Correlation of syndecan-1 level and fluid overload in children with sepsis: A cross-sectional study

Nyoman Budi Hartawan; Ni Putu Indah Kusumadewi Riandra

doi:10.4103/bjoa.bjoa_198_22

ORIGINAL ARTICLE

Year : 2022 | Volume : 6 | Issue : 4 | Page : 221-224

Correlation of syndecan-1 level and fluid overload in children with sepsis: A cross-sectional study

Nyoman Budi Hartawan, Ni Putu Indah Kusumadewi Riandra
Department of Pediatric, Faculty of Medicine, Udayana University, Bali, Indonesia

Date of Submission	03-Aug-2022
Date of Decision	23-Sep-2022
Date of Acceptance	26-Sep-2022
Date of Web Publication	31-Oct-2022

Correspondence Address:
Nyoman Budi Hartawan
Department of Pediatric, Faculty of Medicine, Udayana University, Jl. PB Sudirman, Denpasar 80232, Bali
Indonesia

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bjoa.bjoa_198_22

Abstract

Background: Fluid resuscitation is one of the basic principles for managing sepsis, but excessive fluid causes the shedding of the endothelial glycocalyx (syndecan-1) and can cause capillary leakage and tissue edema. This study aimed to determine the correlation between the syndecan-1 level and fluid overload in children with sepsis. Materials and Methods: This was an analytic, cross-sectional study conducted in a pediatric intensive care unit. A total of 49 children aged 0–18 participated in this study. Factors investigated were age, gender, nutritional status, the site of infection, organ dysfunction, the severity of sepsis, outcome, blood culture, procalcitonin level, and Pediatric Logistic Organ Dysfunction-2 score. The syndecan-1 level was measured by examining the subject’s blood serum. Statistical analysis was done using the Spearman correlation test. Results: Forty-nine sepsis children aged 0–18 were enrolled, with a median age of 12 months. The respiration system was the most common site of infection, and dysfunction of the respiration system was the most common found in the subjects. The median of fluid overload was 8.3%, and the median of procalcitonin and syndecan levels was 17 ng/mL (interquartile range [IQR] = 1.97–64.03 ng/mL) and 372 ng/mL (IQR = 223.5–1389 ng/mL), respectively. The Spearman’s correlation test found a moderate correlation between syndecan-1 and fluid overload (r = 0.469, P = 0.001). Conclusion: The plasma concentrations of syndecan-1, a marker of endothelial glycocalyx shedding, were moderately correlated with the fluid overload in patients with sepsis, indicating the link between the fluid overload and the shedding of the glycocalyx.

Keywords: Intensive care, pediatric, sepsis

How to cite this article:
Hartawan NB, Riandra NP. Correlation of syndecan-1 level and fluid overload in children with sepsis: A cross-sectional study. Bali J Anaesthesiol 2022;6:221-4

How to cite this URL:
Hartawan NB, Riandra NP. Correlation of syndecan-1 level and fluid overload in children with sepsis: A cross-sectional study. Bali J Anaesthesiol [serial online] 2022 [cited 2023 Mar 22];6:221-4. Available from: https://www.bjoaonline.com/text.asp?2022/6/4/221/359932

Introduction

Fluid resuscitation is one of the basic principles for the management of sepsis. There is evidence that the type and amount of fluid affect the outcome. Several clinical studies have shown the adverse effects of hypervolemia on patients, including cardiopulmonary complications, anastomosis insufficiency, and death.^[1] Adequate fluid resuscitation is essential to improve cardiac output, systemic blood pressure, and renal perfusion in patients with septic shock. Appropriate volume management requires the knowledge of the pathophysiology underlying the occurrence of disease, evaluation of volume status, selection of appropriate fluids to replace lost volume, and maintenance and modulation of tissue perfusion.^[2],[3] However, no research has suggested the amount of fluid dosage in sepsis patients.

The endothelial glycocalyx is an integral part of the vascular barrier. Inflammatory state, hyperglycemia, ischemia, and hypervolemia cause damage to glycocalyx and lead to fluid extravasation into the interstitial.^[4] Excessive fluid leads to the dilution of the blood, which reduces its ability to carry oxygen and increases capillary leakage and tissue edema, thus causing more obvious tissue hypoxia.^[5] The mechanisms of glycocalyx shedding have not been directly investigated.^[6] In critical illness, patients with trauma or surgical changes in body fluid homeostasis, persistent fluid shifts to the third or interstitial cavity, causing a buildup of fluid in these cavities. This condition occurs because of damage to the endothelial glycocalyx, an integral vascular wall structure. In experimental studies in recent years, it has been known that ischemia, reperfusion, tumor necrosis factor-α, and atrial natriuretic peptide (ANP) can trigger damage to the endothelial glycocalyx. Because acute hypervolemia can trigger the release of ANP, thus theoretically avoiding intravascular hypervolemia can prevent damage to endothelial glycocalyx.^[7],[8]

Syndecan-1 is a proteoglycan that forms the structure of endothelial glycocalyx. The syndecan family has four members: syndecan-1, syndecan-2, syndecan-3, and syndecan-4. Syndecan-1 has five sites bound to glycosaminoglycan, three sites near the NH₂-ectodomain terminal and two sites adjacent to the transmembrane domain near the COOH terminal.^[9] Syndecan-1 is a single transmembrane protein domain, which plays a vital role in maintaining glycocalyx endothelial integrity.^[10] Increasing plasma syndecan-1 was associated with endothelial damage and glycocalyx degradation.^[4]

Several studies investigated the association of syndecan-1 level with fluid balance in sepsis patients, and Wu et al.^[5] determined that the relationship between fluid resuscitation and syndecan-1 level in adult patients with severe sepsis was significantly correlated. Therefore, this study aimed to determine the correlation between the syndecan-1 level and fluid overload in children with sepsis.

Materials and Methods

This study was a cross-sectional study. The study was conducted in the pediatric intensive care unit (PICU) in a tertiary medical center in Indonesia. The institutional research ethics committee approved this study under registry 1101/UN14.2.2.VII.14/LT/2020 dated December 28, 2020.

The study involved children with sepsis from January 2018 until March 2020. This study’s inclusion criteria were children and adolescents aged 0–18 diagnosed with sepsis, and the exclusion criteria were incomplete medical records. The sample size was calculated by a formula for study design to determine the correlation between two variables.

Sepsis was determined when the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) score is ≥7 without lactate result, or there was evidence of infection from the culture result. Severity sepsis was divided into two categories: sepsis and septic shock. Septic shock was defined as a sepsis condition and requirement of vasopressor therapy to maintain mean arterial pressure ≥ 65 mmHg or lactate level > 2 mmol/L (18 mg/dL) despite adequate fluid resuscitation.

Organ dysfunction includes the dysfunction of the cardiovascular, respiratory, hematological, central nervous system, hepatic systems, and renal systems. Organ dysfunction was established based on the PELOD-2 score. Syndecan-1 is the level of serum syndecan-1 tested by the enzyme-linked immunosorbent assay method. The syndecan-1 level examination was performed on subjects 3 days after sepsis onset. Syndecan-1 levels are expressed in units of ng/mL and are presented on a numerical scale.

The subjects’ characteristics were presented in a descriptive manner by table and narrative, including age, gender, nutritional status, the site of infection, blood culture, and organ dysfunction. Correlation analysis was used to assess the correlation between the level of syndecan-1 and fluid overload in sepsis children. Coefficient correlation (r) was used to determine correlation with a 95% confidence interval. A P value of <0.05 was significant. We used SPSS 25.0 (IBM Corp., released 2017; IBM SPSS Statistics for Windows, Version 25.0, Armonk, NY: IBM Corp.) for data analysis software.

Results

Forty-nine sepsis children aged 0–18 were enrolled during the study period. Twenty-three (46.9%) subjects were male, with a median age of 12 months. Most subjects had mild–moderate malnutrition (59.2%), followed by well-nourished and severe protein energy malnutrition (20.4% and 12.2%, respectively). The respiration system was the most site of infection, and the dysfunction of the respiration system was the most common found in the subjects. We found that 71.4% of subjects had negative blood cultures. The sepsis severity was dominantly septic shock (69.4%). The history of early fluid loading in the previous hospital was only 8.2% of the total subjects. This study’s ratio of survivors to nonsurvivors was 0.9:1.1 [Table 1].

Table 1: Baseline characteristics of subjects

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The median of fluid overload was 8.3%, and the median of procalcitonin and syndecan levels was 17 ng/mL (interquartile range [IQR] = 1.97–64.03 ng/mL) and 372 ng/mL (IQR = 223.5–1389 ng/mL), respectively. The Spearman’s correlation test found a moderate correlation between syndecan-1 and fluid overload (r = 0.469, P = 0.001) as seen in [Table 2].

Table 2: The correlation of syndecan-1 level with fluid overload

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Discussion

Sepsis is a leading cause of childhood morbidity, mortality, and economic burden worldwide. Globally, it is estimated that 22 cases of childhood sepsis per 100,000 person-years translating into 1.2 million cases of childhood sepsis per year. Sepsis has been diagnosed in more than 4% of hospitalized patients less than 18 years and 8% of patients admitted to PICUs in high-income countries.^[11] This study found that the mortality rate in sepsis patients was 49%. Most children who died from sepsis suffered refractory shock or multiple organ dysfunction syndromes. Deaths occurred within the initial 48–72 h after treatment. This finding was similar to a study by Weiss et al.^[11] who reported that mortality with sepsis ranged from 4% to 50% in children, depending on the disease severity, risk factors, and geographic location.

This study’s initial site of infection predominantly originated from respiratory (49%) and central nervous system infection (44.9%). The most common dysfunction was the respiratory (75.5%), central nervous system (53.0%), hematology (12.2%), renal (10.2%), and cardiovascular (8%). This result concurs with Watson et al.^[12] who reported organ involvement in sepsis such as respiratory, cardiovascular, neurological, renal, hematological, and hepatic systems.

Rapid loss of glycocalyx has been directly and indirectly evidenced during vascular endothelial injury, which is the first step in an inflammatory response. Syndecan-1 is an essential marker of damage to the glycocalyx and increases significantly in the setting of glycocalyx degradation. This study revealed that the plasma syndecan-1 concentrations had a moderate positive correlation with an increment of fluid balance (r = 0.469, P = 0.001). A previous study in adult population reported that syndecan-1 concentrations and fluid balance in severe sepsis and control groups were highly correlated (r = 0.974, P = 0.026). Saoraya et al.^[13] also reported that syndecan-1 levels were correlated with subsequent fluid administration over 24 and 72 h and associated with the diagnosis of septic shock. The study also found that higher syndecan-1 levels were associated with higher 90-day mortality (P = 0.03).^[13] Thus, syndecan-1 can be considered a parameter to reflect fluid overload, especially in pediatric patients with sepsis.

Fluid resuscitation is recommended as a firstline treatment, particularly during the first hour, but the volume and type of fluid that should be used remain controversial. The fluid choice should be integrated into a dynamic process (rescue, optimization, stabilization, and de-escalation).^[6] Aggressive fluid resuscitation may have disastrous consequences in these patients by increasing tissue edema and prolonging ventilator treatment and length of stay in PICU. Thus, factors other than fluid resuscitation that can improve tissue perfusion should be considered in these patients. Raina et al.^[14] reported that only 50% of hemodynamically unstable patients benefit from fluid resuscitation. Another study reported that the mean accumulative fluid accumulation in critically ill children was 14.8% ± 2.3% in nonsurvivors and 6.4% ± 0.7% in survivors (P = 0.002).^[15] This study showed that the median fluid accumulation was 8.3%. Therefore, with the development of severe sepsis, the fluid overload of patients should be repeatedly evaluated to avoid a condition of hypervolemia that increases the release of ANP and causes enhanced shedding of the endothelial glycocalyx.^[5]

We recognize that our study has some limitations. Different types of fluids associated with different microvascular responses remain to be determined, and resuscitation with different fluids may have different effects on the endothelial glycocalyx. Second, more prospective studies are needed to determine the influence of different resuscitation fluids.

Conclusion

The plasma concentrations of syndecan-1, a marker of endothelial glycocalyx shedding, were moderately correlated with fluid overload in patients with sepsis, indicating the link between fluid overload and glycocalyx damage. Further large-scale studies analyzing the degradation of the glycocalyx and the outcomes of patients with severe sepsis are warranted.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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