Arterial Compliance is Improved via Enteral Serine Protease Inhibition in Experimental Trauma/Hemorrhagic Shock

Joyce Beverly Li^1*Fernando dos Santos²Cynthia Rodrigues Muller¹Nathalia Juocys Dias Moreira³Luciano F Borges⁴Maria Claudia Costa Irigoyen³Geert W Schmid-Schönbein¹Erik Kistler^2,5

• ¹Department of Bioengineering, University of California, San Diego, La Jolla, United States
• ²Department of Anesthesiology & Critical Care, University of California, San Diego, La Jolla, United States
• ³Instituto do Coração, Universidade de Sao Paulo, São Paulo, Brazil
• ⁴Laboratory of Molecular and Experimental Pathology, Universidade Federal de Sao Paulo, São Paulo, Brazil
• ⁵VA San Diego Healthcare System, San Diego, United States

Background: Systemic hypotension remains a challenge in trauma/hemorrhagic shock (T/HS). Despite intensive vasopressor and fluid therapy, mean arterial blood pressure (MAP) may become refractory to treatment. Arterial compliance (AC) is a critical determinant of arterial hemodynamics but is often overlooked in acute shock states. Considering previous findings on the benefits of enteral protease inhibition in preserving vascular resistance after T/HS, this study investigated both the role of AC and the effects of enteral protease inhibition on AC in T/HS. Methods: Wistar rats underwent experimental T/HS by laparotomy and exsanguination to induce a MAP of ~40mmHg for 90 minutes. Animals were randomized into three groups corresponding to the intervention: shed whole blood (WB), Lactated Ringer's (LR), and LR with enteral gabexate mesilate treatment (LR+GM). Resuscitation (120-minute period) was initiated by fluid reperfusion with a goal MAP of 65mmHg. AC was measured via pulse wave velocity (PWV), passive pressure myography, and atomic force microscopy (AFM), with healthy donor arteries for comparison.Results: PWV increased by ~15% in all groups after shock. After resuscitation, LR-only animals maintained high PWVs, but significantly lower diastolic pressures (27mmHg) compared to GM-treated (37mmHg; p<0.05) and thse reperfused with WB (52mmHg; p<0.01). T/HS arteries, particularly the untreated LR arteries, exhibited leftward shifts in circumferential tension-strain curves. LR arteries exhibited higher tangent moduli (5 N/m; p < 0.01) at low physiological stresses, which was corroborated by reduced opening angles, increased mechanical stiffness, alterations in the extracellular matrix, and increased MMP/elastase-like activity. LR+GM and WB arteries displayed elastic moduli and vascular structures more similar to those of healthy arteries.Conclusions: Experimental T/HS results in impaired AC, which is partially attenuated by enteral GM administration. Vascular biomechanical impairment may underlie the unrestored MAP in fulminant shock. By targeting modulators of AC, with enteral serine protease inhibition as an adjunct intervention, hemodynamic stability and patient outcomes may be improved in T/HS.