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 Recombinant human activated protein C (rhAPC), now withdrawn from the market, has been used in the recent past as an endothelial-protective treatment in patients with septic organ dysfunction.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.