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

Abstract

IntroductionPulmonary 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 Recombinant human activated protein C (rhAPC), now withdrawn from the market, has been used in the recent past as an endothelial-protective treatment in patients with septic organ dysfunction.MethodsWe investigated the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, 3H-benzoyl-Phe-Ala-Pro (BPAP), under first-order reaction conditions, and calculated lung functional capillary surface area before and after treatment with rhAPC.ResultsPulmonary 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).ConclusionrhAPC 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.

The Second Gaddum Lecture: its origins and outcomes

“…It may also be possible to use some of the metabolic properties of the pulmonary circulation as markers of injury and early indicators of compromised respiratory function. For instance, in patients with acute respiratory distress syndrome, the level of ACE activity towards a synthetic peptide substrate could be used as a biomarker for damage to the endothelium in the pulmonary circulation, before changes in gas exchange are detectable, allowing treatment to be started earlier (Kaziani et al, ).…”

Impaired angiotensin II signaling in septic shock

“…Consequently, the constatation of a high ratio in critically ill patients has led to the attribution of the observed alterations primarily to an ACE deficiency [36,39]. Indeed, decreased ACE activity has been found in the subgroup of septic shock patients with acute lung injury, consistent with the dominant pulmonary expression of ACE and suggesting a predominant role of sepsis-associated (pulmonary) endotheliopathy [41][42][43]. Additionally, impaired ACE activity could be linked to the presence of circulating endogenous ACE inhibitors formed during shock [44,45].…”

Endothelial Damage in Acute Respiratory Distress Syndrome

“…Due to the very high enzyme concentrations in the capillaries, monitoring pulmonary endothelial ACE activity practically equals the monitoring of pulmonary capillary endothelium-bound (PCEB) ACE activity [ 66 ]. PCEB-ACE activity has been studied to a great extent in animal models and humans and has proven to comprise a quantifiable and sensitive measurement of endothelial function under normal conditions and lung diseases [ 5 , 7 , 67 , 68 , 69 ]. Pulmonary capillary ACE activity has been proven to be a reliable index of endothelial dysfunction in variable pulmonary diseases [ 70 , 71 , 72 , 73 , 74 ].…”