Received: August 16, 2018
Accepted: January 19, 2019
Mediterr J Hematol Infect Dis 2019, 11(1): e2019014 DOI 10.4084/MJHID.2019.014
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Neonatal sepsis remains an important and potentially life-threatening
clinical syndrome and a major cause of neonatal mortality and
morbidity. The aim of this study to investigate whether values of base
excess before the onset of clinical signs and symptoms of sepsis
indicate infection in the early diagnosis of neonatal sepsis.
Additionally, clinical signs associated with normal physiological disturbances and those of sepsis can overlap. Diagnosis is made by clinical and laboratory findings. Blood culture is the gold standard laboratory technique for diagnosis, but results may take 48-72 h, and false-negative results may occur. Several markers such as C-reactive protein (CRP), interleukins (ILs), procalcitonin (PCT), and immunoglobulins, have been used to diagnose sepsis.[4,5] However, there is no suitable marker for diagnosis of NS, particularly in the early period.
Sepsis is associated with many clinical features, including acidosis. Metabolic acidosis results from a variety of common etiologies, including lactic acidosis, hyperchloremic acidosis, renal failure, and ketoacidosis. Anaerobic respiration begins, and metabolic acidosis develops when an imbalance between oxygen supply and demand. Acidosis can be determined from direct blood gas analysis by examining base excess. Although there are a variety of other causes of metabolic acidosis, the early identification of those infants with tissue dysoxia may facilitate the early diagnosis of NS.[6-10]
This study aimed to investigate whether base excess values before the onset of clinical signs and symptoms of sepsis indicate infection in the early diagnosis of NS.
Materials and Methods
Participants and definitions. Cases with a gestational age ≤ 32 weeks and/or a birth weight ≤ 1,250 g were included in the study.
A diagnosis of clinical sepsis required the presence of at least three of the following: bradycardia (<100/min), tachycardia (>200/min), hypotension, hypotonia, seizure, apnea, tachypnea, cyanosis, respiratory distress, poor skin color and perfusion, feeding difficulty, irritability, and lethargy in addition to laboratory results showing elevated levels of CRP or interleukin-6 (IL-6). Late-onset sepsis (LOS) was defined as sepsis that occurred after the first 72 h of age. Patients with culture positivity were considered to have proven sepsis.
Patients with LOS (group 1) were further divided into two subgroups based on whether they had proven (group 1a: newborns with positive blood cultures, clinical findings in agreement with the diagnosis, and elevated IL-6 and/or CRP levels during the clinical course) or clinical sepsis (group 1b: newborns with clinical findings of infection, plus a significant rise in IL-6 and/or CRP levels during the clinical course, but with negative blood cultures). The control group (group 2) consisted of healthy newborns without sepsis. Infants in the control group had normal physical examination findings and were matched as much as possible in demographic characteristics to those in the proven and clinical sepsis groups.
Methods. Blood gas analysis values in the sepsis group taken 12-24 h before the onset of signs and symptoms of sepsis were evaluated. Hemodynamic findings (heart rate, mean arterial pressure, urine output), actual weight, serum sodium level, and total fluid intake were recorded simultaneously. Hematocrit, complete white blood count (WBC), platelet, CRP, and IL-6 levels as well as blood cultures, which were performed after the appearance of symptoms and signs of sepsis, were also recorded.
Blood gas analysis values and hemodynamic and laboratory findings were recorded at similar times in the control group and compared with those in the sepsis group.
Exclusion criteria were defined as congenital heart disease, heart failure, renal failure, inborn errors of metabolism, chromosomal aberrations, patients with respiratory acidosis, and the presence of definite causes resulting in lactic acidosis such as seizure.
Blood samples for culture were taken from patients with a diagnosis of sepsis before antibiotic therapy. Urine and cerebrospinal fluid cultures were taken when clinically indicated. Blood culture was not taken from healthy controls. The Bactec microbial detection system (Becton-Dickinson, Sparks, MD) was used to detect positive blood cultures. Two-blood culture positivity was required to confirm Staphylococcus epidermidis sepsis.
All capillary blood samples were analyzed using in a RAPIDlab 1265 (Siemens Diagnostic Product Corporation, Los Angeles, CA) blood gas analyzer.
Serum concentrations of CRP were measured by a Tinaquant CRP (Latex) high sensitive immune turbidimetric assay on a Roche Modular P analyzer (Roche kit, Roche Diagnostics, Mannheim, Germany) according to manufacturer instructions. Plasma levels of IL-6 were determined by IL-6 solid phase, enzyme labeled, chemiluminescent sequential immunometric assay on an IMMULITE 2000 analyzer (Siemens Diagnostic Product Corporation, Los Angeles, CA) as per manufacturer instructions.
Statistical Analyses. Statistical analyses were performed using the SPSS software version 20. Categorical variables between groups were analyzed using the chi-squared test. Comparison of mean between two groups was examined using a t-test where the data fit a normal distribution, and the Mann–Whitney U test where the data was non-normal. ROC analysis was used to determine the power of variables to differentiate groups, and the area under the curve (AUC) was calculated; significant cut-off levels were calculated using a Youden index. A p-value of less than 0.05 was considered indicative of statistical significance.
|Table 1. Demographic Characteristics of Sepsis and Control Groups.|
The most frequently isolated microorganisms were Staphylococcus epidermidis (50%), Staphylococcus aureus (12%), Enterobacter cloacae (10%), Klebsiella pneumoniae (6%), Escherichia coli (6%), Pseudomonas aeruginosa (2%).
Table 2 shows the hemodynamic and metabolic status of the infants in each group. No significant differences in hemodynamic findings, total fluid intake, serum sodium levels, hematocrit, or platelet levels were observed between the sepsis and control groups (p > 0.05). However, significant differences were observed for WBC, pH, HCO3, base excess, CRP, and IL-6 levels between the sepsis and control groups (p < 0.05).
|Table 2. Hemodynamic and Laboratory Findings of Sepsis and Control Groups.|
No significant differences were noted between the proven and clinical sepsis subgroups in any of the laboratory parameters (p > 0.05). No significant difference in any variable was noted between infants with gram-negative and -positive culture positivity in the proven sepsis group (p > 0.05).
The optimal cut-off levels for base excess between the sepsis and control groups and between the sepsis subgroups and the control group were calculated by drawing receiver operating characteristic curves. Table 3 shows the cut-off levels. The sepsis group and sepsis subgroups had similar cutoff levels vs. the control group. The optimal base excess cut-off level between groups 1 and 2 was −5 mmol/L. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) values for base excess were 75, 91, 86, and 84%, respectively (Table 3).
|Table 3. Sensitivity, Specificity, PPV, NPV, and Area under the ROC Curve for Base Excess at the Optimal Cut-off Levels Between Groups 1 and 2.|
The development of metabolic acidosis during NS has been attributed to progressive tissue ischemia resulting from reduced oxygen delivery. Sepsis causes hemodynamic instability through several processes, resulting in tissue hypoperfusion. Some studies have shown that base excess is a prognostic factor in patients who develop sepsis. Acidosis is a powerful marker of poor prognosis in critically ill patients.[6-10,26] However, base excess for diagnosis of sepsis has not been investigated previously.
Several routine blood gas analysis strategies are used in neonatal intensive care units, and, so, an evaluation of blood gases should be made every morning or at round visits. Blood gas analysis is performed using 0.2 ml of blood, which is also used for respiratory function analysis, particularly in ventilated newborns. Several sepsis biomarkers have been used for the early diagnosis of sepsis, but the use of more than two markers simultaneously in the same infant is not possible due to excessive blood loss. Therefore analysis of blood gases for the diagnosis of sepsis may be a useful, simple and cost-effective method.
Our study had several limitations due to its retrospective and observational nature. Additionally, serum lactate levels were not evaluated to confirm the diagnosis of acidosis.
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