell signaling, severity of illness, and organ dysfunction in sepsis. Critical Care 2010; 14:R182.
  12. Becker KL, Nylen ES, White JC, Muller B, Snider RH, Jr. Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab 2004;89(4):1512–25.
  13. Elsasser TH, Kahl S. Adrenomedullin has multiple roles in disease stress: development and remission of the inflammatory response. Microsc Res Tech 2002;57(2):120–9.
  14. Struck J, Tao C, Morgenthaler NG, Bergmann A. Identification of an Adrenomedullin precursor fragment in plasma of sepsis patients. Peptides 2004;25(8):1369–72.
  15. Christ-Crain M, Morgenthaler NG, Struck J, Harbarth S, Bergmann A, Muller B. Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care 2005;9(6):R816–24.
  16. Christ-Crain M, Morgenthaler NG, Stolz D, Muller C, Bingisser R, Harbarth S, et al. Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia [ISRCTN04176397]. Crit Care 2006;10(3):R96.
  17. Schuetz P, Wolbers M, Christ-Crain M, Thomann R, Falconnier C, Widmer I, et al. Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections. Crit Care 2010;14(3) R106.
  18. Albrich WC, Dusemund F, Ruegger K, Christ-Crain M, Zimmerli W, Bregenzer T, et al. Enhancement of CURB65 score with proadrenomedullin (CURB65–A) for outcome prediction in lower respiratory tract infections: derivation of a clinical algorithm. BMC infectious diseases 2011;11:112.
  19. Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, Lewis SA, Macfarlane JT. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003 May;58(5):377-82.
  20. Reinhart K, Bauer M, Riedemann NC, Hartog CS. New Approaches to Sepsis: Molecular Diagnostics and Biomarkers. Clin Microbiol Rev October 2012;25(4):609-634.
  21. Castillo JR, Zagler A, Carrillo-Jimenez R, Hennekens CH. Brain natriuretic peptide: a potential marker for mortality in septic shock. Int J Infect Dis 2004;8:271–4.
  22. Turner KL, Moore LJ, Todd SR, Sucher JF, Jones SA, McKinley BA, et al. Identification of cardiac dysfunction in sepsis with B-type 
natriuretic peptide. J Am Coll Surg 2011;213:139–46.
  23. Varpula M, Pulkki K, Karlsson S, Ruokonen E, Pettilä V; FINNSEPSIS Study Group. Predictive value of N-terminal pro-brain natriuretic peptide in severe sepsis and septic shock. Crit Care Med 2007;35:1277–83.
  24. Post F, Weilemann LS, Messow CM, Sinning C, Munzel T. B-type natriuretic peptide as a marker for sepsis-induced myocardial depression in intensive care patients. Crit Care Med Lab Med 2008;46:748–63.
  25. Hur M, Kim H, Lee S, Cristofano F, Magrini L, Marino R, Gori CS, Bongiovanni C, et al. Diagnostic and prognostic utilities of multimarkers approach using procalcitonin, B-type natriuretic peptide, and neutrophil gelatinase-associated lipocalin in critically ill patients with suspected sepsis. BMC Infect Dis 2014 Apr 24;14:224.

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: http://www.jointcommission.org/performance_measurement.aspx
  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: http://clinicaltrials.gov/ct2/show/NCT00472667.
  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.
  31. http://www.ncbi.nlm.nih.gov/pubmed/24005642
  32. http://www.ncbi.nlm.nih.gov/pubmed/23879729
  33. http://www.ncbi.nlm.nih.gov/pubmed/24201179
  34. http://www.ncbi.nlm.nih.gov/pubmed/24176471
  35. http://www.ncbi.nlm.nih.gov/pubmed/23137959
  36. http://www.ncbi.nlm.nih.gov/pubmed/23669296
  37. http://www.ncbi.nlm.nih.gov/pubmed/22305332
Edited by Alex Koyfman