Concise Critical Appraisal: Endothelial Glycocalyx Integrity and Fluid Bolus Types

Fluid resuscitation with crystalloids is an essential component of sepsis management. However, the ideal makeup of the crystalloids is unknown. Normal saline is an unbalanced, chloride-based solution (UBF) with no added buffers, whereas balanced fluid solutions (BF) have a chloride content less than 154 mmol/L, allowing for other buffers to be added to approximate the composition of plasma. Many studies investigating fluid resuscitation with BF versus UBF have yielded conflicting findings, although BF has been shown in some studies to decrease mortality, decrease acute kidney injury (AKI) incidence, and to increase blood pH.^1-3 The increased pH is a significant finding because the endothelial glycocalyx, a thin layer of negatively charged glycoproteins and glycolipids on the luminal side of the vasculature, which is responsible for vascular tone and permeability, may be adversely affected by metabolic acidosis. Fernandez-Sarmiento et al looked at the association between fluid resuscitation with BF versus UBF in pediatric patients with sepsis or septic shock and endothelial glycocalyx integrity.⁴

In this prospective cohort study, the authors recruited pediatric patients aged between 1 month and 18 years who required crystalloid boluses for the management of sepsis or septic shock. The decision to administer fluids was made by the treating physician and was based on specific clinical and laboratory findings. Patients were excluded if they had traumatic brain injury, a metabolic disease, chronic kidney disease, or had received fluid boluses within the previous 24 hours. The BF administered was lactated Ringer solution or a balanced crystalloid solution. The UBF administered was normal saline.

To evaluate glycocalyx degradation, the authors used dark field videomicroscopy. They measured sublingual microcirculation to evaluate the perfused boundary region (PBR), which is inversely proportional to the endothelial glycocalyx dimensions. The PBR was evaluated at 0 hours, 2 hours, 6 hours, and 24 hours after the fluid bolus. At various times, the authors measured plasma syndecan-1 (a biomarker of glycocalyx degradation), plasma angiopoietin-2 (a biomarker of vascular permeability and endothelial activation), and annexin A5 (a biomarker of apoptosis). Other laboratory tests, such as serum electrolytes, lactate, and albumin levels, were also conducted. Clinical parameters, including demographics, Pediatric Index of Mortality 2 (PIM-2), and Pediatric Logistic Organ Dysfunction 2 (PELOD-2) scores, were recorded. The primary outcome was to determine the level of endothelial glycocalyx disruption after fluid administration. Secondary outcomes included the association between fluid bolus type and endothelial activation/injury, amount of apoptosis, and acidosis.

The authors recruited 106 pediatric patients, with 48 receiving BF and 58 receiving UBF. Of the 106 total patients, 77 had increased PBR at baseline, which can occur with sepsis, although the initial average PBR was equal between groups. After receiving fluid boluses, the patients who had received UBF had a higher PBR peak compared with those who had received BF at 6 hours, although the levels returned to baseline at 24 hours. No association was found between elevated PBR and PELOD-2 or PIM-2 scores.

Like the PBR, plasma syndecan-1 levels were elevated at baseline, but were higher at 6 hours in the UBF group, although this did not appear to be statistically significant. Angiopoietin levels did not show any difference. Annexin A5 levels were found to be higher in the UBF group 6 hours after fluid administration. Other findings associated with UBF administration included the development of metabolic acidosis, hyperchloremia, and AKI (particularly in those with metabolic acidosis and elevated PBR). Finally, there was a weak negative correlation between serum albumin and PBR.

Fluid resuscitation in children with sepsis is necessary, but quantitative and qualitative data regarding the fluids administered have not been conclusive. This study offers some insight into the vascular dysfunction that occurs in patients with sepsis or septic shock and provides evidence supporting BF. The authors demonstrated that endothelial glycocalyx integrity may be impaired at baseline, which can worsen with the administration of UBF. Although not a primary goal of the study, the authors also found that the absence of normal serum albumin levels may play a role in glycocalyx degradation. Limitations of this study include the absence of cytokine data as well as data on different volumes of resuscitative fluids. However, studies looking at the vascular endothelium in different inflammatory/shock states, such as this one, can provide a better understanding of the pathophysiology of these diseases and how to treat them.

References:

1. Emrath ET, Fortenberry JD, Travers C, McCracken CE, Hebbar KB. Resuscitation with balanced fluids is associated with improved survival in pediatric severe sepsis. Crit Care Med. 2017 Jul;45(7):1177-1183.
2. Semler MW, Self WH, Rice TW. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018 May 17;378(20):1951.
3. Zampieri FG, Machado FV, Biondi RS, et al; BaSICS investigators and BRICNet members. Effect of intravenous fluid treatment with a balanced solution vs 0.9% saline solution on mortality in critically ill patients: the BaSICS randomized clinical trial. JAMA. 2021 Aug 10;326(9):1-12.
4. Fernandez-Sarmiento J, Salazar-Peláez LM, Acevedo L, et al. Endothelial and glycocalyx biomarkers in children with sepsis after one bolus of unbalanced or balanced crystalloids. Pediatr Crit Care Med. 2023 Mar 124(3):213-221.