2014 Papers - Wetstein


Low Baseline Plasma Citrulline Level Impairs Pulmonary Endothelial Nitric Oxide Function in a Porcine Model of Severe Hemorrhagic Shock

Paul Wetstein Surgical Residency Program, Tripler Army Medical Center


Objectives: Hypoxic pulmonary vasoconstriction in the setting of severe hemorrhagic shock severely limits resuscitative efforts. Plasma levels of endothelial nitric oxide synthase (eNOS) substrates and clearance of its inhibitors may improve vasodilation and pulmonary perfusion. The purpose of this study was to assess the relationship between pulmonary artery pressure (PAP) and serum levels of substrates (Arginine (ARG) and Citrulline (CIT)) and inhibitors (Asymmetric Dimethyl Arginine (ADMA) and Symmetric Dimethyl Arginine (SDMA)) of nitric oxide (NO) production. We hypothesized that elevated eNOS inhibition prior to severe hemorrhagic shock may lead to pulmonary hypertension.

Methods: Hemorrhagic shock was induced in 17 Yorkshire pigs to achieve a shed blood loss of 30 ml/kg, a 50% decrease in mean arterial pressure, and an oxygen debt over 60 ml/kg. Plasma samples were obtained at baseline, one hour after the start of hemorrhage, and at one hour increments up to 3 hours after resuscitation with normal saline, to assess substrate levels for NO production and inhibitors of eNOS.

Results:Baseline CIT and ADMA correlated significantly (r = 0.83, p = 0.0005) and post-resuscitation PAP strongly correlated with baseline levels of CIT (r = 0.71, p = 0.006) and ADMA (r = 0.67, p = 0.012). Stepwise multiple regression analysis revealed ADMA as the most significant predictor of PAP compared to all substrates and inhibitors.

Conclusion: High baseline ADMA levels likely decrease eNOS activity by direct inhibition and by preventing CIT recycling back into ARG through argininosuccinate synthase and argininosuccinate lyase. Results suggest that ADMA strongly influences pulmonary vascular tone. Whether circulating ADMA levels may serve as an indicator of or therapeutic target to improve pulmonary perfusion in traumatic massive blood loss warrants further study.