Evaluation des präventiven Nutzens der Carboanhydraseinhibition in einem Modell des beatmungsinduzierten Lungenschadens

Mechanical ventilation with high tidal volumes can cause ventilator-induced lung injury. Pathophysiologic characteristics include the destruction of the aveolocapillary membrane, lung edema, increased inflammation processes and an elevated pulmonary artery pressure. The carbonic anhydrase (CA) inhibitors Acetazolamid (ACZ) and Methazolamid (MTZ) are known to suppress inflammatory responses, inhibit hypoxic pulmonary vasoconstriction and provide protective effects in models of ischemia reperfusion injury. This study aimed to examine the effects of carbonic anhydrase inhibition on hemodynamics, lung edema formation and pulmonary inflammation in a model of ventilator-induced lung injury. Sprague Dawley rats were anesthetized, tracheotomized, cannulated with arterial and central venous catheters and mechanically ventilated in a pressure-controlled mode. The laboratory animals of the LP-group were ventilated for 180 minutes with a positive endexspiratory pressure of 2 cmH2O and a low peak inspiratory pressure of 9 cmH2O. Animals in the HP-group received the same ventilation for 30 minutes before the peak inspiratory pressure was raised to 30 cmH2O to cause ventilator-induced lung injury. Furthermore CA inhibitor groups were established. In the ACZ- and MTZ-groups animals were ventilated alike the HP-group. Additionally, Acetazolamid and Methazolamid were administered intravenously in different dosages (ACZ: 2, 5, 10 mg/kg bodyweight; MTZ: 1, 3, 7, 10 mg/kg bodyweight). The full dose was administered at the beginning of ventilation. After 90 minutes of ventilation the maintenance dose (50 percent of the initial dose) was administered (e.g. ACZ10-group: initially 10 mg/kg, after 90 minutes 5 mg/kg). Compared to the LP-group, high tidal volume ventilation led to a compromised gas exchange and a drop of the mean arterial pressure in the HP-, ACZ- and MTZ-groups. With carbonic anhydrase inhibition by ACZ 5 and 10 mg/kg as well as MTZ 7 and 10 mg/kg a significant improved arterial oxygenation could be observed at the end of the ventilation period compared to the HP-group. Furthermore, the mean arterial pressure drop was smaller in the ACZ5- and ACZ10-group at the end of the ventilation period compared to the HP-group. High tidal volume ventilation resulted in an increased wet-to-dry-ratio, an elevated protein concentration in the bronchoalveolar lavage fluid and a reduced lung compliance compared to the LP-group. Neither for ACZ nor for MTZ, improvements of any of the mentioned parameters could be observed compared to the HP-group. In this rat model of ventilator-induced lung injury the intravenous administration of the CA inhibitors ACZ and MTZ at higher dosages improved gas exchange and ACZ at higher dosages preserved blood pressure in rats subjected to injurious HP-ventilation. These results suggest a therapeutic (resp. preventive) benefit of CA inhibitors in ventilator-induced lung injury.