RESPIRATORY MECHANICS IN INFANT AND ADULT MICE MODELLING VENTILATOR-INDUCED LUNG INJURY

SUMMARY Mechanical ventilation is critical in the management of patients suffering respiratory failure. However, mechanical ventilation has also the potential to aggravate or induce lung injury. This injury is referred to as ventilator-induced lung injury (VILI). To better understand different aspects and mechanisms involved in VILI age-specific animal models are desirable. However, animal models investigating VILI do not include measurements of accurate respiratory system mechanics and inadequately consider effects of confounding factors such as positive end-expiratory pressure (PEEP), oxygen, and lung volume recruitment maneuvers. The current thesis was designed to investigate major determinants of VILI, namely high tidal volume (VT), inadequate PEEP, high oxygen concentrations, and stress and strain-induced release of inflammatory mediators. Thus, we aimed at investigating effects of high-VT ventilation and PEEP in infant mice, impact of supplemental oxygen in both infant and adult mice, and outcome of lung volume recruitment maneuvers (RM) in adult mice. Different ventilation strategies in healthy infant and adult mice were compared in an interventional controlled manner. The following outcome variables were assessed: a) respiratory system impedance, partitioned into components representing the conducting airways and lung parenchyma, representing dynamic lung function measurements, b) thoracic gas volume, c) pressure-volume curves, characterizing quasi-static lung function measurements, d) inflammatory response, measuring differential cell counts, protein content, and cytokines in lung lavage fluid and serum, and e) histology, quantifiying structural changes and inflammation. While high-VT ventilation produced lung injury in infant mice presumably via overdistension and loss of lung volume, high oxygen concentrations had no impact on respiratory system mechanics in either age group. In addition, we found in adult mice that PEEP increase alone and application of RMs producing peak airway opening pressures <25 cmH2O did not prevent or reverse changes in lung mechanics, whereas frequent application of substantial RMs on top of elevated PEEP levels produced stable lung mechanics without signs of lung injury. These findings underline the need for age-specific small animal models and require that specification of ventilator settings are reported in all studies investigating effects of mechanical ventilation in mice.

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