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Comparison between conventional mechanical ventilation and high-frequency oscillatory ventilation, associated with inhaled nitric oxide, relating to oxygenation, pulmonary histological and oxidative injury in a saline-lavaged rabbit model of ARDS

Grant number: 07/03173-2
Support Opportunities:Regular Research Grants
Duration: March 01, 2008 - February 28, 2010
Field of knowledge:Health Sciences - Medicine - Maternal and Child Health
Principal Investigator:José Roberto Fioretto
Grantee:José Roberto Fioretto
Host Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
Associated researchers:Ana Lucia do Anjos Ferreira ; Cilmery Suemi Kurokawa ; Julio defaveri


Acute respiratory distress syndrome (ARDS) has been associated with high mortality despite its pathophysiology being better understood and recent advances in treatment. Mechanical ventilation (MV) is essential for patients with ARDS. There are two general ventilatory approaches to lung protection in ARDS, one based on conventional mechanical ventilation (CMV) and one based on high-frequency oscillatory ventilation (HFOV). Another important adjunctive therapy is inhaled nitric oxide (iNO); this gas is a selective vasodilator of well-ventilated lung regions, thus reducing intrapulmonary shunt and improving arterial oxygenation. In the early 90s, the beneficial effects of iNO on oxygenation and pulmonary hypertension were described in both adults and children with ARDS. After this, many studies, while confirming those effects, were not able to demonstrate a sustained response to iNO therapy. However, it was demonstrated, in a multicenter randomized controlled trial, sustained response to iNO versus placebo therapy in pediatric patient subgroups (oxygenation index greater than 25 and immunocompromised group). Authors explained that iNO therapy did not sustain improved oxygenation in all patients because they were enrolled in the study in the later stages of the disease. Following this idea of early administration giving beneficial effects, our group published a protocol in 2001 for early iNO introduction associated with conventional therapy in ARDS children. We demonstrated acute and sustained response of oxygenation indexes whilst using iNO as early as 12 hours after ARDS diagnosis, giving weight to the idea that early iNO treatment may be more effective. Later in 2004, we compared early iNO administration plus conventional therapy against conventional therapy in ARDS children. Therapy with iNO was introduced as early as 1.5 hours after ARDS diagnosis, leading to acute improvements in the PaO2/FiO2 ratio and oxygenation index. Prolonged treatment was also associated with improved oxygenation, so that FiO2 and peak inspiratory pressure could be quickly and significantly reduced. Mortality rate for iNO patients was significantly lower. We concluded that early treatment with iNO causes acute and sustained improvement in oxygenation, with earlier reduction in ventilator settings that are associated with a high risk of ventilator induced lung injury and oxygen toxicity; this might contribute to reducing the mortality rate in children with ARDS. Currently, it is known that early iNO exposure is associated with reduced pulmonary leukocyte infiltration and less oxidative injury. Also responsiveness to iNO is better when alveoli are optimally recruited, as in HOFV. Our hypothesis is that HOFV plus iNO improves oxygenation, reduces histological and oxidative lung injury more efficiently than protective conventional mechanical ventilation. Aims: To determine the effects of HOFV associated with iNO on oxygenation indexes and histological/oxidative lung injury comparing with protective conventional mechanical ventilation plus iNO, in a saline-lavaged rabbit model of ARDS. End points were pathophysiological indexes of acute lung injury: gas exchange, the number of polymorphonuclear leukocytes, levels of tumor necrosis factor-alfa in lung lavage fluid, oxidative lung damage, and lung pathology. Methods:Fifty rabbits will be instrumented and randomized into five groups: 1) uninjured ventilated animals (control group; n=10); 2) ARDS animals (n=10) under protective conventional mechanical ventilation, with low tidal volume (8 mL/Kg) and high Peep (10 cmH2O) without iNO; 3) ARDS animals (n=10) under protective conventional mechanical ventilation, with low tidal volume (8 mL/Kg) and high Peep (10 cmH2O) with iNO; 4) ARDS animals (n=10) under high-frequency oscillatory ventilation without iNO; 5) ARDS animals (n=10) under high-frequency oscillatory ventilation with iNO. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FIORETTO, JOSE R.; CAMPOS, FABIO J.; RONCHI, CARLOS F.; FERREIRA, ANA L. A.; KUROKAWA, CILMERY S.; CARPI, MARIO F.; MORAES, MARCOS A.; BONATTO, ROSSANO C.; DEFAVERI, JULIO; YEUM, KYUNG-JIN. Effects of Inhaled Nitric Oxide on Oxidative Stress and Histopathological and Inflammatory Lung Injury in a Saline-Lavaged Rabbit Model of Acute Lung Injury. Respiratory Care, v. 57, n. 2, p. 273-281, . (07/03173-2)

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