In our study, it probably contributed to the increased respiratory impairment in the mixed respiratory acidosis�Cmetabolic alkalosis patients when compared to the subjects with pure respiratory acidosis. In a study investigating the effects of metabolic acid-base changes on central ventilatory chemoregulation in normocapnic and hypercapnic COPD patients, the ventilatory responsiveness to carbon dioxide was not significantly altered by the induced metabolic state. These results may seem inconsistent with our observations, but we believe that they are not comparable for several reasons. In the van de Ven et al. study, chronic metabolic acidosis and alkalosis were experimentally induced by the oral administration of acetazolamide and furosemide, respectively, and were not caused by various comorbidities from their multidrug treatments. The authors evaluated the responses of inspired ventilation and mouth occlusion pressure to changes in PaCO2, while we investigated the possible deleterious effects of metabolic alkalosis on the ventilatory response to hypercapnia by assessing the requirement and duration of NIV in a real clinical scenario. The effect of metabolic alkalosis on the clinical outcome of COPD patients was first reported in a study that showed an improvement in gas exchange and clinical symptoms after correcting the coexistent metabolic alkalosis. Discontinuing furosemide, which is prescribed for peripheral edema in patients with stable COPD, increases the minute ventilation and lowers the PaCO2 by correcting metabolic alkalosis. Hypoventilation in response to metabolic alkalosis has serious implications in patients with high PaCO2 and low PaO2. COPD patients with a tendency toward hypercapnia require extra attention because hypercapnia is believed to be an ominous sign for morbidity and mortality. The increased PaCO2 caused by furosemide may lead to fluid retention, which may counteract the diuretic effects of furosemide. This is of clinical relevance, especially considering that loop diuretics are prescribed to a substantial number of COPD patients. Thus, other types of diuretics should be considered when diuretic therapy is indicated in hypercapnic COPD patients. Spironolactone, which causes no acid/base shifts, or acetazolamide, which causes a metabolic acidosis, may be better options. Because loop diuretics are often necessary in COPD patients with cor pulmonale or cardiac comorbidities, acetazolamide could be added to counteract the metabolic alkalosis. Lactate clearance, as a surrogate for the magnitude and duration of global tissue hypoxia, is used for diagnostic, therapeutic and prognostic purposes.