The dose-dependent intensity of hypoxic ventilatory response in the early phase of LPS-induced endotoxemia

Abstract

Introduction. Systemic inflammation induced by massive administration of gram-negative bacterial endotoxin (lipopolysaccharide, LPS) is often complicated by acute respiratory distress syndrome (ARDS) with concomitant hypoxemia, which causes high mortality of critically ill patients. LPS is known to induce a reaction complex characteristic of the acute phase of inflammation, depending on the dose and time of exposure. However, the dependence of timing of initial manifestations of respiratory insufficiency, direction of acute-phase reactions of individual components in the breathing pattern, and oxygenation on the LPS dose remains unstudied. The aim of this work was to study the effects of low (0.7 mg/kg) and high (7.0 mg/kg) LPS doses on the intensity of hypoxic ventilatory response in the early period of infectious process. Methods. Experiments were conducted on 24 rats anesthetized with urethan (OOO Vekton, Russia, 1000 mg/kg). Hypoxia was produced by the rebreathing method (from normoxia to apnea) with a subsequent analysis performed for severe hypoxia (FiO₂ 8%). Major respiratory parameters, including breathing rate, tidal volume, minute ventilation, and saturation were recorded with a pneumotachograph. Survival rate was studied after hypoxic apnea. Results. During normoxia at the early stage of infectious process, multidirectional changes in breathing pattern parameters were observed. In severe hypoxia, a low LPS dose induced inhibition of the ventilatory response while with a high dose, on the contrary, the intensity of the compensatory ventilatory response was similar to the control value. Mortality after hypoxic apnea was directly related with the high dose of LPS despite the absence of respiratory failure. Conclusion. The results suggest that in endotoxemia, the expression of acute phase mediators in combination with hypoxia results in the inversion of physiological reactions due to disproportional activation of the neuroimmune interaction components involved in peripheral and central mechanisms of respiratory control.