Alveolar fibrinolysis is not altered by mechanical ventilation in humans with healthy lungs

Introduction

Mechanical ventilation (MV) aggravates pulmonary inflammation in patients with acute lung injury. Pulmonary inflammation is characterized by alveolar fibrin depositions, which is the net result of increased thrombin-mediated generation of fibrin and upregulation of plasminogen activator inhibitor (PAI), inhibiting fibrin degradation. We recently showed that injurious MV (using high pressures) induces PAI-1 upregulation in rats, thereby limiting pulmonary fibrinolytic activity. In the present study we determine the influence of MV on alveolar PAI-1 expression in humans with healthy lungs.

Methods

Patients with healthy lungs expected to be mechanically ventilated for ≥ 5 hours (elective surgery) were randomized to a MV strategy using either a tidal volume (V_T) of 12 ml/kg and zero positive end expiratory pressure (HV_T/ZEEP) or VT 6 ml/kg and 10 cmH₂O PEEP (LVT/PEEP). Bronchoalveolar lavage (BAL) was performed directly after initiation of MV, and repeated in the contralateral lung after 5 hours of MV. Pulmonary thrombin generation was quantified by measuring thrombin–antithrombin complexes (TATc) in the BAL fluid; fibrinolytic activity by determining plasminogen activator activity (PAA), PAI-1, and tissue-type plasminogen activator (tPA).

Statistics

Within groups, Wilcoxon signed-rank test; between groups, Mann–Whitney U test. Data are presented as medians with interquartile ranges.

Results

Nine patients were randomized to HV_T/ZEEP, 11 patients to LV_T/PEEP. There were no differences in baseline characteristics or outcome. After 5 hours, patients ventilated with HV_T/ZEEP showed an increase in alveolar thrombin generation (TATc: 0.91 [0.82–0.98] ng/ml vs 0.75 [0.67–0.81] ng/ml at baseline, P < 0.01), in contrast to those with LV_T/PEEP (0.84 [0.74–0.91] ng/ml vs 0.81 [0.72–0.87] ng/ml, not significant [NS]). Pulmonary PAI-1 levels did not change (LV_T/PEEP: 2.0 [1.6–2.2] ng/ml vs 1.9 [1.8–2.1] ng/ml, NS; HV_T/ZEEP: 2.1 [1.8–2.1] ng/ml vs 2.0 [1.7–2.4] ng/ml, NS). Moreover, alveolar PAA was unaffected in both groups (LV_T/PEEP: 106 [102–113]% vs 100 [97–105]%, NS; HV_T/ZEEP: 102 [97–110]% vs 102 [100–104]%, NS), although levels of tPA increased more with HV_T/ZEEP MV (LV_T/PEEP: 0.84 [0.65–0.98] ng/ml vs 0.61 [0.55–0.63] ng/ml, P < 0.001; HV_T/ZEEP: 0.70 [0.70–0.90] ng/ml vs 0.50 [0.40–0.55] ng/ml, P < 0.01; between groups, NS).

Conclusion

Despite upregulation of tPA, alveolar PAA is not altered during 5 hours of MV in patients with healthy lungs. Disturbed alveolar fibrin turnover during MV in healthy lungs seems solely the result of activation of coagulation.