Tag Archives: lactate

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

  1. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R: Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013;39:165–228.
  2. Winters BD, Eberlein M, Leung J, Needham DM, Pronovost PJ, Sevransky JE.
Long-term mortality and quality of life in sepsis: a systematic review. Crit Care Med 2010;38:1276–1283.
  3. Strehlow MC, Emond SD, Shapiro NI, et al. National study of emergency department visits for sepsis, 1992 to 2001. Ann Emerg Med 2006;48:326–31.
  4. 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.
  5. Clerico A and Plebani M. Biomarkers for sepsis: an unfinished journey. Clin Chem Lab Med 2013; 51(6): 1135–1138.
  6. Rivers EP, Jaehne AK, Nguyen HB, Papamatheakis DG, Singer D, Yang JJ, Brown S, Klausner H. Early biomarker activity in severe sepsis and septic shock and a contemporary review of immunotherapy trials: not a time to give up, but to give it earlier. Shock 2013 Feb;39(2):127-37.
  7. Schuetz P, Aujesky D, Mueller C, and Mueller B. Biomarker-guided personalised emergency medicine for all – hope for another hype? Swiss Med Wkly 2015;145:w14079.
  8. Di Somma S, Magrini L, Travaglino F, Lalle I, Fiotti N, Cervellin G, et al. Opinion paper on innovative approach of biomarkers for infectious diseases and sepsis management in the emergency department. Clin Chem Lab Med 2013;51:1167–75.
  9. Jones AE. Lactate Clearance for Assessing Response to Resuscitation in Severe Sepsis. Acad Emerg Med 2013 August;20(8): 844–847.
  10. Marik PE, Bellomo R. Lactate clearance as a target of therapy in sepsis: A flawed paradigm. OA Critical Care 2013 Mar 01;1(1):3.
  11. Puskarich MA. Emergency management of severe sepsis and septic shock. Curr Opin Crit Care 2012 Aug;18(4):295-300.
  12. Gibot S. On the origins of lactate during sepsis. Crit Care 2012 Sep 10;16(5):151.
  13. Anderson LW, Mackenhauer J, Roberts JC, Berg KM, Cocchi MN, Donnino MW. Etiology and therapeutic approach to elevated lactate. Mayo Clin Proc 2013 Oct; 88(10): 1127–1140.
  14. 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.
  15. Trzeciak S, Dellinger R, Chansky ME, et al. Serum lactate as a predictor of mortality in patients with infection. Intensive Care Med 2007; 33:970–7.
  16. Singer AJ, Taylor M, Domingo A, Ghazipura S, Khorasonchi A, Thode HC Jr, Shapiro NI. Diagnostic characteristics of a clinical screening tool in combination with measuring bedside lactate level in emergency department patients with suspected sepsis. Acad Emerg Med 2014 Aug;21(8):853-7.
  17. Jones AE, Leonard MM, Hernandez-Nino J, and Kline JA. Determination of the Effect of In Vitro Time, Temperature, and Tourniquet Use on Whole Blood Venous Point-of-care Lactate Concentrations. Acad Emerg Med 2007;14:587–591.
  18. Adams BD, Bonzani TA, Hunter CJ. The anion gap does not accurately screen for lactic acidosis in emergency department patients. Emerg Med J 2006;23:179-82.
  19. Iberti TJ, Leibowitz AB, Papadakos PJ, Fischer EP. Low sensitivity of the anion gap as a screen to detect hyperlactatemia in critically ill patients. Crit Care Med 1990;18:275-7.
  20. Puskarich MA, Trzeciak S, Shapiro NI, Albers AB, Heffner AC, Kline JA, Jones AE. Whole blood lactate kinetics in patients undergoing quantitative resuscitation for severe sepsis and septic shock. Chest 2013 Jun;143(6):1548-53.
  21. Mikkelsen ME, Miltiades AN, Gaieski DF, Goyal M, Fuchs BD, Shah CV, Bellamy SL, Christie JD. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med 2009 May;37(5):1670-7.
  22. Puskarich MA, Illich BM, Jones AE. Prognosis of emergency department patients with suspected infection and intermediate lactate levels: a systematic review. J Crit Care 2014;29:334-339.
  23. Nichol AD, Egi M, Pettila V, et al. Relative hyperlactatemia and hospital mortality in critically ill patients: a retrospective multi-centre study. Crit Care 2010;14:R25.
  24. Cady LD, Jr., Weil MH, Afifi AA, Michaels SF, Liu VY, Shubin H. Quantitation of severity of critical illness with special reference to blood lactate. Crit Care Med 1973;1:75-80.
  25. Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med 1992;20:80-93.
  26. Bakker J, Gris P, Coffernils M, Kahn R, Vincent JL. Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg 1996; 171:221–6.
  27. Nguyen H, Rivers E, Knoblich B, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004; 32:1637–42.
  28. Arnold RC, Shapiro NI, Jones AE, et al. Multi-center study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock 2009;32:36–9.
  29. Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med 2010;182:752–61.
  30. Jones AE, Kline JA. Use of goal-directed therapy for severe sepsis and septic shock in academic emergency departments. Crit Care Med 2005;33:1888–9.
  31. Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010;303:739–46.
  32. Dugas AF, Mackenhauer J, Salciccioli JD, Cocchi MN, Gautam S, Donnino MW. Prevalence and characteristics of nonlactate and lactate expressors in septic shock. J Crit Care 2012 Aug;27(4):344-50.
  33. Hernandez G, Castro R, Romero C, de la Hoz C, Angulo D, Aranguiz I, Larrondo J, Bujes A, Bruhn A. Persistent sepsis-induced hypotension without hyperlactatemia: is it really septic shock? J Crit Care 2011 Aug;26(4):435.e9-14.
  34. Jin M and Khan AI. Procalcitonin: Uses in the Clinical Laboratory for the Diagnosis of Sepsis. Lab Medicine 2010 Mar;41(3):173-177.
  35. Pieralli F, Vannucchi V, Mancini A, Antonielli E, Luise F, et al. Procalcitonin Kinetics in the First 72 Hours Predicts 30- Day Mortality in Severely Ill Septic Patients Admitted to an Intermediate Care Unit. J Clin Med Res 2015;7(9):706-713.
  36. Assicot M, Gendrel D, Garsin H, et al. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993;341:515–518.
  37. Meisner M. Pathobiochemistry and clinical use of procalcitonin. Clin Chim Acta 2002;323:17–29.
  38. Muller F, Christ-Crain M, Bregenzer T, Krause M, Zimmerli W, Mueller B, et al. Procalcitonin levels predict bacteremia in patients with community-acquired pneumonia: a prospective cohort trial. Chest 2010;138(1):121–9.
  39. Schuetz P, Suter-Widmer I, Chaudri A, Christ-Crain M, Zimmerli W, Mueller B, et al. Prognostic value of procalcitonin in community-acquired pneumonia. Eur Respir J 2011;37(2):384–92.
  40. Christ-Crain M, Muller B. Biomarkers in respiratory tract infections: diagnostic guides to antibiotic prescription, prognostic markers and mediators. Eur Respir J. 2007;30:556–573.
  41. Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, Neidert S, Fricker T, Blum C, Schild U, Regez K, Schoenenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Mueller B; ProHOSP Study Group. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009 Sep 9;302(10):1059-66.
  42. Schuetz P, Muller B, Christ-Crain M, Stolz D, Tamm M, Bouadma L, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev 2012; 9: CD007498.
  43. Jensen J, et al. Procalcitonin as a Marker of Infection, Sepsis, and Response to Antibiotic Therapy. Crit Care Med 2006:34;2596-2602.
  44. Anand D, Das S, Bhargava S, Srivastava LM, Garg A, Tyagi N, Taneja S, Ray S. Procalcitonin as a rapid diagnostic biomarker to differentiate between culture-negative bacterial sepsis and systemic inflammatory response syndrome: a prospective, observational, cohort study. J Crit Care 2015 Feb;30(1):218.e7-12.
  45. Wacker C, Prkno A, Brunkhorst FM, et al. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis 2013;13:426-435.
  46. Schuetz P, Briel M, Mueller B. Clinical outcomes associated with procalcitonin algorithms to guide antibiotic therapy in respiratory tract infections. JAMA 2013;309(7):717–8.
  47. Freund Y, Delerme S, Goulet H, et al. Serum lactate and procalcitonin measurements in emergency room for the diagnosis and risk-stratification of patients with suspected infection. Biomarkers 2012;17:590-596.
  48. Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, Schortgen F, Lasocki S, Veber B, Dehoux M, Bernard M, Pasquet B, Régnier B, Brun-Buisson C, Chastre J, Wolff M; PRORATA trial group. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010 Feb 6;375(9713):463-74.
  49. Hoeboer SH, Van der Geest PJ, Nieboer D, Groeneveld AB. The diagnostic accuracy of procalcitonin for bacteraemia: a systematic review and meta-analysis. Clin Microbiol Infect. 2015;21:474–481.
  50. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD; Joint ESC/ACCF/AHA/WHF Task Force for Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012 Oct 16;60(16):1581-98.
  51. Newby LK, Jesse RL, Babb JD, et al. ACCF 2012 expert consensus document on practical clinical considerations in the interpretation of troponin elevations: a report of the American College of Cardiology Foundation task force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2012;60:2427–63.
  52. Mahler SA, Riley RF, Hiestand BC, Russel GB, Hoekstra JW, Lefebvre CW, et al. The HEART Pathway Randomized Trial Identifying Emergency Department Patients With Acute Chest Pain for Early Discharge. Circ Cardiovasc Qual Outcomes March 2015;8 (2):195 – 203.
  53. Thygesen K, Mair J, Giannitsis E, et al. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J 2012;33:2252–7.
  54. Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med 2009;361: 858–67.
  55. Kelley, W. E., J. L. Januzzi, and R. H. Christenson. Increases of Cardiac Troponin in Conditions Other than Acute Coronary Syndrome and Heart Failure. Clinical Chemistry 2009;55(12):2098-112. Web.
  56. Korff, S. Differential Diagnosis of Elevated Troponins. Heart 2006;92(7):987-93.
  57. Court O, Kumar A, Parrillo JE, Kumar A. Clinical review: Myocardial depression in sepsis and septic shock. Crit Care 2002;6:500-508.
  58. Hamilton MA, Toner A, Cecconi M. Troponin in critically ill patients. Minerva Anestesiol 2012 Sep;78(9):1039-45.
  59. Patil H, Vaidya O, Bogart D. A review of causes and systemic approach to cardiac troponin elevation. Clin Cardiol 2011 Dec;34(12):723-8.
  60. Bouhemad B, Nicolas-Robin A, Arbelot C, et al: Acute left ventricular dilatation and shock-induced myocardial dysfunction. Crit Care Med 2009; 37:441–447.
  61. Wilhelm J, Hettwer S, Schuermann M, Bagger S, Gerhardt F, Mundt S, Muschik S, Zimmermann J, Amoury M, Ebelt H, Werdan K. Elevated troponin in septic patients in the emergency department: frequency, causes, and prognostic implications.Clin Res Cardiol 2014 Jul;103(7):561-7.
  1. Bessière F, Khenifer S, Dubourg J, Durieu I, Lega JC. Prognostic value of troponins in sepsis: a meta-analysis. Intensive Care Med 2013 Jul;39(7):1181-9.
  2. Sheyin O, Davies O, Duan W, Perez X. The prognostic significance of troponin elevation in patients with sepsis: a meta-analysis. Heart Lung 2015 Jan-Feb;44(1):75-81.
  3. Landesberg G, Jaffe AS, Gilon D, Levin PD, Goodman S, Abu-Baih A, Beeri R, Weissman C, Sprung CL, Landesberg A. Troponin elevation in severe sepsis and septic shock: the role of left ventricular diastolic dysfunction and right ventricular dilatation*. Crit Care Med 2014 Apr;42(4):790-800.
  4. Clemente G, Tuttolomondo A, Colomba D, Pecoraro R, Renda C, Della Corte V, Maida C, Simonetta I, Pinto A. When sepsis affects the heart: A case report and literature review. World J Clin Cases 2015 Aug 16;3(8):743-50.
  5. Klouche K, Pommet S, Amigues L, Bargnoux AS, Dupuy AM, Machado S, Serveaux-Delous M, Morena M, Jonquet O, Cristol JP. Plasma brain natriuretic peptide and troponin levels in severe sepsis and septic shock: relationships with systolic myocardial dysfunction and intensive care unit mortality. J Intensive Care Med 2014 Jul-Aug;29(4):229-37.
  6. Cheng H, Fan WZ, Wang SC, Liu ZH, Zang HL, Wang LZ, Liu HJ, Shen XH, Liang SQ. N-terminal pro-brain natriuretic peptide and cardiac troponin I for the prognostic utility in elderly patients with severe sepsis or septic shock in intensive care unit: A retrospective study. J Crit Care 2015 Jun;30(3):654.e9-14.
  7. Courtney D, Conway R, Kavanagh J, O’Riordan D, Silke B. High-sensitivity troponin as an outcome predictor in acute medical admissions. Postgrad Med J 2014 Jun;90(1064):311-6.
  8. de Groot B, Verdoorn RC, Lameijer J, van der Velden J. High-sensitivity cardiac troponin T is an independent predictor of inhospital mortality in emergency department patients with suspected infection: a prospective observational derivation study. Emerg Med J 2014 Nov;31(11):882-8.
  9. Skibsted S, Jones AE, Puksarich MA, Arnold R, Sherwin R, Trzeciak S, et al. Biomarkers of endothelial cell activation in early sepsis. Shock 2013 May; 39(5): 427–432.
  10. Hack CE, Zeerleder S. The endothelium in sepsis: source of and a target for inflammation. Crit Care Med 2001; 29:S21–7.
  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.

PEM Playbook – Big Labs, Little People: Troponin, BNP, D-Dimer, and Lactate

Originally published at Pediatric Emergency Playbook on April 1,
2016 – Visit to listen to accompanying podcast. Reposted with permission.

Follow Dr. Tim Horeczko on twitter @EMTogether

It’s a busy shift.  Today no one seems to have a chief complaint.

Someone sends a troponin on a child.  Good, bad, or ugly, how are you going to interpret the result?

And while we’re at it – what labs do I need to be careful with in children – sometimes the normal ranges of common labs can have our heads spinning!

Read on for bread-and-butter pediatric blood work and further, to answer the question – what’s up with troponin, lactate, d-dimer, and BNP in kids?


A fundamental tenet of emergency medicine:

We balance our obligation to detect a dangerous condition with our suspicion of the disease in given patient.

Someone with a cough and fever may simply have a viral illness, or he may have pneumonia.  Our obligation is to evaluate for the pneumonia.  It’s ok if we “miss” the diagnosis of a cold. It could be bad if we don’t recognize the pneumonia.

How do we decide?  Another fundamental concept:

The threshold.

Depending on the disease and the particular patient, we have a threshold for testing, and a threshold for treating.  Every presentation – and every patient for that matter – has a complicated interplay between what we are expected to diagnose, how much we suspect that particular serious diagnosis, and where testing and treating come into play.

What’s wrong with “throwing on some labs”?

Easy to do right?  They are but a click away…

Often a good history and physical exam will help you to calibrate your investigational thresholds.  This is especially true in children – the majority of pediatric ambulatory visits do not require blood work to make a decision about acute care.  If your patient is ill, then by all means; otherwise, consider digging a bit deeper into the history, get collateral information, and make good use of your general observation skills.

First, a brief word about basic labs.

The punchline is, use a pediatric reference.

If you don’t have a trusted online reference available during your shift, make sure you have something like a Harriett Lane Handbook accessible to you. Don’t rely on your hospital’s lab slip or electronic medical record to save you, unless you are sure that they use age-specific pediatric reference ranges to flag abnormal values. Believe it or not, in this 21st century of ours, some shops still use adult reference ranges when reporting laboratory values on children.

Notable differences in basic chemistries

Potassium: tends to run a bit higher in infants, because for the first year of life, your kidneys are inefficient in excreting potassium.

BUN and creatinine: lower in children due to less muscle mass, and therefore less turnover (and usually lack of other chronic disease)

Glucose: tends to run lower, as children are hypermetabolic and need regular feeding (!)

Alkaline phosphatase: is always high in normal, growing children, due to bone turn over (also found in liver, placenta, kidneys)

Ammonia: high in infancy, due to immature liver, trends down to normal levels by toddlerhood

ESR and CRP: low in healthy children, as chronic inflammation from comorbidities is not present; both increase steadily with age

Thyroid function tests: all are markedly high in childhood, not as a sign of disease, but a marker of their increased metabolic activity

Big Labs


Reliably elevated in myocarditis, and may help to distinguish this from pericarditis (in addition to echocardiography)

Other causes of elevated troponin in children include: strenuous activity, status epilepticus, toxins, sepsis, myocardial infarction (in children with congenital anomalies).  Less common causes of troponemia are: Kawasaki disease, pediatric stroke, or neuromuscular disease.

Don’t go looking, if you won’t do anything with the test.

Brain natriuretic peptide (BNP)

In adults, we typically think of a BNP < 100 pg/mL as not consistent with symptoms caused by volume overload.

Luckily, we have data in children with congenital heart disease as well.  Although each company’s assay reports slightly different cut-offs, in general healthy pediatric values match healthy adult values.

One exception is in the first week of life, when it is high even in healthy newborns, due to the recent transition from fetal to newborn circulation.

Use of BNP in children has been studied in both clinic and ED settings. Cohen et al. in Pediatrics used BNP to differentiate acute heart failure from respiratory disease in infants admitted for respiratory distress. They compared infants with known CHF, lung disease, and matched them with controls.

Later, Maher et al. used BNP in the emergency department to differentiate heart failure from respiratory causes in infants and children with heart failure and those with no past medical history.

The bottom line is:

BNP reliably distinguishes cardiac from respiratory causes of shortness of breath in children with a known diagnosis of heart failure.


To cut to the chase: d-dimer for use as a rule-out for pulmonary embolism has not been studied in children.

The only data we have in using d-dimer in children is to prognosticate in established cases. It is only helpful to track therapy for children who have chronic clots.

This is where our adult approach can get us into trouble. Basically, think of the d-dimer in children like it doesn’t even exist. It’s not helpful in our setting for our indications.   An adult may have an idiopathic PE – in fact, up to a third of adults with PE have no known risk factor, which makes decision tools and risk stratification important in this population.

Children with PE almost always have a reason for it.


There is at least one identifiable risk factor in up to 98% of children with pulmonary embolism. The majority have at least two risk factors.

If you’re suspecting deep venous thrombosis, perform ultrasonography, and skip the d-dimer.

If you’re worried about PE, go directly to imaging. In stable patients, you may elect to use MR angiography or VQ scan, but most of us will go right to CT angiography. Radiation is always a concern, but if you need to know, get the test.

This is yet another reminder that your threshold is going to be different in children when you think about PE – they should have a reason for it. After you have excluded other causes of their symptoms, if they have risk factors, and you are still concerned, then do the test you feel you need to keep this child safe.

You are the test.

Risk factors only inform you, and you’ll have to just pull the trigger on testing in the symptomatic child with risk factors.


A sick child with sepsis syndrome?

The short answer – yes.

In the adult literature, we know that a lactate level above 4 mmol/L in patients with severe sepsis was associated with the need for critical care. This has been studied in children as well, and an elevated lactate in children – typically above 4 – was a predictor of prolonged ICU course and mortality in septic patients.

The acute recognition and treatment of sepsis is first and foremost, clinical.

Our goal is to promote perfusion and provide oxygen to the tissues. Laboratory testing is not a substitute for clinical assessment – it should be used as an extension of your assessment.  There are two main reasons for an elevated lactate: the stress state and the shock state.

The stress state is due to hypermetabolism and an increase in glycolysis, as an example, in early sepsis. The shock state is due to tissue hypoxia, seen in septic shock. The confusion and frustration with lactate is that we often test the wrong people for it.

We could use it to track treatment, and see if we can clear the lactate; decreased lactate levels are associated with a better outcome in adults. Serial clinical assessments are even more useful to gauge your success with treatment.

We should use lactate to detect occult shock. Children compensate so well for shock, that subtle tissue hypoxia may not be detected until later. It may inform your decision for level of care, intensive care versus some other lower level.

Have you every been in this situation:

“Why, oh why, did we send a lactate?”

There are times when a lactate is ordered – maybe by protocol or maybe accidentally – or maybe in retrospect, the patient didn’t need it. Here is a quick mnemonic to remember the reasons for an elevated lactate: LACTATES


Lliver – any liver disease affects how lactate is metabolized by the Cori cycle
Aalbuterol (or for our international friends, salbutamol), beta-agonists like albuterol, increase lactate production via cyclic amp
C“can’t breathe” – respiratory distress and increased work of breathing shifts the ratio of aerobic and anerobic repiration
Ttoxins – all kinds of wonder drugs and recreational drugs do it – look up your patient’s list if you’re suspicious
Aalcohol, not an infrequent offender
Tthiamine deficiency – think of this in your cachectic or malnourished patients
Eepinephrine – a by-product of the Cori cycle, how lactate is metabolized. Difficult to interpret lactates when a patient is on an epinephrine drip.
Sseizure or shock – most commonly septic, but can be any type: cardiogenic, bstructive, hypovolemic, distributive.

Bottom line: high serum lactate levels have been associated with morbidity and mortality in children with sepsis and trauma, the two best-studied populations.

A summary of how labs can help you – or hurt you – in pediatric emergency medicine:

  1. Have a good reference for normal values and always be skeptical of how your lab reports them.
  2. Troponin testing is great for the child with suspected cardiogenic shock, myocarditis, or in unwell children with congenital heart disease.
  3. BNP in children can be used just like you do in adults – to get a sense of whether the presenting symptoms are consistent with heart failure.
  4. D-dimer is mostly a waste of time in the PED.
  5. Lactate can be useful in the right patient – use it to risk-stratify the major trauma patient or the patient with sepsis that may be suffering from occult shock.
  6. And lastly, make sure that you are mindful of your threshold for testing, and our threshold for treatment. If will vary by disease and by the patient at hand.



Gupta SK, Naheed Z. Chest Pain in Two Athletic Male Adolescents Mimicking Myocardial Infarction. Pediatr Emer Care. 2014;30: 493-495.

Kelley WE, Januzzi JL, Christenson RH. Increases of Cardiac Troponin in Conditions other than Acute Coronary Syndrome and Heart Failure. Clinical

Chemistry. 2009; (55) 12:2098–2112.

Kobayashi D, Aggarwal S, Kheiwa A, Shah N. Myopericarditis in Children: Elevated Troponin I Level Does Not Predict Outcome. Pediatr Cardiol. 2012; 33:1040–1045.

Koerbin G, Potter JM, Abhayaratna WP et al. The distribution of cardiac troponin I in a population of healthy children: Lessons for adults. Clinica Chimica Acta. 2016; 417: 54–56.

Liesemer K, Casper TC, Korgenski K, Menon SC. Use and Misuse of Serum Troponin Assays in Pediatric Practice. Am J Cardiol. 2012;110:284 –289.

Newby KL et al. for the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. ACCF 2012 Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations. J Am Coll Cardiol. 2012; 60(23): 2427-2463.

Schwartz MC, Wellen S, Rome JJ et al. Chest pain with elevated troponin assay in adolescents. Cardiology in the Young; 2013. 23: 353–360.


Auerbach SR, Richmond ME, Lamour JM. BNP Levels Predict Outcome in Pediatric Heart Failure Patients Post Hoc Analysis of the Pediatric Carvedilol Trial. Circ Heart Fail. 2010;3:606-611.

Cohen S, Springer C, Avital A et al. Amino-Terminal Pro-Brain-Type Natriuretic Peptide: Heart or Lung Disease in Pediatric Respiratory Distress? Pediatrics. 2005;115:1347–1350.

Fried I, Bar-Oz B, Algur N et al. Comparison of N-terminal Pro-B-Type Natriuretic Peptide Levels in Critically Ill Children With Sepsis Versus Acute Left Ventricular Dysfunction. Pediatrics. 2006; 118(4): 1165-1168.

Koch A, Singer H. Normal values of B type natriuretic peptide in infants, children, and adolescents. Heart. 2003;89:875–878.

Maher KO, Reed H, Cuadrado A et al. , B-Type Natriuretic Peptide in the Emergency Diagnosis of Critical Heart Disease in Children. Pediatrics. 2008;121:e1484–e1488.

Mir TS, Marohn S, Laeer S, Eistelt M. Plasma Concentrations of N-Terminal Pro-Brain Natriuretic Peptide in Control Children From the Neonatal to Adolescent Period and in Children With Congestive Heart Failure. Pediatrics. 2002;110(6)1:6.

Mir TS, Laux R, Hellwege HH et al. Plasma Concentrations of Aminoterminal Pro Atrial Natriuretic Peptide and Aminoterminal Pro Brain Natriuretic Peptide in Healthy Neonates: Marked and Rapid Increase After Birth. Pediatrics. 2003;112:896–899.


Goldenberg NA, Knapp-Clevenger RA, Manco-Johnson MJ. Elevated Plasma Factor VIII and d-Dimer Levels as Predictors of Poor Outcomes of Thrombosis in Children for the Mountain States Regional Thrombophilia Group. Pediatrics. 2003;112:896–899.

Manco-Johnson MJ. How I treat venous thrombosis in children. Blood. 2006; 107(1)21-31.

Naqvi M, Miller P, Feldman L, Shore BJ. Pediatric orthopaedic lower extremity trauma and venous thromboembolism. J Child Orthop. 015;9:381–384.

Parasuraman S, Goldhaber SZ. Venous Thromboembolism in Children. Circulation. 2006;113:e12-e16.

Strouse JJ, Tamma P, Kickler TS et al. D-Dimer for the Diagnosis of Venous Thromboembolism in Children. N Engl J Med. 2004;351:1081-8.


Andersen LW, Mackenhauer J, Roberts JC et al. Etiology and therapeutic approach to elevated lactate. Mayo Clin Proc. 2013; 88(10): 1127–1140.

Bai et al. Effectiveness of predicting in-hospital mortality in critically ill children by assessing blood lactate levels at admission. BMC Pediatrics. 2014; 14:83.

Scott HF, Donoghue AJ, Gaieski DF et al. The Utility of Early Lactate Testing in Undifferentiated Pediatric Systemic Inflammatory Response Syndrome. Acad Emerg Med. 2012; 19:1276–1280.

Shah A, Guyette F, Suffoletto B et al. Diagnostic Accuracy of a Single Point-of-Care Prehospital Serum Lactate for Predicting Outcomes in Pediatric Trauma Patients. Pediatr Emer Care. 2013; 29:715-719.

Topjian AA, Clark AE, Casper TC et al. for the Pediatric Emergency Care Applied Research Network. Early Lactate Elevations Following Resuscitation From Pediatric Cardiac Arrest Are Associated With Increased Mortality. Pediatr Crit Care Med. 2013; 14(8): e380–e387.

This post and podcast are dedicated to Daniel Cabrera, MD for his vision and his leadership in thinking ‘outside the box’.


Troponin     |     BNP     |     D-Dimer     |     Lactate

Powered by #FOAMed — Tim Horeczko, MD, MSCR, FACEP, FAAP

Ready for the New Sepsis 3.0?

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


Sepsis is an all too common condition managed in EDs and ICUs around the world. A wide range of estimates for prevalence exists, with 300 to 1000 cases per 100,000 persons per year.  Unfortunately, there is no validated gold standard criterion or standard diagnostic test for this syndrome, which results from the host response to infection, often with organ dysfunction. The syndrome consists of a constellation of clinical signs and symptoms with suspected infection. 

The Old Definition

To meet SIRS criteria, two of the following must be present: HR > 90 bpm, RR > 20 or PaCO2 < 32, temperature < 36oC or > 38oC, and a WBC count < 4 x 109 cells/L or > 12 x 109 cells/L or > 10% bands. Two or more of these equals SIRS, and two or more with a source of infection equals sepsis.1,2 Unfortunately these criteria are non-specific, and the criteria alone do not provide a diagnosis or predict outcome. The definitions are shown below in Figure 1, along with severe sepsis and septic shock:

Screen Shot 2016-03-16 at 9.07.16 PM

Figure 1 – SEPSIS Criteria, from Canetnacci MH, King K. Severe Sepsis and Septic Shock: Improving Outcome in the Emergency Department. Emerg Med Clin N Am 2008;26:603–623.

Many have questioned the use of SIRS and the old definition of sepsis. Patients with sepsis and this old definition include a heterogeneous group, and it may go unrecognized. According to the SIRS naysayers, one of the major issues with SIRS is that it misses 1 out of 8 patients with diagnosed severe sepsis (notice this is not sepsis, but severe sepsis), reported in a recent study from the NEJM.3 However, another way of thinking about this is it catches 7 out of 8 patients with severe sepsis, for a sensitivity of 88%. There are multiple positives and negatives of this study, which was conducted in ICU patients, where SIRS was retrospectively applied. Mortality was 24.5% in SIRS positive patients, compared to 16.1% in SIRS negative patients. The SIRS negative patients also had shorter ICU and hospital stays, as well as higher rates of discharge to their own home. All patients were diagnosed and treated, and most importantly, it demonstrates a decrease in mortality of both SIRS negative and positive patients. Please see this blog post by Justin Morgenstern, creator of First10EM, @ http://first10em.com/2016/03/04/sirs-vs-sofa/ for further information on SIRS and the study.


Now onto “Sepsis 3.0” with qSOFA and SOFA…

A task force consisting of the European Society of Intensive Care Medicine and the Society of Critical Care Medicine recently proposed a new definition for sepsis and septic shock. These definitions are based on the use of two scores, qSOFA and SOFA, which are validated in the ICU, not ED. Please see http://www.jamasepsis.com for the full overview of the new definitions.4-6

The resulting publication has stirred a large amount of controversy, with some advocating strongly for the new changes, and others decrying the change. The FOAM world has blown up with important aspects of the new changes.

Please see the following resources, each with thorough, complete descriptions of the new proposed definitions, as well as the potential issues with using these definitions: http://rebelem.com/sepsis-3-0/, http://icmwk.com/2016/02/25/sepsis-3/, http://foamcast.org/2016/02/21/sepsis-redefined/, http://stemlynsblog.org/sepsis-16/, and http://emcrit.org/pulmcrit/problems-sepsis-3-definition/.

This post will provide an overview of Sepsis 3.0. We will not delve into the controversies surrounding the updated definitions. For further reading, see the above excellent blog posts.

  1. Sepsis is defined as life-threatening organ dysfunction due to dysregulated host response in the setting of infection.
  2. Organ dysfunction can be identified based on total SOFA score > 2 points. A score > 2 points is associated with a mortality of 10%.
    1. The SOFA score is based on blood pressure, vasopressor use, platelet count, bilirubin, GCS, creatinine, PaO2/FiO2 ratio, and presence of mechanical ventilation. Here is an easy plug in tool while on shift, from MDCalc: http://www.mdcalc.com/sequential-organ-failure-assessment-sofa-score/

Screen Shot 2016-03-16 at 9.05.56 PM

Figure 2 – SOFA score from http://www.jamasepsis.com

  1. The qSOFA score does not require laboratory tests and can be used quickly at the bedside. This consists of hypotension (SBP < 100 mm Hg), altered mental status (or a GCS of 13 or less), and tachypnea with RR > 22/min. Greater than or equal to 2 suggests poor outcome.
  2. Septic shock is defined by persisting hypotension that requires vasopressor use to keep MAP > 65 mmHg with a lactate > 2mmol/L, despite adequate volume resuscitation.
    1. Mortality for this group exceeds 40%.
  3. A flow chart for the new definition is shown below in Figure 3.

Screen Shot 2016-03-16 at 9.05.32 PM

Figure 3 – Updated Sepsis Diagram, from http://www.jamasepsis.com

For emergency providers, Justin Mandeville’s “rule of 2’s” is a helpful resource, from http://icmwk.com/2016/02/25/sepsis-3/

Screen Shot 2016-03-16 at 9.06.13 PM



– Notice that a patient with qSOFA > 2 on the chart still requires assessment for evidence of organ dysfunction, thus necessitating use of the SOFA score. However, on his excellent interview with Merv Singer, one of the lead authors of the new definition, Scott Weingart of EMCrit fame questioned this concern (http://emcrit.org/podcasts/sepsis-3/). Dr. Singer advocates for the use of clinical gestalt. Neither the qSOFA nor SOFA scores are management triggers. They instead function as markers for mortality, risk stratification, and as prompts to consider sepsis. If the clinician is worried for infection, begin treatment and resuscitation, even with negative qSOFA and SOFA scores.

– There is no longer “severe sepsis,” which was present in the older definition.

– These scores (qSOFA and SOFA) are not screening tools. They have only been validated as markers for mortality.

Pediatric sepsis is not included in this update.

Lactate is in the criteria for septic shock, but it is not present in the bedside criteria for sepsis identification. This test can be used as a marker for hemodynamic stress and mortality, as well as resuscitation (10% clearance), and likely should still be used.

– These definitions are not endorsed by American College of Emergency Physicians (ACEP), American College of Chest Physicians (ACCP), or the Latin American Sepsis Institute.

– These scores are validated for ICU patients, not the ED.


References/Further Reading

  1. Elixhauser A, Friedman B, Stranges E. Septicemia in U.S. Hospitals, 2009. Agency for Healthcare Research and Quality, Rockville, MD. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb122.pdf.
  2. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–637.
  3. Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. The New England journal of medicine. 372(17):1629-38.
  4. Singer M, Deutschman CS, Seymour CW, et al: The Sepsis Definitions Task Force The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). AMA. 2016;315(8):801-810.
  5. Seymour CW, Liu V, Iwashyna TJ, et al. Assessment of clinical criteria for sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):762-774.
  6. Shankar-Hari M, Phillips G, Levy ML, et al. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).  (JAMA, Feb 22, 2016).


Lactate in Sepsis: Pearls & Pitfalls

Author: Erik Hofmann, MS, MD (EM Resident Physician, LAC + USC Medical Center) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF)

Case Presentation

A 56 year-old female with a past medical history of recurrent urinary tract infections and hyperlipidemia presents with 1 week of suprapubic pain and fever. The patient states that she has been having progressively worsening suprapubic pain, sharp, constant, and radiating to the right flank. She has had subjective fever over the past 3 days and burning with urination for the past week. The patient states that the burning with urination is similar to her prior episodes of UTI, but that she has never had pain like this. The patient took ibuprofen 400 mg PO Q4 hours but it only provided temporary relief. Vital signs include a temperature of 101.2, HR 100, BP 132/80, RR 16, and SaO2 100% on room air. Positive physical exam findings include CVT. Blood cultures, lactate, CBC, urine analysis, urine culture and chem 7 are drawn within 3 hours of presenting to the ED. Significant laboratory results include WBC 15K and a lactate of 3.0 mmol/L. Urinalysis demonstrates pyuria, moderate blood, and positive leukocyte esterase. The patient is started on ceftriaxone 1g IV Q24 hours and 2L of crystalloid. A second lactate drawn within 6 hours of presenting to the ED is 2.55 mmol/L.

Question: Where should you send this patient?

Lactate Metabolism

Most of our pyruvate and lactate is generated via a redox-coupled interconversion catalyzed by lactate dehydrogenase (LDH) during anaerobic glycolysis. NADH is oxidized to NAD when pyruvate is converted to lactate producing protons in the process. LDH is a tetramer with five isoforms that is composed of various combinations of LDHA and LDHB subunits.1 There is a higher concentration of LDHA subunits in tissues that favors the reduction of pyruvate to lactate due to LDHA’s higher affinity for pyruvate.1 The normal concentration of serum lactate to pyruvate is in a 10:1 ratio that increases significantly with increasing concentrations of NADH:NAD.1

The human body normally produces 20 mmol/kg of lactate daily.1 Skeletal muscle, which contains a higher concentration of LDHA, is responsible for a majority of the lactate that is produced on a daily basis during normal metabolism.1 Lactate can be converted to pyruvate in a number of organs and tissues. The Cori cycle is involved in the production of lactate via glycolysis in skeletal muscle producing 2 ATP. Lactate is then transported to the liver and converted to glucose via gluconeogenesis using ATP generated from fatty acid metabolism. Lactate is also transported into mitochondrial cells via the monocarboxylic acid transporter and converted to pyruvate via LDH producing NADH. The pyruvate is decarboxylated via pyruvate dehydrogenase to acetyl-CoA. Acetyl-CoA enters the TCA cycle which produces additional NADH used in the production of ATP, CO2, and H2O through a series of reactions in the electron transport chain. The generation of lactate produces 2 ATP and 2 protons which is normally balanced by the consumption of these products through the re-conversion to pyruvate and NADH.

Causes of Lactic Acidosis

The cause of lactic acidosis can be categorized into either type A or type B. Type A includes disorders associated with impaired tissue oxygenation while type B is associated with causes other than impaired tissue oxygenation.1 Most cases of type A lactic acidosis can be attributed to tissue hypoperfusion due to either cardiogenic shock, hypovolemic shock, cardiac failure, severe trauma, or sepsis.1 However, there is considerable overlap between type A and type B lactic acidosis in a number of disease states.1

The true source of hyperlactemia is multifactorial and likely includes a combination of global tissue hypoxia, microcirculatory dysfunction, enzymatic dysfunction, and a metabolic stress response. Hyperlactemia occurs when there is an imbalance in the consumption or production of lactate ions and its equivalent protons. Glucose utilization during tissue hypoxia results in the production of lactate and ATP thus causing a net increase in lactate during anaerobic metabolism. There have been a number of studies that demonstrate the relationship between lactic acidosis and tissue hypoxia due to either a decrease in oxygen saturation, cardiac output, or blood volume causing decreased clearance. An extensive review of lactic acidosis by Madias et al. demonstrates that there is a decrease in lactate uptake by the liver with graded increases in hypoxia of the liver parenchyma converting the liver from a net consumer of lactic acid to a net producer.2 One in vivo animal study shows that a reduction of oxygen tension to a mean of 47 mmHg or more decreases hepatic uptake of lactic acid2. Decreases in blood flow of 30% or more to the liver causes a decrease in lactate utilization and a net increase in lactic acidosis.2 A phenomenon called microcirculatory and mitochondrial distress syndrome also plays a key role in organ dysfunction during sepsis. The auto-regulatory mechanism in the microcirculation is severely affected due to the heterogeneous expression of iNOS during sepsis3. Organs become under-perfused and red blood cells become less deformable as a result of decreases in NO-induced vasodilation.3 A sepsis induced inflammatory response activates leukocytes which release reactive oxygen species thereby disrupting the microcirculatory barrier leading to tissue edema and a worsening oxygen extraction deficit.3 Revelly et al. describes how glucose turnover increases during septic shock causing a commensurate increase in lactate production.4 This effect is largely due to a combination of increased glycolysis and increased insulin resistance secondary to inflammatory mediators during septic shock.4

A number of studies in the 1980s found that improved outcome from septic shock and cardiogenic shock was dependent on lactate clearance as well as overproduction.5 A single center prospective study by Levraut et al. in 1998 found that mild hyperlactemia in stable septic patients was due to altered lactate utilization rather than overproduction due to tissue hypoxia during sepsis.6 They found that the hyperlactemic group had a lower lactate clearance than the normal lactate group while both groups had a similar lactate production. The hyperlactemic group had a lactate clearance of 437 ml/kg/h whereas those with normal lactate had a clearance of 1002 ml/kg/hr. They concluded that hyperlactemia is likely due to a disturbance in lactate metabolism rather than a defect in cellular oxygenation alone. There are a number of mechanisms at play that can affect lactate clearance during severe sepsis and septic shock. Lactate consumers under normal basal conditions include the liver, renal cortex and heart.2 Lactate usage by the liver and kidneys for gluconeogenesis increases during hyperlactemia in addition to increased renal excrection.2 Pyruvate dehydrogenase is inactivated through dephosphorylation during sepsis thereby increasing the conversion of pyruvate to lactate.6 However, one study by Revelly et al. found that there was no significant difference in lactate clearance between critically ill patients and healthy subjects with the administration of exogenous lactate.4

Hyperlactemia can also occur as a result of endotoxemia during sepsis despite normal systemic perfusion, blood pressure, and oxygen delivery.7 A study by Michaeli et al. found that lipopolysaccharide (LPS) administration in healthy volunteers increased net lactate production.8 Another study by Traves et al. found that LPS induced immune cell activation during sepsis increased glucose consumption and lactate production by macrophages through an ERK1/2-dependent mechanism.8

There is a competing theory to the traditional concept that hyperlactemia is induced by tissue hypoxia called aerobic glycolysis. Studies have shown that there is an increased release of epinephrine during sepsis that is triggered by neuroendocrine and cardiovascular stimuli.9 Epinephrine in turn increases the activity of the Na, K-ATPase pump in a number of well oxygenated tissues including erythrocytes, vascular smooth muscle, neurons, and glia.9 Increased Na, K-ATPase activity generates ADP which stimulates phosphofructokinase (PFK).9 PFK, and then up-regulates membrane glycolytic pathways that are in close proximity to the Na, K-ATPase pumps.9 Cyclic AMP is also increased by epinephrine in skeletal muscle cells stimulating both Na, K-ATPase activity and glycogenolysis.9 Overall, these processes produce a large, rapid supply of glucose during a hyper-dynamic state that outpaces lactate utilization thereby causing hyperlactemia. Marik et al. argues that activation of the evolutionary stress response is the main source of hyperlactemia and hyperglycemia during sepsis.5 He points out that the heart normally oxidizes free fatty acids for a majority of its bioenergetic need.5 However, the heart shifts its substrate utilization during shock and starts metabolizing lactate at a higher rate.5 The brain also increases lactate oxidation for its bioenergetic needs during episodes of acute stress.5 This is supported by two randomized control trials that demonstrated an increase in mortality in patients who failed to increase lactate and glucose in response to epinephrine during septic shock.5 He concludes that the fall in lactate concentration during sepsis resuscitation is most likely due to a blunting of the stress response and can actually be harmful to cardiovascular and brain function.5

The Evidence for Lactate Clearance

There have been a number of studies that have demonstrated an association between hyperlactemia, multi-system organ failure (MSOF), and mortality in severe sepsis and septic shock. Bakker et al. in 1996 found that the duration of lactic acidosis was a significant predictor of multi-system organ failure and death in septic shock patients.10 The duration of lactic acidosis or “lactime” was defined as the time during which blood lactate was ≥ 2.0 mmol/L. This “lactime” was found to be the only significant marker of organ failure in their study. The study also found a significant difference in the decrease in blood lactate levels during the first 24 hours between survivors and non-survivors. However, the study failed to demonstrate statistical significance in initial lactate levels between survivors and non-survivors.

In 2001, Rivers et al. examined whether early goal directed therapy before admission to an ICU decreased multi-organ dysfunction, mortality, and the use of hospital resources.11 They found that early goal directed therapy was associated with a 15% decrease in in-hospital mortality over standard therapy at the time. Serum lactate concentration was measured at 0, 3, 6, 12, 24, 36 , 48, 60 and 72 hours in order to calculate the acute physiology and chronic health evaluation (APACHE II) score, the simplified acute physiology score II (SAPS II) and the multiple organ dysfunction score (MODS). They found that there was a statistically significant decrease in serum lactate of 3.0 mmol/L versus 3.9 mmol/L in survivors versus non-survivors respectively. Although serum lactate was only used in this study as a means to calculate MOSF, it did provide evidence that end goal directed therapy was associated with a decrease in mortality in patients who had a lower lactate level after resuscitation.

McNelis et al. in 2001 examined the correlation between the time to normalization of lactate and outcome in post-operative SICU patients.12 They found that prolonged lactate clearance correlated with mortality. Patients that failed to clear their lactate during their hospital course had a 100% mortality rate. The mortality rate at 24, 48, and 96 hours was 3.9%, 13.3%, and 42.5% respectively.

Levraut et al. in 2003 looked at the prognostic value of lactate clearance and lactate production in severe sepsis and septic shock patients with initial lactate levels < 3.0 mmol/L. Percent lactate clearance was defined as lactate at hour 0 minus lactate at hour 6 divided by lactate at ED presentation multiplied by 100.13 There was no difference in initial blood lactate level between survivors and non-survivors. Lactate clearance was significantly lower and production was significantly higher in non-survivors. They concluded that decreased lactate clearance was a significant independent predictor of increased mortality, and proposed that tracking lactate clearance could be used as an early predictor of increased mortality.

Nguyen et al. in 2004 studied the clinical utility of lactate clearance in the emergency department as an indicator of MSOF and 60-day in-hospital mortality for patients presenting with severe sepsis and septic shock.14 Survivors had a lactate clearance of 38% versus 12% in non-survivors within the first 6 hours. There was an 11% decrease in likelihood of mortality for each 10% increase in lactate clearance. Overall, patients with a lactate clearance of ≥ 10% had a lower 60-day mortality rate. They argued that serial lactate measurements within the first 6 hours was a better prognostic indicator of organ failure and mortality than a single lactate measurement.

Arnold et al. in 2009 studied the clinical utility of using serial lactate measurements, in a protocoled resuscitation bundle, as a predictor of in-hospital mortality in patients presenting to the ED with severe sepsis.15 Lactate clearance was defined as a repeat lactate decrease of 10% or greater at 6 hours, or both initial lactate and repeat levels < 2.0 mmol/L. In-hospital mortality was 60% for non-lactate clearance versus 19% for lactate clearance, and they found that lactate non-clearance was a significant independent predictor of death.

Jansen et al. in 2010 presented a multi-center open-label randomized control study investigating whether patients with elevated lactate levels ≥ 3.0 mEq/L on ICU admission would benefit from serial lactate monitoring and protocoled therapy directed at decreasing lactate levels.16 Patients with a lactate level ≥ 3.0 mEq/L were given more fluids and more vasodilators during an 8 hour treatment period. Treatment was aimed at decreasing lactate levels by 20% every 2 hours during an 8 hour treatment period. They found that the lactate group was given significantly more fluids and vasodilators during the 8 hour treatment period. There was a significant decrease in in-hospital mortality in the lactate group when the authors adjusted for predefined risk factors. They also found a significant decrease in length of stay, organ failure, ventilation time, and inotrope use in the lactate group. However, they did not find a difference in the rate of lactate reduction between the control group and the lactate group despite a more aggressive resuscitation strategy. It should be noted that the patients in this study also received a comprehensive resuscitation strategy including ScvO2.17

Puskarich et al. in 2012 presented a multi-center ED prospective randomized control trial studying the prognostic value of achieving a “lactate clearance goal” on in-hospital mortality in septic shock patients using goal directed therapy.17 Lactate clearance goal was defined as a decrease of ≥ 10% from an initial lactate of ≥ 2.0 mM, or both initial and repeat lactate levels < 2.0mM. Serum lactate was measured every 2 hours until the lactate goal was achieved or at hour 6 of the resuscitation period. They found that the lactate clearance only group was associated with a lower mortality than the ScvO2 only group. The authors concluded that failure to achieve a lactate clearance of ≥ 10% was associated with a worse prognosis than failure to achieve a ScvO2 of 70%.

Marty et al. in 2013 presented a prospective observational case series investigating the prognostic value of serial lactate measurements and lactate clearance on 28 day in-hospital mortality in the ICU after initial resuscitation in the ED.18 The mean time between a diagnosis of severe sepsis and ICU admission was 8 hours. The goals of management were dictated by the international guidelines for sepsis management in the first 24 hours. Mean serum lactate concentrations at time H0, H6, H12, and H24 were significantly lower in survivors than non-survivors. Lactate clearance was significantly higher in survivors than non-survivors for the H0-H6 time period and the H0-H24 time period as well. They found that lactate clearance for the H0-H24 time period was the best predictor of mortality at day 28, and lactate clearance at H0-H24 was independently correlated to survival status. The authors concluded that lactate concentration and lactate clearance were both predictive of 28-day in-hospital mortality.

Puskarich et al. in 2013 presented a preplanned analysis of his previous multi-center ED-based randomized control trial looking at the association between whole blood lactate kinetics and survival in patients with septic shock receiving a protocoled resuscitation bundle.19 Normalization of lactate (decline to < 2.0 mM), absolute clearance (initial minus delayed value), relative clearance (absolute divided by initial multiplied by 100), and clearance rate (relative clearance divided by clearance time) were calculated. Relative lactate clearance ≥ 50% after excluding for vasopressor administration and lactate normalization at 6 hours were the only statistically significant predictors of in-hospital survival. Interestingly, lactate clearance ≥ 10%, absolute clearance, and relative clearance were not significantly associated with in-hospital survival.

Surviving Sepsis Campaign Guidelines and Lactic Acidosis

Phase I of the surviving sepsis campaign was presented with the Barcelona Declaration in October 2002 in order to improve survival in severe sepsis. Phase II of the SSC introduced by Dellinger et al. in 2004 represented the culmination of a multi-organizational effort by experts in critical care and infectious disease in the development and publication of guidelines for the management of severe sepsis and septic shock.20 Lactate clearance was not included in the initial 6 hour bundle because it lacked “precision as a measure of tissue metabolic status.”20 In 2010 Levy et al. presented data from phase III of the SSC which included guideline implementation, behavior change and data collection.21 They found that the mortality rate for septic patients who had both hypotension and a lactate ≥ 4 mmol/L was 46.1% while the mortality rate was 30% for patients who initially presented with a lactate of ≥ 4.0 mmol/L. The third edition of the SSC guidelines in 2013 by Dellinger et al. recommended protocoled quantitative resuscitation of patients with sepsis-induced tissue hypo-perfusion.22 They suggested “targeting resuscitation to normalize lactate in patients with elevated lactate levels as a marker of tissue hypo-perfusion.”22 They cited a number of observational studies in addition to the 2001 Rivers et al. study and the SSC study by Levy et al. in 2010 as their rationale for using a lactate target of ≥ 4 mmol/L and targeting resuscitation to normalize lactate. However, they noted that some hospitals had “lowered the lactate threshold for triggering quantitative resuscitation in the patient with severe sepsis but that these thresholds had not been subjected to randomized trials.” The revised SSC guidelines also emphasized the utility of following lactate in association with ScvO2.22 They stated that lactate normalization was an appropriate alternative for assessing resuscitation if ScvO2 was not available. Their rationale for following lactate normalization included two randomized trials. One of the studies by Jones et al. found that a lactate clearance ≥ 10% was non-inferior to using ScvO2 ≥ 70% as a way to measure early quantitative resuscitation. The other study that they cited as evidence was the 2010 study Jansen et al. A number of changes were made to the SSC guidelines in April of 2015 which included the exclusion of measuring ScvO2 in the event of persistent hypotension despite volume resuscitation.23 The current guidelines still included measuring a lactate level and administering 30 ml/kg of crystalloid for a lactate of ≥ 4 mmol/L within 3 hours of declaration and remeasuring lactate within 6 hours if the initial lactate was elevated.

The utility of using lactate clearance as a marker of inadequate oxygen delivery and a measure of resuscitation in the updated SSC bundle remains controversial. A 2011 study by Nguyen et al. set out to examine the effectiveness of the phase III SSC resuscitation bundle with the addition of lactate clearance.24 Lactate clearance in this study was defined as any decrease in lactate within 12 hours from baseline or an initial lactate of < 2.0 mmol/L. Patients with lactate clearance had a lower APACHE II score and baseline lactate. The lactate group also had lower CVP and MAP but higher ScvO2 at baseline compared with the group who did not clear lactate. Overall they found that there was a 23% decrease in mortality in the lactate clearance group, and lactate clearance was independently associated with a decreased mortality. However, as Napoli et al notes global perfusion markers including CVP, MAP, and ScvO2 were near normal at baseline regardless of whether the bundle did or did not include lactate clearance as a marker of resuscitation.25 They also note that baseline hemodynamics, vasopressor use, and the amount of fluids given were the same for both lactate clearance and non-lactate clearance groups in the revised SSC bundle.25 These findings indicated that the mechanism of lactate clearance was unrelated to traditional hemodynamic markers.

Clinical Bottom Line

It is hard to deny the overwhelming evidence demonstrating an association between lactate clearance and mortality. Despite the ongoing controversy regarding the optimal endpoints of early sepsis resuscitation and the source of hyperlactemia, lactate remains the best non-invasive marker of illness severity. Given the current data, a ≥ 10% lactate clearance at 6 hours is an appropriate marker to follow when resuscitating a septic patient. However, recent research by Puskarich et al. showed that lactate normalization to < 2.0 mmol/L within the first 6 hours of resuscitation is superior to the rate of clearance.19 The best approach to current SSC guidelines when encountering a patient with systemic inflammatory response syndrome (SIRS) is to measure a lactate level and obtain blood cultures prior to giving antibiotics. If the MAP is ≥ 65 mmHG and initial lactate is < 2.0 mmol/L, all available data suggest that this patient has a low risk for MOSF and inpatient mortality and can go to the ward or an observation unit depending on other comorbidities. 26 If the MAP is ≥ 65 mmHg and the initial lactate is 2.0 to 3.9 mmol/L, provide 2 L of crystalloid and start source specific antibiotics.26 Remeasure the lactate within 6 hours and if there is a ≥ 10% decrease in lactate clearance, admit to either the ward or the observation unit.26 If the lactate clearance is < 10% after 2L of crystalloid, provide an additional 1L of crystalloid, and admit to the ICU.26 If the MAP is ≥ 65 mmHg and initial lactate is ≥ 4.0 mmol/L, provide either 3L or 4L of crystalloid within the first 6 hours depending on volume status and other comorbidities and admit to the ICU.26 If the patient presents with a MAP of < 65mmHg, begin fluid resuscitation, start source specific antibiotics, start norepinephrine targeted at a MAP ≥ 65 mmHg, and admit to the ICU.26

References/Further Reading

  1. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014 Dec 11;371(24):2309-19.
  2. Madias NE. Lactic acidosis. Kidney Int. 1986 Mar;29(3):752-74.
  3. Ince C. The microcirculation is the motor of sepsis. Crit Care. 2005;9 Suppl 4:S13-9.
  4. Revelly JP, Tappy L, Martinez A, Bollmann M, Cayeux MC, Berger MM, Chioléro RL. Lactate and glucose metabolism in severe sepsis and cardiogenic shock. Crit Care Med. 2005 Oct;33(10):2235-40.
  5. Marik PE, Bellomo R, Demla V. Lactate clearance as a target of therapy in sepsis: a flawed paradigm. OA Critical Care 2013 Mar 01;1(1):3.
  6. Levraut J, Ciebiera JP, Chave S, Rabary O, Jambou P, Carles M, Grimaud D. Mild hyperlactatemia in stable septic patients is due to impaired lactate clearance rather than overproduction. Am J Respir Crit Care Med. 1998 Apr;157(4 Pt 1):1021-6.
  7. Chertoff J, Chisum M, Garcia B, Lascano J. Lactate kinetics in sepsis and septic shock: a review of the literature and rationale for further research. J Intensive Care. 2015 Oct 6;3:39.
  8. Gibot S. On the origins of lactate during sepsis. Crit Care. 2012 Sep 10;16(5):151.
  9. James JH, Luchette FA, McCarter FD, Fischer JE. Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis. Lancet. 1999 Aug 7;354(9177):505-8.
  10. Bakker J, Gris P, Coffernils M, Kahn RJ, Vincent JL. Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg. 1996 Feb;171(2):221-6.
  11. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77.
  12. McNelis J, Marini CP, Jurkiewicz A, Szomstein S, Simms HH, Ritter G, Nathan IM. Prolonged lactate clearance is associated with increased mortality in the surgical intensive care unit. Am J Surg. 2001 Nov;182(5):481-5.
  13. Levraut J, Ichai C, Petit I, Ciebiera JP, Perus O, Grimaud D. Low exogenous lactate clearance as an early predictor of mortality in normolactatemic critically ill septic patients. Crit Care Med. 2003 Mar;31(3):705-10.
  14. Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, Tomlanovich MC. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med. 2004 Aug;32(8):1637-42.
  15. Arnold RC, Shapiro NI, Jones AE, Schorr C, Pope J, Casner E, Parrillo JE, Dellinger RP, Trzeciak S; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock. 2009 Jul;32(1):35-9.
  16. Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, Willemsen SP, Bakker J; LACTATE study group. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010 Sep 15;182(6):752-61.
  17. Puskarich MA, Trzeciak S, Shapiro NI, Arnold RC, Heffner AC, Kline JA, Jones AE; Emergency Medicine Shock Research Network (EMSHOCKNET). Prognostic value and agreement of achieving lactate clearance or central venous oxygen saturation goals during early sepsis resuscitation. Acad Emerg Med. 2012 Mar;19(3):252-8.
  18. Marty P, Roquilly A, Vallée F, Luzi A, Ferré F, Fourcade O, Asehnoune K, Minville V. Lactate clearance for death prediction in severe sepsis or septic shock patients during the first 24 hours in Intensive Care Unit: an observational study. Ann Intensive Care. 2013 Feb 12;3(1):3.
  19. Puskarich MA, Trzeciak S, Shapiro NI, Albers AB, Heffner AC, Kline JA, Jones AE. Whole blood lactate kinetics in patients undergoing quantitative resuscitation for severe sepsis and septic shock. Chest. 2013 Jun;143(6):1548-53.
  20. 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 Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004 Mar;32(3):858-73.
  21. Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, Schorr C, Artigas A, Ramsay G, Beale R, Parker MM, Gerlach H, Reinhart K, Silva E, Harvey M, Regan S, Angus DC. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med. 2010 Feb;36(2):222-31.
  22. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228.
  23. Updated Bundles in Response to New Evidence (n.d.): n. pag. Surviving Sepsis Campaign. Apr. 2015. Web. 15 Dec. 2015.
  24. Nguyen HB, Kuan WS, Batech M, Shrikhande P, Mahadevan M, Li CH, Ray S, Dengel A; ATLAS (Asia Network to Regulate Sepsis care) Investigators. Outcome effectiveness of the severe sepsis resuscitation bundle with addition of lactate clearance as a bundle item: a multi-national evaluation. Crit Care. 2011;15(5):R229.
  25. Napoli AM, Seigel TA. The role of lactate clearance in the resuscitation bundle. Crit Care. 2011;15(5):199. doi: 10.1186/cc10478. Epub 2011 Oct 24.
  26. “Quality Review Gets Septic.” Review. Audio blog post. EM:RAP. Cameron Berg, MD FAAEM and Rob Orman, MD. Aug. 2015. Web. 15 Dec. 2015.

Utility of Obtaining a Lactate Measurement in the ED

Utility of Obtaining a Lactate Measurement in the ED

Authors: Tyler Hurst, DO and Christopher Doty, MD
(Residency Physician and Program Director, respectively, for University of Kentucky Emergency Medicine Residency Program)
Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Stephen Alerhand, MD


  • Lactate was first proposed as a prognostic biomarker in 1964 by Broder and Weil who observed that a lactate excess of >4 mmol/L was associated with poor outcomes in patients with undifferentiated shock (1).
  • After the Rivers Trial, the majority of medical studies regarding lactate have examined its use as a biomarker and resuscitation endpoint in patients with sepsis and septic shock.
  • An elevated lactate is not specific to septic shock. Any process that causes tissue hypoperfusion and subsequent anaerobic metabolism can lead to an elevated lactate.
  • There are many conditions other than shock that may lead to an elevated lactate: mesenteric ischemia, liver failure, DKA, and certain medications/toxicological causes.


The Basics
  • Lactate is the byproduct of anaerobic metabolism. It is cleared primarily by hepatic metabolism and to a lesser extent by renal excretion. The half-life of lactate is approximately 20 min.
  • Lactate is generally measured in mmol/L with the normal value considered to be < 2 mmol/L and an abnormal value is generally considered > 4 mmol/L.
  • Lactic acidosis is a common cause of metabolic anion gap acidosis. The blood lactate level in mmol/L contributes to elevating the anion gap in a 1:1 ratio.
  • Lactic acidosis is broken down into two subtypes
    •        Type A lactic acidosis is seen in states of hypoperfusion or poor oxygenation.
      • Type B lactic acidosis is seen in states of high metabolism, organ dysfunction, and toxins.
  • Blood samples should be processed within < 15-30 min after being drawn. Samples are run on a blood gas analyzer with results obtained in 2-3 min.
  • Venous lactate levels are equivalent to arterial lactate levels, which negates the need for an arterial puncture when obtaining a lactate measurement (2).


  • Advanced trauma life support is heavily reliant on vital sign abnormalities to identify patients in shock. Tissue hypoperfusion, usually from blood loss, is common in trauma patients and will not always be apparent from vital sign abnormalities. For this reason most trauma protocols include a lactate measurement.
  • In trauma, a lactate >4 mmol/L is associated with a mortality of nearly 20%. Amongst patients with an initial lactate > 4mmol/L, clearance at 6 hours is associated with increased survival (3).
Septic Shock
  • One-half of patients with severe sepsis will have a systolic BP >90mmHg and one-fifth will have a normal blood pressure with a MAP of > 100mmHg. This has led experts to propose lactate as a screening tool on any patient meeting SIRS criteria (4).
  • Normotensive patients with a lactate >4 mmol/L have a mortality rate of 30% (5).
  • Amongst septic patients with a lactate greater than 4 mmol/L, clearance at 6 hours is associated with increased survival (6). Studies comparing lactate clearance and SVO2 monitoring as a guide to adequate resuscitation have shown lactate clearance to be non-inferior to SVO2 in terms of in-hospital mortality (7).
Cardiogenic/Obstructive shock
  • Fewer studies have been performed studying lactate in cardiogenic and obstructive shock. In patients with ST-segment myocardial infarction, a lactate clearance of <10% at 12 hours identified a subset of patients at higher risk for death (8).
  • Patients with pulmonary embolism and a lactate level ≥ 2 mmol/L had a mortality of nearly 20% (9).
Regional tissue ischemia
  • Mesenteric ischemia is a potentially difficult condition to diagnose. Lactate has a high sensitivity (96%) but low specificity (38%) when studied as a biomarker for acute mesenteric ischemia (10). In a patient with abdominal pain, an elevated lactate should raise the concern for mesenteric ischemia.
  • An elevated lactate can also be seen in acute limb ischemia, compartment syndrome, and necrotizing fasciitis.
Other causes
  • Acute or chronic liver failure can lead to an elevated lactate, as the liver is the primary organ responsible for its metabolism. In critically ill patients with chronic liver disease, an elevated lactate is still associated with increased risk of mortality (11).
  • In patients with diabetic ketoacidosis, lactate is commonly found to be elevated. The mechanism is not completely understood, but is thought to be due to hypoperfusion as well as altered glucose metabolism. An elevated lactate in patients with DKA does not correlate with increased mortality or increased ICU length of stay (12).
  • Common drugs/toxins associated with an elevated lactate are: alcohols, stimulants, carbon monoxide, cyanide, linezolid, nucleoside reverse transcriptase inhibitors, Metformin, Propofol, and acetaminophen.
Hypermetabolic states
  • Any state of prolonged vigorous muscular activity can lead to an elevated lactate. Commonly seen examples in an ED population are: patients who just suffered a seizure, those who are restrained and are straining against restraints, and athletes recently engaged in intense physical activity.
  • Asthmatics may have elevated lactate both from greatly increased muscular work of breathing and the fact that beta-agonists like albuterol can increase lactate levels.
 Additional Editor Pearls
  • Elderly patients may  not necessarily produce lactate levels corresponding to their level of illness severity. Do not disregard an elderly sick patient simply based on a low-normal lactate.
  • An elevated lactate in a patient with otherwise normal vital signs may be a harbinger of coming vital sign instability and/or SIRS, as shown by the Rivers trial (above).
  • Lactate may only be a late finding in acute mesenteric ischemia.
So I’ve obtained a lactate, now what?
  • A normal lactate does not exclude dangerous conditions, just as a high lactate does not always correlate with increased mortality.
  • In a patient with a lactate >4 mmol/L or even >2 mmol/L, this should raise your concern for a potentially dangerous condition. If this patient is clinically stable and without deranged vital signs, it is reasonable to judiciously resuscitate them with fluids and recheck a lactate level in 2 hours. If the patient is unstable or has vital sign abnormalities suggestive of shock, this patient is likely critically ill and in need of emergent intervention.
  • In the clinically stable patient whose lactate remains elevated despite adequate resuscitation, the clinician must consider that this patient could be seriously ill and look for possible confounding sources such as: mesenteric ischemia, occult hemorrhage, or untreated infection.


Bottom line
  • A venous lactate is an easy-to-obtain and quick-to-result biomarker for mortality in critically ill patients.
  • One of the main responsibilities of an ER doctor is to identify those patients who are at highest risk for mortality. Unfortunately, not all critically ill patients will present with abnormal vital signs or obvious blood loss. Obtaining a lactate can potentially identify those patients in occult shock and reduce mortality by expediting definitive treatment.



References / Further Reading

1.) Broder G, Weil MH. Excess Lactate: An Index of Reversibility of Shock in Human Patients. Science. 1964; 143:1457–1459.
2.) Younger JG, Falk JL, Rothrock SG. Relationship between arterial and peripheral venous lactate levels. Acad Emerg Med 1996; 3:730-4.
3.) Odom SR, Howell MD, Silva GS, et al. Lactate clearance as a predictor of mortality in trauma patients. The journal of trauma and acute care surgery 2013; 74(4):999–1004.
4.) Singer AJ, Taylor M, Domingo A, Ghazipura S, Khorasonchi A, Thode, HC, Shapiro NI. Diagnostic characteristics of a clinical screening tool in combination with measuring bedside lactate level in emergency department patients with suspected sepsis. Academic emergency medicine 2014; 21:853–857
5.) Shapiro NI, Howell MD, Talmor D, et al. Serum lactate as a predictor of mortality in emergency department patients with infection. Annals of emergency medicine 2005; 45(5):524–528.
6.) Arnold RC, Shapiro NI, Jones AE, et al. Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock 2009; 32(1):35–39.
7.) Jones AE, Shapiro MI, Trzeciak S, et al. Lactate clearance vs. central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010; 303:739–46.
8.) Attana P, Lazzeri C, Chiostri M, Picariello C, Gensini GF, Valente S. Lactate clearance in cardiogenic shock following ST elevation myocardial infarction: a pilot study. Acute cardiac care 2012; 14(1):20–26.
9.) Vanni S, Viviani G, Baioni M, et al. Prognostic value of plasma lactate levels among patients with acute pulmonary embolism: the thrombo-embolism lactate outcome study. Annals of emergency medicine 2013; 61(3):330–338.
10.) Lange H, Toivola A. Warning signals in acute abdominal disorders. Lactate is the best marker of mesenteric ischemia. Lakartidningen 1997; 94(20):1893–1896.
11.) Kruse JA, Zaidi SA, Carlson RW. Significance of blood lactate levels in critically ill patients with liver disease. The American journal of medicine 1987; 83(1):77–82.
12.) Cox, KC.; NC; Carney, EE.; Howell, MD.; Donnino, MW. Prevalence and significance of lactic acidosis in diabetic ketoacidosis. Journal of Critical Care 2012; 27(2):132–137.
13.) http://www.ncbi.nlm.nih.gov/pubmed/25186838
14.) http://www.ncbi.nlm.nih.gov/pubmed/25450570
15.) http://www.ncbi.nlm.nih.gov/pubmed/25432592
16.) http://www.ncbi.nlm.nih.gov/pubmed/25466313
17.) http://www.ncbi.nlm.nih.gov/pubmed/25325409
18.) http://www.ncbi.nlm.nih.gov/pubmed/25124137
19.) http://www.ncbi.nlm.nih.gov/pubmed/24776606
20.) http://www.ncbi.nlm.nih.gov/pubmed/24079682

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