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Fluid resuscitation is essential to antagonize the deleterious effects of tissue hypo-perfusion in sepsis. If not thoroughly monitored and individually tailored, fluid therapy increases the risk of volume overload. Volume overload is associated with higher mortality in sepsis. Although considerable progress has been made to understand the complex nature of the cardiovascular derangements in sepsis and septic shock, the optimal fluid resuscitation strategy is yet to be defined. Current guidelines recommend balanced crystalloids and albumin for resuscitation; synthetic colloids are harmful and no longer in use. In search of adjuvant therapies to fluid resuscitation in sepsis and sepsis related complications with a volume sparing potential, this doctoral thesis aimed at exploring the effects of two endogenous molecules involved in fluid homeostasis. In Study I, the peptide containing the active site of the endogenous protein antisecreterory factor (AF-16) reduced lung edema formation, as reflected in a reduction in extra vascular lung water (EVLW), in a model of ventilator induced lung injury (VILI). The aim of Study I was to test the intervention AF-16 in a well-established porcine model of lung edema and capillary leak. In Study II, the intervention AF-16 was tested in a model of fecal peritonitis sepsis. The first aim of Study II was to elaborate a clinically relevant porcine model of fecal peritonitis-sepsis, including a standardized resuscitation protocol. Second aim was to test the effect of the intervention on volume status and inflammation. Wet-to-dry ratio was lower in liver samples of the intervention group, indicating less edema formation. No other differences were detected between intervention and control groups. In Study III, the intervention high molecular weight hyaluronan (HMW-HA) was tested in our model of fecal peritonitis as adjuvant to standardized fluid resuscitation. Fluid balance and the inflammatory response were comparable throughout the experi

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 counteract intravascular volume depletion and contribute to endothelial glycocalyx integrity 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 2 h of peritonitis. Stroke volume variation and hemoconcentration were comparable in the two groups throughout the experiment. Cardiac output was higher in the intervention group during the infusion of hyaluronan (3.2 ± 0.5 l/min in intervention group vs 2.7 ± 0.2 l/min in the control group) (p = 0.039). The increase in lactate was more pronounced in the intervention group (3.2 ± 1.0 mmol/l in the intervention group and 1.7 ± 0.7 mmol/l in the control group) at the end of the experiment (p < 0.001). 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. However, this finding is hampered by the short observation period and a beneficial effect of HMW-HA in peritonitis sepsis cann, Title in the list of papers of Annelie Barrueta Tenhunen's thesis: Fluid restrictive resuscitation with high molecular weight hyaluronan infusion in early peritonitis-sepsis

Background: Acute respiratory distress syndrome (ARDS) is an acute inflammatory condition with pulmonary capillary leakage and lung oedema formation. There is currently no pharmacologic treatment for the condition. The antisecretory peptide AF-16 reduces oedema in experimental traumatic brain injury. In this study, we tested AF-16 in an experimental porcine model of ARDS. Methods: Under surgical anaesthesia 12 piglets were subjected to lung lavage followed by 2 hours of injurious ventilation. Every hour for 4 hours, measurements of extravascular lung water (EVLW), mechanics of the respiratory system, and hemodynamics were obtained. Results: There was a statistically significant (p = 0.006, two-way ANOVA) reduction of EVLW in the AF-16 group compared with controls. However, this was not mirrored in any improvement in the wet-to-dry ratio of lung tissue samples, histology, inflammatory markers, lung mechanics, or gas exchange. Conclusions: This pilot study suggests that AF-16 might improve oedema resolution as indicated by a reduction in EVLW in experimental ARDS.

Despite forming an integral part of sepsis treatment, 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 infusion was associated with higher CO and diastolic blood pressure in the intervention group during the infusion. However, the increase in lactate throughout the experiment was more pronounced in the intervention group.