title: High-tidal volume ventilation aggravates sepsis-induced multiorgan dysfunction in a dexamethasone-inhibitable manner.
abstract: High-tidal volume (Vt) ventilation induces lung injury and systemic inflammation, and small doses of endotoxin have been shown to increase the susceptibility to ventilation-induced lung injury. We studied whether high-Vt ventilation increases organ injury in a model of bacterial sepsis and whether an anti-inflammatory treatment averts those changes. Anesthetized rats, monitored with an arterial catheter and a blood flow probe in the aorta, were assigned to one of four different groups: nonseptic low-Vt group (Vt = 9 mL/kg, positive end-expiratory pressure = 8 cm H2O, control group), septic low-Vt group, septic overventilated group (Vt = 35 mL/kg, positive end-expiratory pressure = 0), and septic overventilated group pretreated with dexamethasone (6 mg/kg i.p., 30 min before mechanical ventilation). Rats were ventilated for 75 min. Septic rats had undergone cecal ligation and puncture 48 h before mechanical ventilation. We measured hemodynamics, lung mechanics, blood chemistry and gas exchange, liver and heart expression of cyclooxygenase 2 (COX-2) and iNOS (reverse transcriptase-polymerase chain reaction), and lung histopathology. Septic rats showed metabolic acidosis, hyperlactatemia, lung and liver injury, increased liver and heart COX-2, and liver iNOS expression. High-Vt ventilation of septic rats was associated with more marked liver injury and heart COX-2 upregulation, as well as lung inflammation and dysfunction (impaired oxygenation, increased bronchoalveolar lavage fluid protein and IL-6 concentration, decreased thoracic system compliance) and systemic hypotension. All inflammatory changes, as well as pulmonary and vascular dysfunctions, were abrogated by dexamethasone. High-Vt ventilation in bacterial sepsis upregulates the inflammatory response and aggravates the sepsis-induced cardiovascular, pulmonary, and liver dysfunction. Dexamethasone averts mechanical ventilation-induced changes under conditions of bacterial sepsis.
authors.affiliation: Hospital Universitario de Getafe and Universidad Europea de Madrid, Madrid, Spain.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Nin
authors.forename: José A
authors.initials: JA
authors.lastname: Lorente
authors.forename: Pilar
authors.initials: P
authors.lastname: Fernández-Segoviano
authors.forename: Marta
authors.initials: M
authors.lastname: De Paula
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferruelo
authors.forename: Andrés
authors.initials: A
authors.lastname: Esteban
mesh_terms: D000818:Animals; D002432:Cecum / Q000293:injuries; D051546:Cyclooxygenase 2 / Q000235:genetics; D003907:Dexamethasone / Q000627:therapeutic use*; D015870:Gene Expression; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology* / Q000517:prevention & control; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D011175:Positive-Pressure Respiration / Q000009:adverse effects*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications*
chemical_list: D012313:RNA; D003907:Dexamethasone; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2