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The first 24 hours for a patient with early signs of sepsis are critical. The first hour after this patient arrives in the emergency department is equivalent to the “golden” hour of trauma. The initial evaluation, with particular emphasis on the laboratory findings are vital in the effective management of a septic patient. 

Septic shock strikes an estimated 750,000 people each year in the United States. If untreated, this inflammatory reaction can eventually lead to organ dysfunction or failure and death. In fact, sepsis claims 215,000 lives per year and is the leading cause of non-cardiac ICU death [Angus DC et al. Crit Care Med. 2001]. All told, sepsis is responsible for more deaths each year than breast cancer, acute myocardial infarction or AIDS – and is on the rise due to an aging population, increased use of invasive diagnostic procedures, immunosuppressive and cytotoxic therapies and an increased number of immunocompromised patients. Early recognition of sepsis, specific clinical interventions and timely initiation of appropriate therapy is critical for improving patient outcomes. 

It has been estimated that more than 458,000 sepsis cases annually (or 61 percent of sepsis presentations) are first encountered in the Emergency Department (ED) [Talan, D, Infect Dis Clin N Am. 22; 2008: 1-31] With the discovery of new strategies and therapies to optimize the outcome of patients with severe sepsis/septic shock, increasing emphasis is being placed on rapid diagnosis and treatment initiated in the ED. Unfortunately, sepsis often presents with nonspecific findings that may be difficult to detect early in a busy ED. The disease can be difficult to distinguish from other, non-infectious conditions in critically ill patients–for example, congestive heart failure, myocardial infarction and thromboembolic disease–especially for those with clinical signs of acute inflammation and unavailable microbiological results. As no single test or marker exists to accurately diagnose sepsis, the historical focus has been on supporting failing organ systems rather than on identifying the underlying disease [Angus DC, Crit Care Med. 2001; 29: 1303-1310]. Oftentimes, by the time an accurate diagnosis is made, patients may have progressed to the final stages of the disease. Clearly there is an urgent need for more effective strategies to help ED physicians rapidly intervene in and manage sepsis to make the most of those initial hours and ensure the best possible outcome for sepsis patients.

Procalcitonin in the Diagnosis of Sepsis

Only through early identification of patients with this often insidious illness is it possible to implement early goal-directed therapy (EGDT) appropriately [Rivers E. N Engl J Med. 2001; 345:1368-77]. Any reliable tool available to help take the guesswork out of early treatment decisions for suspected sepsis patients, is extremely valuable. Early Goal Directed Therapy EGDT GDT is directly linked to significant improvement in sepsis patient outcomes. Anand Kumar demonstrated that patients who received antibiotics within the first hour of hypotension related to a diagnosis of sepsis had a 79.9 percent survival rate. However, each hour of delay in receiving antibiotics was associated with an average decrease in survival of 7.6 percent [Kumar A. Crit Care Med. 2006; 34: 1589-1596]. A four hour delay in appropriate antibiotics resulted in a survival rate of only 49.5 percent, a reduction of 30.4 percent!

Fig 1. PCT’s unique kinetics following a bacterial challenge make it a rapid and specific marker for sepsis. Kinetics of various markers of the inflammatory host response after endotoxin challenge in human volunteers. CRP, C-reactive protein; IL, interleukin; PCT, procalcitonin; TNF, tumor necrosis factor


 

Laboratory data currently available to help guide most physicians in sepsis risk stratification include white blood cell count, C-reactive protein (CRP), , Gram staining and finally cultures – which can take up to two days for results. At our facility, we were fortunate in being able to add procalcitonin (PCT) to our sepsis panel soon after its introduction into the United States. We have been working with PCT since early 2008 and incorporating its use into our hospital’s sepsis protocol. We have found that PCT testing in the ED and ICU is incredibly useful in expediting the assessment of patients suspected of having sepsis, especially when the diagnosis using conventional data is ambiguous.

Fig 2. PCT has demonstrated performance superior to that of other markers for sepsis. The serum CTpr assay is compared with circulating interleukin-5, C-reactive protein, and laetate measurements in critically ill patients with systemic infections (i.e. sepsis, severe sepsis, or septic shock) on admission. They are displayed in a receiver operating curve (ROC) analysis (adapted from [2]).


 

Rapid decrease = half-life about 20 hours = rapid reflection of treatment efficacy (in 24 hours, PCT decrease is about 50 % per day)

Kinetics of procalcitonin in iatrogenic sepsis. F. M. Brunkhorst, U. Heinz and Z. F. Forycki Intensive Care Medicine . Volume 24, Number 8, 888-889

In healthy people, plasma PCT concentrations are found to be below 0.05 ng/ml; however, much higher values are observed during acute disease conditions with severe systemic reaction to bacterial infection. In septic conditions, increased PCT levels can be observed within three-to-six hours after an infectious “challenge.” PCT can increase to 1,000 ng/ml in patients with severe sepsis or septic shock [Harbarth S. Am J Resp Crit Care. 2001;164: 396-402 and Muller, B. Critic Care Med. 28 (4); 977-983, April 2000].

In the normal situation cleaved calcitonin (CT) is secreted by the C-cells of the thyroid gland after hormonal stimulation at very low levels. In the setting of an acute systemic bacterial insult, uncleaved PCT is secreted from multiple tissues in significantly larger quantities by a factor of up to 2,000. Severe systemic bacterial infections prompt a rapid and highly specific increase in plasma PCT levels. 

Not only is this short timeframe key to ensuring the swiftest possible intervention, but as demonstrated in a number of studies, PCT has shown the best performance among other laboratory parameters for differentiating patients with sepsis from those with a systemic inflammatory reaction not related to an infectious cause. In a study published in Critical Care Medicine in 2000 [Muller, B. Critic Care Med. 28 (4); 977-983, April 2000], calcitonin sensitivity (89 percent) and specificity (94 percent) far exceeded that of interleukin-6, CRP and lactate, underscoring the biomarker’s reliability. Moreover, PCT has demonstrated itself to be the only laboratory parameter that has made a significant contribution to the clinical diagnosis of sepsis. Conversely, information obtained from interleukin-6, interleukin-8, and CRP have not had an impact on the clinical diagnosis of sepsis on admission. Finally, a study published in Critical Care Medicine in 2006 [Jensen et al Crit Care Med 2006; 34:2596-2602] demonstrated that a high and increasing level of PCT recorded within the first 24 hours represents an early independent predictor of all-cause mortality in a 90-day follow-up period after ICU discharge. Risk of mortality increases for every day that PCT increases, whereas increases in CRP or white blood cell count did not seem to predict mortality. 

An Additional Tool in an Emergency Physician’s Armamentarium

The integration of PCT into diagnostic and treatment algorithms in the ED can be beneficial for earlier recognition and treatment of sepsis. In a study comparing clinical models with and without PCT, it was found that when PCT was added, the ability to diagnose sepsis was significantly improved [Harbarth S. Am J Resp Crit Care. 2001;164: 396-402] 

False negative results with PCT can occur in very early presentation of systemic infection or with a localized process such as an abscess. False positive elevations can occur in patients with chemical pneumonitis, ARDS, burns, pancreatitis and neuroendocrine cell line tumors. The dynamic characteristics are however different from those seen with sepsis. We recommend using PCT like a troponin (when ruling out myocardial infarction). Our protocol is to obtain serial PCTs, initially when obtaining blood cultures at time zero then at 12 hours and again at 24 hours.

While no single test is used in isolation, when PCT is utilized in the correct clinical setting it is an invaluable addition to our diagnostic armamentarium when addressing an infected, possibly septic patient. This novel biomarker can also help optimize antibiotic treatment decisions and assist clinicians in developing more targeted use of their clinical resources. 


Devendra N. Amin, MD, FCCM, FCCP, is an assistant professor in the Dept. of Family Practice, University of South Florida at Morton Plant Hospital and Medical Director of Critical Care Services at Morton Plant Hospital. Dr. Amin is one of the earliest adopters of the new rapid PCT testing in the U.S. and is in the process of collecting data for a manuscript on the role of PCT testing in the management of septic patients.

 

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