American Association for Clinical Chemistry
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NACB - Scientific Shorts
NACB - Scientific Shorts (formerly NACB Blog)
By Alison Woodworth, PhD, DABCC, FACB
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Sepsis is systemic inflammation due to infection.  It is the most common cause of death in intensive care units (1), with a mortality rate up to 50% depending on severity.  Sepsis can be considered in individuals with systemic inflammatory response syndrome (SIRS) manifested by alterations in at least two of temperature, heart rate, respiratory rate, and/or white blood cell count.  These SIRS criteria are non-specific for sepsis and may be present in alternative pathophysiologic states, both medical and surgical (1).

 

The earlier sepsis is identified and treated the better the prognosis (1).  Currently diagnosis involves documentation of infection (by culture) in patients with SIRS.  Cultures take at least 24 hours and > 50% may be false negative and 30% false positive.  A biomarker that could identify sepsis early in a population of patients with overlapping clinical symptoms, i.e. patient’s with non-infectious SIRS would improve patient care. 

 

Many suggest that Procalcitonin (PCT) is an ideal sepsis biomarker.  PCT is the pro-hormone form of calcitonin and is produced by extra-thyroidal immune cells within 2-4 hours of a bacterial insult and/or inflammatory response.  Elevated PCT is seen in septic patients and concentrations correlate with severity of disease.  Increasing PCT over time is associated with poor prognosis, while decreasing concentrations correlate to good prognosis and/or response to antibiotic therapy.  Thus, proponents suggest that the clinical utilities of PCT are:  to differentiate patients with sepsis from those with non-infectious SIRS; to guide antibiotic therapy; and to predict prognosis of critically ill patients (2). 

 

Procalcitonin: an early predictor of sepsis?

Thousands of studies have investigated the clinical utility of almost 200 biomarkers of sepsis (3).  Among these, PCT and CRP are most often referenced.  In comprehensive reviews comparing their diagnostic accuracies, PCT consistently performs better, but sensitivity and specificities to predict sepsis are <90% for both markers.  Two meta-analyses recommend routine use of PCT for diagnosis of sepsis while two others discourage its use (3-6).  Why the discrepancy? Lack of a gold standard for sepsis diagnosis. Diverse patient populations--PCT is elevated postsurgery, trauma, or in other instances of systemic inflammation limiting its diagnostic accuracy. Different PCT cut-offs are used. Sepsis is diagnosed retrospectively with knowledge of bacterial cultures and a full clinical picture in most studies.  To date, few studies have addressed the utility of PCT to predict sepsis in “real time”.  Until, large real time studies with well defined patient populations are completed, the utility of PCT to predict sepsis will remain controversial.      

 

Does PCT have a role in tailoring antibiotic therapy?

Overuse of antibiotics in ICU settings has contributed to the increase in antibiotic resistant bacteria.  Most randomized control trials demonstrate that using serial PCT based algorithms to guide continuation/cessation of antibiotic therapy reduces the number of days patients are on antibiotics without adverse effects.  None has demonstrated a reduction in multidrug resistant (MDR) bacterial infections (7).  In practice, there is limited utility for PCT to guide initiation of antimicrobial therapy because most ICU patients are taking antibiotics at admission.  Further, these algorithms are not effective in patients with recent trauma, surgery or other global inflammation.  Thus, PCT based algorithms for guiding antibiotic therapy are limited to guiding secession/continuation of therapy in non-surgical/trauma ICU patients.  And even in these populations, serial PCT measurements may be cost prohibitive if no reduction in MDR infections is observed.

 

Can procalcitonin be used to predict prognosis?

Increasing PCT concentrations correlate with increasing severity of sepsis and poor outcome, while decreasing or low PCT predicts a good prognosis for ICU patients.  Most studies exclude patients with a recent trauma, surgery or other inflammatory event (6). 

 

Given the complicated pathobiology of sepsis and significant overlap in clinical symptoms with SIRS patients, it may be that no one biomarker works for sepsis.  Studies looking at multi-biomarker panels have shown promise in the prediction and monitoring of sepsis in ICU and ED patients (3).

 

With today’s ED and ICU populations, is procalcitonin the answer to the sepsis dilemma?

 

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Posted by
On 4/21/2011

In addition to the well-known cause of lactate elevation by an oxygen deficit, lactate also rises whenever the mitochondria are unable to perform oxidative phosphorylation. An obvious example would be cyanide poisoning, where O2 can be abundant, but cannot be utilized. This also applies to sepsis, where the cell-mediated products (ILs, TNFs, etc) are being shown to inhibit mitochondrial function. John Toffaletti, PhD Duke Medical Center

Posted by
On 4/7/2011

We have found PCT to be a very reliable marker for predicting sepsis and guiding appropriate antibiotic use. However, in patients of liver injury for eg a post liver transplant or severe hepatitis , we have observed elevations of PCT even in the absence of sepsis. I would be interested to know whether there are other conditions wherein such PCT elevations are observed in the absence of sepsis. Pragna Rao, MD,PhD. Professor of Biochemistry,KMC, Manipal.India

Posted by
On 4/6/2011

Shame that IL-6 is not mentioned in your article. Not to dispute the value of PCT and CRP in diagnosis and therapy guidance in patients with SIRS and associated characteristics, the role of IL-6 as a marker able to recognise inflammation earlier than either PCT or CRP should not be understated. Although IL-6 tends to be labeled as "unspecific for "sepsis", it is specific for inflammation. moreover, its early rise indicates the acuteness of that inflammation. In certain situations (e.g. emergency presentations with complex multimorbidities, candidates for elective surgery, paitents returning from elective surgery, and others) monitoring inflammatory progression from phenomenon as early as possible (not alone, but in concert with additonal diagnostic information) could enable a clinician to intervene more quickly, or at an earlier stage. I would be interested to see how the kinetics of all three of these markers measured over time in controlled clinical circumstances. in the best case, situations can be revealed where all of the markers collaborate to deliver a better picture of the patient's clinical status. This comment was approved by the NACBLOG editorial board. Please remember to add your name and affiliation!

Posted by
On 3/31/2011

There is strong evidence for the use of lactate as a part of the sepsis resuscitation bundle, a group of tests aimed at assessing and directing therapy for patients with severe sepsis and septic shock. Specifically elevated and inappropriately cleared lactate is associated with tissue hypoperfusion that occurs in septic shock. An elevated lactate >4 mmol/L suggests that a patient receive goal directed therapies such as vasopressors. The difference in clinical utility between lactate and PCT is that PCT may be a good early predictor of sepsis prior to progression to severe disease. It is elevated within four hours if bacterial insult and its concentrations correlate with degree of infection as evidenced by its role in targeting antibiotic therapy. I view lactate and PCT as complementary tests. While lactate guides pressor therapy late in the septic disease process, PCT may predict early sepsis and guide antibiotic therapy in patients very early in the disease. Alison Woodworth, PhD, DABCC, FACB

Posted by
On 3/31/2011

I would like to see a study comparing lactate to PCT to determine which analyte is more appropriate. Since lactate can be performed either by POCT or on a blood gas analyzer, it may be an appropriate first test. Due to technical restrictions, PCT may be a better test to follow the septic course. This comment was approved by the NACBLOG editorial board. Please remember to add your name and affiliation!

About the Author
Alison Woodworth, PhD, DABCC, FACB
Alison Woodworth, PhD, DABCC, FACB  
 

References

 

1. Russell JA. Management of sepsis. N Engl J Med. 2006 Oct 19;355(16):1699-713.

2. McGee KA. Procalcitonin: Clinical Utility in Diagnosing Sepsis. Clinical Laboratory News. 2009;35(7).

3. Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care. 2010;14(1):R15.

4. Jones AE, Fiechtl JF, Brown MD, Ballew JJ, Kline JA. Procalcitonin test in the diagnosis of bacteremia: a meta-analysis. Annals of emergency medicine. 2007 Jul;50(1):34-41.

5. Tang BM, Eslick GD, Craig JC, McLean AS. Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis. Lancet Infect Dis. 2007 Mar;7(3):210-7.

6. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med. 2006 Jul;34(7):1996-2003.

7. Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, et al. 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.