Non-acidotic hypercapnia limits atrophy and loss of specific force in rat diaphragm after 5 days of controlled mechanical ventilation in parallel with increased local inflammation

Abstract Background Controlled Mechanical Ventilation (CMV) is associated with Ventilator Induced Lung Injury (VILI) and Ventilator Induced Diaphragm Dysfunction (VIDD). VIDD delays weaning from the respirator and increases the risk of further complications and health care costs, which are disproportionately increased with increasing duration of mechanical ventilation. Hypercapnia is frequently observed and tolerated as “permissive hypercapnia” during lung protective MV strategies. The systemic effects of hypercapnia are well known and considered potentially protective for diaphragm muscle in acute and short-time experimental MV studies. However, hypercapnia is commonly associated with acidosis, affecting immunity and inflammation pathways. Methods This study aims to determine the potential of hypercapnia in the absence of acidosis on diaphragm muscle structure and function in a well-established clinically relevant experimental ICU model, not limited by early mortality. The effects of hypercapnia at physiological pH on diaphragm single fibers cross sectional area (CSA) and specific force (maximum force normalized to CSA) were investigated. Results Non-Acidotic Hypercapnia (NAH) reduced body mass loss, diaphragm muscle fiber atrophy and loss of specific force, in parallel with an increased gene expression of proinflammatory cytokines (TNF-α and IL-1β) and of the MuRF-1 atrogene. In the diaphragm, TNF-α gene expression was significantly increased in NAH rats compared with 5 days normocapnic and controls, while IL-1β showed an increasing trend. In the lung lysates, IL-1β gene expression was significantly increased in 5 days normocapnic rats compared with the controls, while gene expression of TNF-α was increased in the NAH rats compared with controls. In NAH rats the increase was not significant. The gene expression of mitochondrial factors TFAM (regulator of mitochondrial gene expression), MFN2 (involved in mitochondrial fusion, quality control and cell metabolism), PARKIN (involved in mitochondrial quality control and mitophagy), ULK-1 (activator of mitophagy) was analyzed. NAH reversed, significantly the decreased gene expression of ULK 1 observed in the 5 days normocapnic rats. Conclusions These results suggest that non-acidotic hypercapnia limits the development of VIDD, irrespective of amplified local muscle inflammation. Therefore, we suggest its clinical role may be complementary to the known anti-inflammatory effects of hypercapnic acidosis (HCA), which has preventive VIDD effects as well.