Abstract
Sepsis is a life-threatening condition due to a dysregulated immunological response to infection. Apart from source control and broad-spectrum antibiotics, management is based on fluid resuscitation and vasoactive drugs. Fluid resuscitation implicates the risk of volume overload, which in turn is associated with longer stay in intensive care, prolonged use of mechanical ventilation and increased mortality. Antisecretory factor (AF), an endogenous protein, is detectable in most tissues and in plasma. The biologically active site of the protein is located in an 8-peptide sequence, contained in a synthetic 16-peptide fragment, named AF-16. The protein as well as the peptide AF-16 has multiple modulatory effects on abnormal fluid transport and edema formation/resolution as well as in a variety of inflammatory conditions. Apart from its' anti-secretory and anti-inflammatory characteristics, AF is an inhibitor of capillary leakage in intestine. It is not known whether the protein AF or the peptide AF-16 can ameliorate symptoms in sepsis. We hypothesized that AF-16 decreases the degree of hemodynamic instability, the need of fluid resuscitation, vasopressor dose and tissue edema in fecal peritonitis. To test the hypothesis, we induced peritonitis and sepsis by injecting autologous fecal solution into abdominal cavity of anesthetized pigs, and randomized (in a blind manner) the animals to intervention (AF-16, n = 8) or control (saline, n = 8) group. After the onset of hemodynamic instability (defined as mean arterial pressure < 60 mmHg maintained for > 5 minutes), intervention with AF-16 (20 mg/kg (50 mg/ml) in 0.9% saline) intravenously (only the vehicle in the control group) and a protocolized resuscitation was started. We recorded respiratory and hemodynamic parameters hourly for twenty hours or until the animal died and collected post mortem tissue samples at the end of the experiment. No differences between the groups were observed regarding hemodynamics, overall fluid balance, lung mechanics, gas exchange or histology. However, liver wet-to-dry ratio remained lower in AF-16 treated animals as compared to controls, 3.1 ± 0.4, (2.7-3.5, 95% CI, n = 8) vs 4.0 ± 0.6 (3.4-4.5, 95% CI, n = 8), p = 0.006, respectively. Bearing in mind the limited sample size, this experimental pilot study suggests that AF-16 may inhibit sepsis induced liver edema in peritonitis-sepsis.
Highlights
Sepsis is defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection” [1]
No lesions were detected in skin biopsies. In this experimental study of peritonitis induced sepsis, intervention with the anti-secretory and anti-inflammatory peptide Antisecretory factor (AF)-16 did not yield any reversal of sepsis/septic shock symptoms as reflected in signs of inflammation, overall fluid balance, hemodynamics, norepinephrine consumption, gas exchange or respiratory mechanics
We used a model of fecal peritonitis induced sepsis, previously described by Correa et al [26]
Summary
Sepsis is defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection” [1]. In septic shock profound circulatory and metabolic abnormalities contribute to an increase in mortality, with up to 40% in-hospital mortality [1,2,3]. Requirement of vasopressor therapy to sustain a mean arterial pressure (MAP) > 65 mmHg in combination with persistent serum lactate level > 2 mmol/L after fluid resuscitation are the clinical hallmarks of septic shock [1]. Sepsis management is based on fluid resuscitation, broad-spectrum antibiotics, source control and vasoactive drugs [6]. A positive fluid balance and volume overload is associated with longer stay in intensive care, prolonged use of mechanical ventilation and increased mortality [8,9,10,11]
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