Fluid resuscitation remains a mainstay of sepsis treatment in children and adults. Historically, pediatric guidelines endorsed early, “aggressive” fluid resuscitation for children with sepsis. Compliance with these guidelines, that often-included large amount of fluid resuscitation, led to early recognition of sepsis and significant reductions in mortality in both developed and developing countries (1). More recently, however, there is growing recognition that IV fluids are not innocuous. Both quantitative and qualitative aspects of fluid resuscitation are being questioned, and concerns over issues such as fluid overload or fluid-induced hyperchloremic acidosis are being increasingly debated. These changes were reflected on the most recent pediatric Surviving Sepsis Campaign recommendations, that now support a more individualized approach to the use of fluid boluses and recommend the use of balanced/buffered crystalloids over 0.9% saline for the initial resuscitation of children with septic shock (2).

The latter recommendation on balanced fluids was based on “very low quality of evidence” and the Campaign appropriately called for further high-quality pediatric data. In this issue of Pediatric Critical Care Medicine, Fernández-Sarmiento et al (3) make their important contribution to this topic. The authors assessed glycocalyx disruption associated with balanced and unbalanced fluid boluses in children with sepsis. The authors measured perfused boundary region (PBR) on sublingual video microscopy to assess endothelial glycocalyx thickness and blood levels of syndecan-1 as a biomarker for glycocalyx degradation. The study found that glycocalyx thickness decreased significantly 6 hours after fluid bolus in children receiving unbalanced fluids, while it remained mostly unchanged in children receiving a balanced fluid. The glycocalyx thickness reduction was associated with chloride and albumin levels, as well as markers of infection and inflammation.

This is a very interesting topic because the glycocalyx regulates many of the key pathophysiological processes associated with sepsis and organ dysfunction. The glycocalyx is a ubiquitous protective layer lining the luminal surface of endothelial cells. It functions as more than just a physical barrier, it regulates essential aspects of microvascular homeostasis, helping to control microvascular permeability, mediate shear-induced vasorelaxation, and modulate cell-wall interactions (4,5). Glycocalyx loss exposes the endothelium and leads to increased fluid shift, edema, loss of vascular responsiveness, and leukocyte/platelet endothelial interaction with increased inflammation and hypercoagulability. Controlling these processes would likely have a massive effect on the management and outcome of patients with sepsis.

Although the glycocalyx was first visualized more than 50 years ago, its direct visualization in vivo remains a challenge. In the study by Fernández-Sarmiento et al (3), the authors used two indirect methods to evaluate the glycocalyx. The first is the use of sublingual video microscopy to indirectly measure glycocalyx thickness. This technique looks at the erythrocyte exclusion zone lining the endoluminal side of the endothelial cells in the microcirculation and measures the PBR, which is inversely correlated with the glycocalyx thickness. Under stress conditions, a perturbed glycocalyx allows the erythrocytes to penetrate deeper toward the endothelium, resulting in an increase in the PBR, what represents a decrease in the glycocalyx layer. This is a well-known technique that has been associated with clinical outcomes in several groups of patients, including sepsis (6). In the study by Fernández-Sarmiento et al (3), PBR at baseline was high, indicating a reduced thickness of the glycocalyx in children with sepsis. This is in keeping with animal and adult data that shows that sepsis-induced inflammatory mediators and cell-released proteases induce glycocalyx breakdown and thinning (4,7). After fluid bolus, however, PBR measurement had an interesting trajectory. PBR of children receiving unbalanced fluids increased over the initial 6 hours and remained high after 24 hours. In contrast, PBR of children receiving balanced solutions decreased over the initial 6 hours (achieving statistical significance when compared with unbalanced group) but increased to high levels at 24 hours, similar to children receiving unbalanced fluids. Two aspects of these findings need to be highlighted. First, the magnitude of the PBR changes observed were not big, with a relative change of less than 5% compared with baseline in each group. Second, at 24 hours, PBR was equally high in both groups. The second method used to evaluate glycocalyx in the study by Fernández-Sarmiento et al (3) adds to this discussion. The authors measured syndecan-1, a blood marker of glycocalyx degradation. Glycocalyx is composed of membrane-anchored proteoglycans (such as syndecan-1), glycosaminoglycans, and glycoproteins. When the glycocalyx is damaged, membrane-bound glycoproteins such as syndecan-1 are cleaved from the endothelial surface, resulting in an increase of these glycoproteins in the plasma. Elevated plasma syndecan-1 concentrations have been associated with severity of illness in children and adults (8,9). In the study by Fernández-Sarmiento et al (3), syndecan-1 levels in sepsis were high in most children, but there was not a significant change in syndecan-1 between children receiving balanced or unbalanced fluids within the initial 6 hours. The relatively small and transitory aspect of the changes observed in PBR allied with the lack of a significant difference in syndecan-1 between groups raises a question about clinical relevance of these findings, and the possibility that balanced fluid’s contribution to preserve glycocalyx could be overshadowed by the significant glycocalyx damage evident in sepsis. Balanced fluids, however, have other possible advantages that have been studied in a few pediatric clinical trials. Meta-analysis of these small trials suggest that balanced fluids are associated with less acidity, improved bicarbonate levels, and possibly a slightly reduced length of PICU stay (10,11). Well designed and powered clinical trials on this topic are needed, and Pragmatic Pediatric Trial of Balanced versus Normal Saline Fluid in Sepsis (PRoMPT BOLUS) trial (12) (www.clinicaltrials.gov/NCT04102371) is currently recruiting help to fill this evidence gap.

Among adults, multiple trials have assessed the clinical effect of balanced fluids on the outcome of critically ill patients with conflicting results. Over the recent years, more than 30,000 ICU patients were recruited into these trials and a recent meta-analysis suggest that the estimated effect of using balanced fluids rather than saline for IV fluid therapy in critically ill adults ranges from a 9% relative reduction to a 1% relative increase in death by 90 days (13). This implies that there is a high probability that balanced fluids reduce mortality in adults, but the effect size is very small. However, for an intervention as frequently used as IV fluid therapy, even very small effect sizes could be important (14). For example, a true 0.1% absolute reduction mortality between balanced fluids and 0.9% saline in children admitted to PICU would equate to at least 200 preventable deaths annually in the United States alone (15). Whether the clinical effect of balanced fluids is related to glycocalyx protection or not still need to be investigated.

Until more solid evidence exists, pediatric intensivists will continue to choose which fluid to use in their patients based on local protocols and/or informed individual choice. It is critical that inertia do not prevent critical appraisal of available evidence and individualization of patient treatment. There is growing evidence that 0.9% saline is not “normal” and growing recognition that an individualized approach to IV fluids should became the new normal.

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