TIP peptide inhalation in experimental acute lung injury: effect of repetitive dosage and different synthetic variants.

BACKGROUND: Inhalation of TIP peptides that mimic the lectin-like domain of TNF-α is a novel approach to attenuate pulmonary oedema on the threshold to clinical application. A placebo-controlled porcine model of acute respiratory distress syndrome (ARDS) demonstrated a reduced thermodilution-derived extravascular lung water index (EVLWI) and improved gas exchange through TIP peptide inhalation within three hours. Based on these findings, the present study compares a single versus a repetitive inhalation of a TIP peptide (TIP-A) and two alternate peptide versions (TIP-A, TIP-B). METHODS: Following animal care committee approval ARDS was induced by bronchoalveolar lavage followed by injurious ventilation in 21 anaesthetized pigs. A randomised-blinded three-group setting compared the single-dosed peptide variants TIP-A and TIP-B as well as single versus repetitive inhalation of TIP-A (n = 7 per group). Over two three-hour intervals parameters of gas exchange, transpulmonary thermodilution, calculated alveolar fluid clearance, and ventilation/perfusion-distribution were assessed. Post-mortem measurements included pulmonary wet/dry ratio and haemorrhage/congestion scoring. RESULTS: The repetitive TIP-A inhalation led to a significantly lower wet/dry ratio than a single dose and a small but significantly lower EVLWI. However, EVLWI changes over time and the derived alveolar fluid clearance did not differ significantly. The comparison of TIP-A and B showed no relevant differences. Gas exchange and ventilation/perfusion-distribution significantly improved in all groups without intergroup differences. No differences were found in haemorrhage/congestion scoring. CONCLUSIONS: In comparison to a single application the repetitive inhalation of a TIP peptide in three-hour intervals may lead to a small additional reduction the lung water content. Two alternate TIP peptide versions showed interchangeable characteristics.

The dynamics of carbon dioxide equilibration after alterations in the respiratory rate.

Manual or automated control of mechanical ventilation can be realized as an open or closed-loop system for which the regulation of the ventilation parameters ideally is tuned to the dynamics and equilibration time of the biological system. We investigated the dynamic, transient state and equilibration time (teq) of the CO2 partial pressure (PCO2) after changes in the respiratory rate (RR). In 17 anaesthetized patients without known history of lung disease, respiratory rate was alternately increased and decreased and end-tidal CO2 partial pressures (PetCO2) were measured. Linear relations were found between ΔRR and PetCO2 changes (ΔPetCO2 = 0.3 − 1.1 ΔRR) and between ΔRR and teq for increasing and decreasing RR (teq(hypervent) = 0.5 |ΔRR|, teq(hypovent) = 0.7 |ΔRR|). Extrapolation of the transition between two PCO2 steady-states allowed for the prediction of the new PCO2 steady-state as early as 0.5 teq with an error <4 mmHg. At bedside or in automated ventilation systems, the linear dependencies between ΔRR and ΔPCO2 and between ΔRR and teq as well as early steady-state prediction of PCO2 could be used as a guidance towards a timing and step size regulation of RR that is well adapted to the biological system.