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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

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

 

 

Leukemia

 

Lymphoma

 

Thiamine deficiency

 

Pancreatitis

 

Hepatic or renal failure

 

Short bowel syndrome

Phenformin

Metformin

Epinephrine

Norepinephrine

Xylitol

Sorbitol

Lactate-based dialysate fluid

Cyanide

Beta-agonist

Alcohols: Methanol, Ethylene Glycol

Salicylates

Nitroprusside

Isoniazid

Fructose

Paracetamol

Biguanides

Anti-retroviral agents

Pyruvate carboxylase deficiency

 

Glucose-6-phosphatase deficiency

 

Fructose-1,6-bisphosphatase deficiencies

 

Oxidative phosphorylation enzyme defects

Screening

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.

Prognostication

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.

Clearance

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

 Pitfalls

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

 

Procalcitonin

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

Diagnosis

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

Troponin

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)

Cardioversion

Direct Myocardial Trauma

Hypertrophic Cardiomyopathy

Tachycardia/Tachyarrhythmia

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

Sepsis

Severe Pulmonary Hypertension

Strenuous Exercise/Extreme Exertion

Risk Stratification

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

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

 

Novel Biomarkers

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

Endothelial Markers

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

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

Proadrenomedullin (ProADM)

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

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

Acute-Phase Reactants

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

Cardiac Biomarkers

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

 

Key Points:

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

 

References/Further Reading

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