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Anaemia, platelets, immature platelet fraction and procalcitonin levels on survival outcome in systemic inflammatory response syndrome and sepsis

Research Article                                         Vol:3,Issue:1

Michelle H Djuang, Fransiscus Ginting, Stephen CL Koh, Herman Hariman

Abstract

Sepsis remains a major cause of morbidity and mortality. Anaemia in sepsis is multifactorial in origin and thrombocytopenia is identified as a major risk factor. The immature platelet fraction (IPF) has been suggested to predict the development of sepsis. Elevated procalcitonin (PCT) levels was shown to be a good diagnostic marker for suspected sepsis. The objective was to determine the anaemia status, platelets, immature platelet fraction and procalcitonin levels and survival outcome in patients with systemic inflammatory response syndrome (SIRS) and sepsis .71 patients (males n=45) were recruited. Their mean age was 48.04 ± 15.0 years and ranged between 18 and 84 years old. Haemoglobin, platelets, IPF and PCT was determined. Anaemia was seen in 52.9 % (SIRS), sepsis/severe sepsis (69.0%). Thrombocytopenia was evident in sepsis/severe sepsis (27.8%) and SIRS (11.8%). Reduced platelets were seen in severe sepsis. The IPF were elevated in SIRS (41.2%) and in sepsis and severe sepsis (37.0%). Mortality within 31 days from admission was 33.3% in SIRS, sepsis/severe sepsis (56.4%). Platelets were significantly reduced in non-survivors. Only platelets and IPF had significant correlation. Our study suggests that elevated PCT is not the main cause for non-survival outcome. The survivors could possibly be due to their response to therapy which was not determined. Anaemia and thrombocytopenia are evident in SIRS and sepsis. Elevated IPF and PCT levels was evident. However, elevated PCT may not be associated with survival outcome but may serve as a marker for sepsis.

Key words: survival outcome in sepsis.

SAJMED. 2018: 3(1): 63-71                                                              PDF Download

Introduction

Sepsis is a life-threatening condition emanating from the body’s response to an infection where it injures its own tissues and organs (1). It refers to the response to infection by microbial agents like bacteria, fungi and yeast resulting in fever, tachycardia, tachypnea and leucocytosis. Microbiological cultures from blood or infection site frequently may not be invariably positive. Sepsis is a potential risk for patients in hospital admitted for other serious illness. The fatality rate in patients with sepsis remained high at 30% to 60% worldwide (2) and remains a major cause of morbidity and mortality in ICU (3, 4). Even if discharged the sequelae including deteriorated cognitive or physical function or poor outcome after the ICU and hospital discharge was seen (5). Early identification of high risk patients with sepsis may help initiate rapid and appropriate therapeutic interventions have great impact on sepsis-related survival outcome (6). The systemic inflammatory response syndrome (SIRS) where a patient having two or more of the clinical symptoms noted in sepsis: fever or hypothermia, tachypnea, tachycardia and leucocytosis or leukopenia even though infection is not deemed to be present. Severe sepsis is associated with hypo-perfusion or dysfunction of at least one organ and when severe sepsis is accompanied by hypotension or multiple organ system failure then it becomes septic shock. Endothelial dysfunction contributes to the pathogenesis of severe sepsis and multi-organ dysfunction impaired microvascular blood flow and the inability of the body to restore homeostasis. In sepsis, anaemia is multifactorial in origin and can contribute to the onset or progression of the anaemia (7). Thrombocytopenia in ICU population was identified as a major risk factor in sepsis (8). Inflammatory mediators and bacterial products contribute to sepsis with associated thrombocytopenia enhancing platelet reactivity and adhesiveness (9). The immature platelet fraction (IPF), a modern parameter that measures young reticulated platelets in peripheral blood and found in about 1% to 5% of total platelet count. The % IPF can be a sensitive measure in evaluating thrombopoietic recovery during aplastic chemotherapy. IPF was capable to predict the development of sepsis before sepsis become clinically manifest was suggested (10) but it could not discriminate SIRS from sepsis (11). Higher IPF values in severe sepsis patients might reflect the formation and recruitment of newly formed platelets and supporting the potential of IPF as a sepsis biomarker (11) but this association with sepsis and severe sepsis remains to be determined. Procalcitonin (PCT) the pre-hormone of calcitonin has been investigated in infectious diseases. It is a protein that consist of 116 amino acids, peptide precursor of calcitonin and synthesized by the parafollicular C cells of the thyroid and involved in calcium homeostasis. It is also produced by the neuroendocrine cells of the lung and intestine, released as an acute-phase reactant in response to inflammatory stimuli especially those of bacterial origin. PCT is a promising biomarker of sepsis among critically ill patients especially at the time of admission (12). Elevated levels may be associated with prognostic outcome in sepsis (13) and are strongly related to all-cause mortality in septic patients (14, 15). The clinical use of PCT apart from diagnosing infection (16) helps in guiding therapeutic decision-making (17). PCT levels are usually low in viral infections, chronic inflammatory disorders or autoimmune processes. PCT can be detected around 6 hours after an infection insult and peaks around 12 to 48 hours, the half-life is around 20 to 35 hours. Currently PCT and C-reactive protein (CRP) are among the best studied biomarkers for diagnosis and monitoring of sepsis (18, 19). A PCT value was a better predictor of all-cause short-term mortality than CRP (20). The objective of the study was to determine the anaemia status, thrombocytopenia, immature platelet fraction and procalcitonin levels and the association with survival outcome in patients with systemic inflammatory response syndrome and sepsis/severe sepsis admitted to the intensive care unit.

Materials and Methods

The study received ethical approval from the Health Research Committee, Medical Faculty, University of North Sumatera/Haj Adam Malik Hospital (No 619/TGL/KEPK FK USU-RSUP Ham/2016). Patient informed consent was obtained. Subjects. Patients who were admitted to the hospital and Intensive Care Unit (ICU) who showed clinical symptoms of sepsis had the PCT done. Only those with PCT levels above 0.05 ng/mL were recruited into the study after giving written informed consent. A total of 71 patients (males n = 45, females n=26) were recruited. Their mean age was mean 48.04 ± 15.0 years and ranged between 18 and 84 years old.  Inclusion criteria; patient should be 18 years old and above, diagnosed to have clinical symptoms of sepsis and have given signed informed consent. Exclusion criteria: less than 18 years old. Blood sampling. A clean venepuncture from the antecubital vein and about 3 mL of blood was drawn into the EDTA-vacutainer for haemoglobin, platelets and IPF determination. Another 5 mL of blood were collected into plain vacutainer tube for serum collection.  After about 2 hours the plain blood tube were spun at 2500g for 15 minutes and the serum aliquoted and stored at -70oC for PCT analysis. Laboratory investigation.  Haemoglobin, platelets and IPF were determined in the Sysmex XN-1000 automated haematology analyser. PCT were analysed using the Enzyme Linked Fluorescent Assay (ELFA) ( Mini Vidas Biomerieux Co). Statistical analysis. Statistical package for Social Sciences (SPSS 22, IBM Corp, USA) was used to perform statistical analysis. The group mean samples independent t-test for differences between groups was performed. Pearson’s correlation was calculated. A P-value of less than 0.05 was considered statistically significant.

Results

An interpretation of procalcitonin results for the differentiation diagnosis of sepsis (NICE 2014) was followed: PCT <0.05 ng/mL normal values for healthy individuals, sepsis not likely; PCT ≥ 0.5 to <2.0 ng/mL moderate systemic inflammatory reaction, sepsis is possible; PCT ≥ 2 to <10 ng/mL severe systemic inflammatory response, sepsis likely and high risk of progression to severe sepsis; PCT ≥ 10 ng/mL likely severe bacterial infection or septic shock (21). Patients in the study were categorized according to PCT levels mentioned above: SIRS:PCT <2.0 ng/mL, sepsis PCT ≥ 2.0 to < 10.0 ng/mL, severe sepsis PCT ≥ 10.0 ng/mL. Comparison of parameters studied between systemic inflammatory response syndrome (SIRS) and sepsis/severe sepsis and survival outcome within 31 days from admission (Table 1) IRS.  The mean PCT level was 0.77 ± 0.3 ng/mL (range 0.17-1.23ng/mL). IPF was mean 4.7 ± 3.0%, platelets mean 332.4 ± 155.7 x109/L, haemoglobin mean 12.0 ± 3.6 g/L. The mortality outcome within 31 days from admission excluding five lost to follow up was 33.3%.Sepsis. The mean PCT level was 4.8 ± 2.2/ng/mL (range 2.17-9.45 ng/mL) which was significantly greater than seen in SIRS (P=<0.001). When compared with SIRS, no significant differences were seen for age, IPF and platelets with lower mean trend in haemoglobin (10.4 ± 2.4 g/L) but they did not reach statistical significance (P= 0.08). The mortality outcome excluding nine lost to follow up was 61.1%.Severe sepsis. The mean PCT level was 50.4 ± 50.8 ng/mL (range 10.1-200.00 ng/mL) which was significantly greater than seen in SIRS (P=<0.001). When compared with SIRS, no significant differences were seen for age, IPF with lower mean trend for haemoglobin (10.0 ± 3.2 g/L, P=0.08) and significantly reduced platelets mean 201.2 ± 141.6 x109/L, P=0.008). The mortality outcome excluding six lost to follow up was 52.4%.Sepsis/severe sepsis. The mean PCT level was mean 32.1 ± 45.0 ng/mL which was significantly greater than seen in SIRS. When compared with SIRS, no significant differences were seen for age and IPF with a lower mean trend seen for platelets and haemoglobin but they did not reach statistical significance (P= 0.06 and 0.07) respectively. The mortality outcome excluding fifteen lost to follow up was 56.4%.Sepsis vs severe sepsis. The severe sepsis cohorts were significantly older than in sepsis patients (P=02) with no significant differences in IPF and haemoglobin except for a lower mean trend in platelet numbers (P=0.06) Table 1.Comparison of parameters studied between survival and non-survival outcome within 31 days from admission in systemic inflammatory syndrome (SIRS) and sepsis excluding those lost to follow-up (Table 2).No significant differences in the parameters studied; age, PCT, IPF, platelets and haemoglobin between survivors and non-survivors within the 31 days from admission in SIRS, severe/sepsis. However, in the overall study of 52 patient cohorts where 25 patients died, only significantly lower platelets (P=0.02) were seen in non-survivors (Table 2).Evaluation of levels below and above normal in the parameters studied in systemic inflammatory response syndrome (SIRS), sepsis and severe sepsis (Table 3).Evaluation of parameters studied in the 71 patients showed that normal IPF levels was seen between 58.8% (SIRS) to 63.0% in sepsis and severe sepsis. IPF levels above normal reference of 5% was seen in sepsis and severe sepsis (37%) and SIRS (41.2%). Thrombocytopenia (platelets ≤100 x 109/L) was seen in 11.8% (SIRS), sepsis (22.2%) and severe sepsis (33.3%).  Haemoglobin (≤ 12.0 g/L) was seen in 52.9% (SIRS), sepsis (70.4%) and in severe sepsis (77.8%).  Only 11.8% (SIRS) had haemoglobin levels greater than 15.0 g/L and 3.7% in both sepsis and severe sepsis. The PCT levels were above the normal reference of 0.05 ng/mL in the SIRS and sepsis cohorts (Table 3). The mean PCT levels and mortality outcome in SIRS and sepsis cohorts are shown in Figure 1. Correlation studies.  Pearson’s correlation was determined. Only platelets were negatively correlated with IPF levels in SIRS (P=0.04, r=-0.505); sepsis (P= 0.04, r= -0.403); severe sepsis (P= 0.001, r=-0.615). No significant correlation was observed between the other parameters studied (PCT and haemoglobin/IPF).

Discussion

Despite the advances in medical science and antibiotic therapy, sepsis remains a major cause of morbidity and mortality in ICU (3, 4). Mortality due to sepsis worldwide was 30% to 60% (2) and recent reported range of between 18% to 56% was reported (22), others reported 41% (20). Anaemia in sepsis is multifactorial in origin and in severe sepsis, a consequence of bleeding and multi-organ dysfunction can contribute to the onset or progression of anaemia. Thrombocytopenia in critically ill patients serve as a marker of haemostasis system dysfunction (23, 24) and has been identified as a major risk factor in sepsis (8). Elevated PCT levels at ICU admission was shown as a good diagnostic marker for suspected sepsis (25) and a highly specific marker for chronic and persistent infection occurring in the late phase of sepsis (26). Elevated levels may be associated with prognostic outcome in sepsis and are strongly related to all-cause mortality in septic patients (14, 15). Elevated PCT levels and PCT non-clearance have been associated with a higher mortality rate in sepsis (15). The IPF can be a sensitive measure in evaluating thrombopoiesis recovery during aplastic chemotherapy and suggested to predict the development of sepsis (10) but could not discriminate SIRS from sepsis (11).In our study, patients were categorized according to PCT levels as mentioned (NICE 2014). Anaemia was evident in sepsis and severe sepsis on admission (Table 1) and comprised of 52.9% in SIRS, sepsis (70.4%) and 77.8% in severe sepsis with overall cases (69.0%) (Table 3). Thrombocytopenia (platelets ≤100 x 109/L) was evident only in sepsis (22.2%,) severe sepsis (33.3%) and SIRS (11.8%)., overall cases 23.9%.  Reduced platelets were seen in severe sepsis compared with SIRS. The IPF (>5.0%) was elevated in SIRS (41.2%) and in sepsis and severe sepsis (37.0%), overall cases 38.0% (Table 3). Mortality within 31 days from admission was seen in 33.3% (SIRS); 61.1% (sepsis) and 52.4% (severe sepsis). Overall mortality for sepsis and severe sepsis was 56.4% (Table 1). The mortality outcome was similar to earlier reports (2, 20, 21) There were no significant differences in the parameters studied between survivors and non-survivors in the study (Table 2) except that platelets were significantly reduced in non-survivors when overall analysis was carried out. No correlation with the parameters studied except for IPF and platelets with significant negative correlation. Our study suggests that elevated PCT may not be the main cause for non-survival outcome in sepsis as mortality arose from those with differing wide range of PCT levels (2.39 to 200 ng/mL) on admission and survivors with levels between 2.26 to 200 ng/mL. In SIRS, PCT mortality level was between 0.17 and 1.21 ng/mL.  PCT may be useful to categorise the grades between sepsis. The survivors with elevated PCT levels could possibly be due to their response to therapy which was not determined. Anaemia occurs in 52.9% of patients with SIRS, sepsis (70.4%) and severe sepsis (77.8%). Thrombocytopenia was seen in sepsis/severe sepsis (23.9%) with elevated IPF in 38.0% overall cases. The IPF level could not discriminate between SIRS and sepsis and may not be suitable for use as sepsis marker as suggested (10).