Skorup, P. | Search bioRxiv

bioRxiv2023

Fluid restrictive resuscitation with high molecular weight hyaluronan infusion in early peritonitis-sepsis

Sepsis is a condition with high morbidity and mortality. Prompt recognition and initiation of treatment is essential. Despite forming an integral part of sepsis management, fluid resuscitation may also lead to volume overload, which in turn is associated with increased mortality. The optimal fluid strategy in sepsis resuscitation is yet to be defined. Hyaluronan, an endogenous glycosaminoglycan with high affinity to water is an important constituent of the endothelial glycocalyx. We hypothesized that exogenously administered hyaluronan would contribute to endothelial glycocalyx integrity and counteract intravascular volume depletion in a fluid restrictive model of peritonitis. In a prospective, blinded model of porcine peritonitis-sepsis, we randomized animals to intervention with hyaluronan (n=8) or 0.9% saline (n=8). The animals received an infusion of 0.1% hyaluronan 6 ml/kg/h, or the same volume of saline, during the first two hours of peritonitis. Stroke volume variation and hemoconcentration were comparable in the two groups throughout the experiment. Cardiac output (p=0.008 and p=0.017) and diastolic blood pressure (p=0.015 and p=0.019) were higher in the intervention group during the infusion of hyaluronan, but these effects disappeared as the experiment proceeded. The increase in lactate was more pronounced in the intervention group (p=0.041) throughout the experiment, while concentrations of surrogate markers of glycocalyx damage; syndecan 1 (0.6 {+/-} 0.2 ng/ml vs 0.5 {+/-} 0.2 ng/ml, p=0.292), heparan sulphate (1.23 {+/-} 0.2 vs 1.4 {+/-} 0.3 ng/ml, p=0.211) and vascular adhesion protein 1 (7.0 {+/-} 4.1 vs 8.2 {+/-} 2.3 ng/ml, p=0.492) were comparable in the two groups at the end of the experiment. In conclusion, hyaluronan did not counteract intravascular volume depletion in early peritonitis sepsis. The intervention was associated with higher cardiac output and diastolic blood pressure, than placebo, during the infusion. However, the increase in lactate throughout the experiment was more pronounced in the intervention group.

pharmacology and toxicology↗

bioRxiv2021

High molecular weight hyaluronan - a potential adjuvant to fluid resuscitation in porcine abdominal sepsis

While fluid resuscitation is fundamental in the treatment of sepsis-induced tissue hypo-perfusion, a sustained positive fluid balance is associated with excess mortality. Crystalloids are the mainstay of fluid resuscitation and use of either synthetic colloids or albumin is controversial. Hyaluronan, an endogenous glycosaminoglycan with high affinity to water, has not been tested as adjuvant in fluid resuscitation. We sought to evaluate the effects of hyaluronan as an adjuvant to fluid resuscitation in peritonitis induced sepsis. In a prospective, parallel-grouped, blinded model of porcine peritonitis-sepsis, we randomized animals to intervention with adjuvant hyaluronan (add-on to standard therapy) (n=8) or 0.9% saline (n=8). After the onset of hemodynamic instability the animals received an initial bolus of 0.1 % hyaluronan 1 mg/kg/10 min or placebo (saline) followed by a continuous infusion of 0.1% hyaluronan (1 mg/kg/h) or saline during the experiment. We hypothesized that the administration of hyaluronan would reduce the volume of fluid administered (aiming at stroke volume variation <13%) and/or attenuate the inflammatory reaction. Total volumes of intravenous fluids infused were 17.5 {+/-} 11 ml/kg/h vs. 19.0 {+/-} 7 ml/kg/h in intervention and control groups, respectively (p = 0.442). Plasma IL-6 increased to 2450 (1420 - 6890) pg/ml and 3700 (1410 - 11960) pg/ml (18 hours of resuscitation) in the intervention and control groups (NS). In a post-hoc analysis, modified shock index remained lower in intervention group (p = 0.011 - 0.037). In conclusion adjuvant hyaluronan did not reduce the volume needed for fluid administration or decrease the inflammatory reaction. Adjuvant hyaluronan was, however, associated with lower modified shock index. Bearing in mind that the experiment has a limited group-size we suggest that further studies on hyaluronan in sepsis are warranted.

pharmacology and toxicology↗