Activated Protein C has No Effect on Pulmonary Capillary Endothelial Function in Septic Patients with Acute Respiratory Distress Syndrome: Association of Endothelial Dysfunction with Mortality

Introduction Pulmonary capillary endothelium-bound (PCEB) angiotensin-converting enzyme (ACE) activity is a direct and quantifiable index of pulmonary endothelial function that decreases early in acute respiratory distress syndrome (ARDS) and correlates with its severity. Endothelial dysfunction is a major pathophysiology that underlies sepsis-related ARDS. Recombinant human activated protein C (rhAPC), now withdrawn from the market, has been used in the recent past as an endothelial-protective treatment in patients with septic organ dysfunction. Methods We investigated the effect of rhAPC on pulmonary endothelial function in 19 septic patients suffering from ARDS. Applying indicator-dilution type techniques, we measured single-pass transpulmonary percent metabolism (% M ) and hydrolysis ( v ) of the synthetic, biologically inactive, and highly specific for ACE substrate, 3 H-benzoyl-Phe-Ala-Pro (BPAP), under first-order reaction conditions, and calculated lung functional capillary surface area before and after treatment with rhAPC. Results Pulmonary endothelium ACE activity was severely impaired in septic patients with ARDS, and was not affected by rhAPC treatment. Additionally, poor outcome was related to a more profound decrease in PCEB-ACE activity. Angiotensin-converting enzyme–substrate utilization was statistically significantly lower in non-survivors as compared to survivors, with no changes over time within each group: BPAP % M : 32.7 ± 3.4% at baseline to 25.6 ± 2.9% at day 7 in survivors versus 20.8 ± 2.8 to 15.5 ± 5%, respectively, in non-survivors ( p = 0.044), while hydrolysis ( v ): 0.41 ± 0.06 at baseline to 0.30 ± 0.04 at day 7 in survivors compared to 0.24 ± 0.04 to 0.18 ± 0.06, respectively, in non-survivors ( p = 0.049). Conclusion rhAPC administration in septic patients with ARDS did not improve PCEB-ACE activity indices. However, these indices might be useful in the early recognition of septic patients with ARDS at high risk of mortality.