Exhaled breath condensate in mechanically ventilated brain-injured patients with no lung injury or sepsis.

BACKGROUND: The inflammatory influence of prolonged mechanical ventilation in uninjured lungs remains a matter of controversy and largely unexplored in humans. The authors investigated pulmonary inflammation by using exhaled breath condensate (EBC) in mechanically ventilated, brain-injured patients in the absence of acute lung injury or sepsis and explored the potential influence of positive end-expiratory pressure (PEEP). METHODS: Inflammatory EBC markers were assessed in 27 mechanically ventilated, brain-injured patients with neither acute lung injury nor sepsis and in 12 healthy and 8 brain-injured control subjects. Patients were ventilated with 8 ml/kg during zero end-expiratory pressure (ZEEP group, n = 12) or 8 cm H(2)O PEEP (PEEP group, n = 15). EBC was collected on days 1, 3, and 5 of mechanical ventilation to measure pH; interleukins (IL)-10, 1ß, 6, 8, and 12p70; and tumor necrosis factor-α. RESULTS: EBC pH was lower, whereas IL-1ß and tumor necrosis factor-α were greater in both patient groups compared with either control group; IL-6 was higher, whereas IL-10 and IL-12p70 were sporadically higher than in healthy control subjects; no differences were noted between the two patient groups, except for IL-10, which decreased by day 5 during PEEP. Leukocytes, soluble IL-6, and soluble triggering receptor expressed on myeloid cells-1 in blood were constantly higher during zero end-expiratory pressure; EBC cytokines appeared mostly related to soluble IL-8 and inversely related to soluble triggering receptor expressed on myeloid cells-1. CONCLUSIONS: In brain-injured, mechanically ventilated patients with neither acute lung injury nor sepsis, EBC markers appear to indicate the presence of subtle pulmonary inflammation that is mostly unaffected by PEEP. There is evidence for a systemic inflammatory response, especially in patients during zero end-expiratory pressure.

Plasma pro- and anti-inflammatory cytokine levels and outcome prediction in unselected critically ill patients.

PURPOSE: To determine the inter-relationships between cytokine levels and physiological scores in predicting outcome in unselected, critically ill patients. METHODS: To this end, 127 patients (96 men), having a mean+/-SD age of 45+/-20 years, with a wide range in admission diagnoses (medical, surgical, and multiple trauma patients) were prospectively investigated. Severity of critical illness and organ dysfunction were graded by acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) scores, respectively. Blood samples were drawn on admission in the ICU to determine pro- and anti-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, and IL-10. The main outcome measure was 28-day mortality. RESULTS: Overall, 88 patients survived and 39 patients died. Univariate logistic regression analysis showed that SOFA, APACHE II, IL-8, IL-6, and IL-10 on admission in the ICU were related to mortality. Multiple logistic regression analysis in the entire cohort of critically ill patients revealed that SOFA (OR=1.341, p<0.001) and IL-6 (OR=1.075, p=0.01) constituted independent outcome predictors. receiver operator characteristics curve analysis showed that SOFA, APACHE II, and IL-6 had the highest area under the curve values. IL-6 correlated with APACHE II (r(s)=0.44, p<0.0001) and SOFA (r(s)=0.40, p<0.0001) scores. CONCLUSIONS: In mixed ICU patients cytokine concentrations on admission in the ICU represent independent outcome predictors in the presence of disease severity scores.

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, 3H-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.

Preclinical pulmonary capillary endothelial dysfunction is present in brain dead subjects.

Pulmonary endothelium is a major metabolic organ affecting pulmonary and systemic vascular homeostasis. Brain death (BD)-induced physiologic and metabolic derangements in donors' lungs, in the absence of overt lung pathology, may cause pulmonary dysfunction and compromise post-transplant graft function. To explore the impact of BD on pulmonary endothelium, we estimated pulmonary capillary endothelium-bound (PCEB)-angiotensin converting enzyme (ACE) activity, a direct and quantifiable index of pulmonary endothelial function, in eight brain-dead patients and ten brain-injured mechanically ventilated controls. No subject suffered from acute lung injury or any other overt lung pathology. 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, under first order reaction conditions, and calculated lung functional capillary surface area (FCSA). Substrate %M (35 ± 6.8%) and v (0.49 ± 0.13) in BD patients were decreased as compared to controls (55.9 ± 4.9, P = 0.033 and 0.9 ± 0.15, P = 0.033, respectively), denoting decreased pulmonary endothelial enzyme activity at the capillary level; FCSA, a reflection of endothelial enzyme activity per vascular bed, was also decreased (BD patients: 1,563 ± 562 mL/min vs 4,235 ± 559 in controls; P = 0.003). We conclude that BD is associated with subtle pulmonary endothelial injury, expressed by decreased PCEB-ACE activity. The applied indicator-dilution type technique provides direct and quantifiable indices of pulmonary endothelial function at the bedside that may reveal the existence of preclinical lung pathology in potential lung donors.