Procalcitonin as a Diagnostic Marker for ICU Bacteremia

Introduction: Treating Critically Ill ICU Patients

The main objective of providing treatment to patients is to relieve symptoms while decreasing the progression of disease and reducing mortality and morbidity. However, in some cases this objective is not fully achieved, particularly for patients admitted to the ICU with serious or terminal illness. For example, when elderly patients are admitted to the ICU, their immunity is extremely low, creating ideal conditions for opportunistic infections to worsen their prognosis. Many infections are specifically associated with patients admitted to hospital settings. Pseudomonas aeruginosa is a well-documented microorganism that causes bacterial pneumonia and bacteremia in terminally ill patients receiving hospital-based treatment.

Since most ICU patients are not conscious or are in a comatose state, it becomes very difficult for doctors and nursing staff to make an early diagnosis of these infections. By the time clinicians and paramedics identify the deteriorating condition caused by opportunistic pathogens, it is usually too late to save the patient's life.

Definition of Key Terms

Before beginning the discussion based on the PICO question, it is useful to define some key terms that appear frequently throughout this paper.

The term "adult patients" is used in two contexts. First, adult patients are most prone to infections because they often have a depressed immune system. Second, adult patients are those most frequently admitted to the ICU with a terminal or very serious illness.

The term "critically ill" refers to patients admitted to the ICU with a potentially fatal disease or those in the terminal stages of any illness.

"Bacteremia" refers to the presence of bacteria of any strain in the circulating bloodstream, with the potential to cause systemic infections whose outcome is typically sepsis or septic shock.

"Bacterial pneumonia" is infection of the lungs or lower respiratory tract caused by a bacterium, whether gram-positive or gram-negative.

The term "adjunctive measurement", as used in relation to procalcitonin in systemic infections, implies the use of supplementary diagnostic tools alongside primary methods. Some of these tools are referred to as surrogate markers and can assist doctors and nursing staff in the early diagnosis of conditions that may be potentially fatal for critically ill patients.

PICO Question and Outline

The PICO question around which this paper is organized concerns adult patients admitted to the ICU who are terminally ill. These patients almost always develop bacteremia or bacterial pneumonia, which further worsens their condition and decreases their survival rate. The purpose of the question is to determine whether adjunctive measurement of procalcitonin (PCT) levels can aid in the early diagnosis of bacteremia and bacterial pneumonia, enabling prompt and appropriate treatment that reduces mortality and morbidity.

Researchers continue to work on assessment techniques that would allow clinical professionals to make an early diagnosis of such infections. One such diagnostic criterion is the adjunctive measurement of PCT levels. This paper discusses how this method and its alternatives may help save patients' lives. It also examines statistics on the deaths of critically ill patients due to bacteremia and, after analyzing available data, reaches a conclusion about whether PCT measurement offers a clear benefit or whether the evidence remains inconclusive. The PICO question is answered at the end of the paper.

Relevance to Clinical Practice

Doctors and paramedic staff are deeply concerned about ICU patients developing septic shock from opportunistic infections. Once patients develop septicemia or bacteremia, saving their lives becomes extremely difficult. This section examines why it is so important for researchers and clinicians to develop methods for the early diagnosis of pathogen invasion, in order to decrease mortality and morbidity.

Most patients admitted to the ICU are elderly and therefore have very low immunity. Furthermore, because they are in the ICU, they are receiving strong medications for serious underlying conditions, which further suppresses their immune systems. Under these circumstances, opportunistic bacteria can invade the body and cause life-threatening septicemia or bacterial pneumonia. Early-stage diagnosis is critical. Although fever and dropping blood pressure may signal developing bacteremia, these signs are not specific enough for a definitive clinical diagnosis. Hence, the development of specific methods — such as PCT level measurement — for the early detection of worsening health is essential. The next step would be to treat patients with bacterial pneumonia and bacteremia appropriately and promptly.

According to theory, automated continuous-monitoring systems allow doctors and nursing staff to detect bacterial invasion within a few hours of blood sample collection. In actual clinical practice, however, it takes at least 12 to 24 hours to obtain Gram stain results after blood is drawn. This delay is one of the main reasons patients face worse outcomes and extended ICU stays. By contrast, newer methods such as the polymerase chain reaction allow reliable and rapid identification of bacteria, but the facilities for conducting such tests are not available in most clinical centers. While clinical manifestations remain the best approach to diagnosis, recently discovered surrogate markers can offer significant assistance in identifying major human bacterial strains within the first few hours of managing bacteremic patients.

A study based on 147 patients admitted across five different ICUs found that the most common source of infection was the lower respiratory tract, affecting 32.0% of patients infected with opportunistic pathogens. Drugs tested for treating these infections included ceftazidime, imipenem, and ciprofloxacin, which were found to be the most effective against bacteria isolated from blood cultures. The independent risk factors for mortality were identified as the development of septic shock and fatal underlying conditions. Treatment with appropriate antibiotics did not prove to significantly improve survival in these patients. The findings suggested that preventing bacterial pneumonia and lower respiratory tract colonization are critical for reducing hospital-acquired gram-negative septicemia in ICU patients, and that the most significant risk factors for death are the underlying disease and septic shock (Jang et al., 1999).

Effectiveness of Procalcitonin as Evidence

Serum procalcitonin (PCT) is a peptide based on 116 amino acids. A strong association has been established between elevated PCT and systemic bacterial infections. The measurement of serum PCT relies on a fast, routine laboratory test with a documented ability to distinguish between non-infectious acute inflammatory conditions and systemic bacterial infection (Digiovine et al., 1999). By contrast, serum C-reactive protein and white blood cell count lack this discriminatory ability. Furthermore, results have shown that the magnitude of PCT elevation has a close association with outcomes in critically ill patients (Beekmann, 2003).

Some studies have also suggested that the degree of PCT elevation varies according to the underlying pathogen. This means that different magnitudes of serum PCT elevation are expected in cases of infective endocarditis, bacterial pneumonia, and bacteremia (Luzzani et al., 2003). Nonetheless, only a handful of conflicting results regarding which PCT magnitude can differentiate between gram-positive and gram-negative bacterial strains have been published when considering critically ill patients who have simultaneously developed sepsis (Opal et al., 1999). However, differences in the signaling pathways of the inflammatory response induced by the two bacterial species have been established. Since PCT elevation is considered to have an intricate relationship with the host's cytokine response to microbial challenge, it is assumed that differences in PCT values according to bacterial strain exist from the onset of bacterial manifestation (Harbarth et al., 2001).

Conclusion

Based on the available studies and research on PCT elevation for the early detection of bacteremia, the conclusion is that serum PCT levels increase when pathogens invade the body. This finding is of particular importance for critically ill patients who require rapid intervention. It has also been observed that when gram-negative bacteria are the causative agent of bacteremia and bacterial pneumonia, PCT elevation is greater than when a gram-positive bacterium is responsible. This distinction has clinical importance because evidence shows that in most cases the underlying agent of bacteremia and bacterial pneumonia in critically ill patients is a gram-negative bacterium. These patients are also more prone to developing sepsis, while bacteremia caused by gram-positive bacteria tends to produce milder symptoms in comparison. The value of adjunctive PCT measurement lies in enabling doctors to initiate empiric treatment much earlier. The conventional method of differentiating between gram-negative and gram-positive bacterial strains — Gram staining — typically takes 3 to 4 days to yield documented results. It has therefore been demonstrated that measurement of elevated PCT levels supports earlier diagnosis in critically ill patients who have developed bacteremia.

However, it should also be noted that because PCT elevation is attributed to the signaling pathways of the inflammatory response and the cytokine mediators involved, differences in those pathways or cytokines in certain cases of bacteremia may affect the magnitude of PCT elevation. Nonetheless, empiric treatment should always be initiated promptly in critically ill patients suspected of having developed bacteremia.

The answer to the PICO question discussed at the beginning of this paper is therefore that adjunctive measurement of PCT levels, used alongside other specific and non-specific diagnostic tools, can aid in the early detection of bacteremia and bacterial pneumonia in adult patients admitted to the ICU. The importance of this early detection is that it allows doctors to begin empiric treatment as soon as possible, thereby improving patient survival and reducing mortality and morbidity.

References

Beekmann, S. E., Diekema, D. J., Chapin, K. C., & Doern, G. V. (2003). Effects of rapid detection of bloodstream infections on length of hospitalization and hospital charges. Journal of Clinical Microbiology, 41, 3119–3125.

Boussekey, N., Leroy, O., Georges, H., Devos, P., d'Escrivan, T., & Guery, B. (2005). Diagnostic and prognostic values of admission procalcitonin levels in community-acquired pneumonia in an intensive care unit. Infection, 33, 257–263.

Charles, P. E., Dalle, F., Aho, S., Quenot, J. P., Doise, J. M., Aube, H., Olsson, N. O., & Blettery, B. (2006). Serum procalcitonin measurement contribution to the early diagnosis of candidemia in critically ill patients. Intensive Care Medicine, 32, 1577–1583.

Digiovine, B., Chenoweth, C., Watts, C., & Higgins, M. (1999). The attributable mortality and costs of primary nosocomial bloodstream infections in the intensive care unit. American Journal of Respiratory and Critical Care Medicine, 160, 976–981.

Garrouste-Orgeas, M., Timsit, J. F., Tafflet, M., Misset, B., Zahar, J. R., Soufir, L., Lazard, T., Jamali, S., Mourvillier, B., Cohen, Y., De Lassence, A., Azoulay, E., Cheval, C., Descorps-Declere, A., Adrie, C., Costa de Beauregard, M. A., & Carlet, J. (2006). Excess risk of death from intensive care unit-acquired nosocomial bloodstream infections: A reappraisal. Clinical Infectious Diseases, 42, 1118–1126.

Harbarth, S., Holeckova, K., Froidevaux, C., Pittet, D., Ricou, B., Grau, G. E., Vadas, L., & Pugin, J. (2001). Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. American Journal of Respiratory and Critical Care Medicine, 164, 396–402.

Ibrahim, E. H., Sherman, G., Ward, S., Fraser, V. J., & Kollef, M. H. (2000). The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest, 118, 146–155.

Jang, T. N., Kuo, B. I., Shen, S. H., Fung, C. P., Lee, S. H., Yang, T. L., & Huang, C. S. (1999). Nosocomial gram-negative bacteremia in critically ill patients: Epidemiologic characteristics and prognostic factors in 147 episodes.

Luzzani, A., Polati, E., Dorizzi, R., Rungatscher, A., Pavan, R., & Merlini, A. (2003). Comparison of procalcitonin and C-reactive protein as markers of sepsis. Critical Care Medicine, 31, 1737–1741.

Meisner, M., Tschaikowsky, K., Palmaers, T., & Schmidt, J. (1999). Comparison of procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations at different SOFA scores during the course of sepsis and MODS. Critical Care, 3, 45–50.

Muller, B., Becker, K. L., Schachinger, H., Rickenbacher, P. R., Huber, P. R., Zimmerli, W., & Ritz, R. (2000). Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Critical Care Medicine, 28, 977–983.

Munson, E. L., Diekema, D. J., Beekmann, S. E., Chapin, K. C., & Doern, G. V. (2003). Detection and treatment of bloodstream infection: Laboratory reporting and antimicrobial management. Journal of Clinical Microbiology, 41, 495–497.

Opal, S. M., & Cohen, J. (1999). Clinical gram-positive sepsis: Does it fundamentally differ from gram-negative bacterial sepsis? Critical Care Medicine, 27, 1608–1616.

Prat, C., Dominguez, J., Andreo, F., Blanco, S., Pallares, A., Cuchillo, F., Ramil, C., Ruiz-Manzano, J., & Ausina, V. (2006). Procalcitonin and neopterin correlation with aetiology and severity of pneumonia. Journal of Infection, 52, 169–177.

Tavares, E., Maldonado, R., Ojeda, M. L., & Minano, F. J. (2005). Circulating inflammatory mediators during start of fever in differential diagnosis of gram-negative and gram-positive infections in leukopenic rats. Clinical and Diagnostic Laboratory Immunology, 12, 1085–1093.