Conservative fluid management prevents age-associated ventilator induced mortality

Abstract

Background Approximately 800 thousand patients require mechanical ventilation in the United States annually with an in-hospital mortality rate of over 30%. The majority of patients requiring mechanical ventilation are over the age of 65 and advanced age is known to increase the severity of ventilator-induced lung injury (VILI) and in-hosptial mortality rates. However, the mechanisms which predispose aging ventilator patients to increased mortality rates are not fully understood. Ventilation with conservative fluid management decreases mortality rates in acute respiratory distress patients, but to date there has been no investigation of the effect of conservative fluid management on VILI and ventilator associated mortality rates. We hypothesized that age-associated increases in susceptibility and incidence of pulmonary edema strongly promote age-related increases in ventilator associated mortality. Methods 2 month old and 20 month old male C57BL6 mice were mechanically ventilated with either high tidal volume (HVT) or low tidal volume (LVT) for up to 4 hours with either liberal or conservative fluid support. During ventilation, lung compliance, total lung capacity, and hysteresis curves were quantified. Following ventilation, bronchoalveolar lavage fluid was analyzed for total protein content and inflammatory cell infiltration. Wet to dry ratios were used to directly measure edema in excised lungs. Lung histology was performed to quantify alveolar barrier damage/destruction. Age matched non-ventilated mice were used as controls. Results At 4hrs, both advanced age and HVT ventilation significantly increased markers of inflammation and injury, degraded pulmonary mechanics, and decreased survival rates. Conservative fluid support significantly diminished pulmonary edema and improved pulmonary mechanics by 1hr in advanced age HVT subjects. In 4hr ventilations, conservative fluid support significantly diminished pulmonary edema, improved lung mechanics, and resulted in significantly lower mortality rates in older subjects. Conclusion Our study demonstrates that conservative fluid alone can attenuate the age associated increase in ventilator associated mortality.

Aging effects on airflow dynamics and lung function in human bronchioles

“…Several experiments were previously conducted on mice [ 8 – 10 ] in order to evaluate the underlying mechanisms in aging, For example, Jonathan et al [ 9 ] mechanically ventilated mice at 10 ml/kg tidal volume for about 3 minutes prior to initiating mechanical perturbations to investigate respiratory system mechanics and lung morphology across a more complete spectrum of age groups, 2-, 6-, 18-, 24-, and 30-month-old mice. This experiment showed the aging related decrease in respiratory system resistance and increase in lung compliance between 2-month-old and 24-month-old mice.…”

“…This experiment showed the aging related decrease in respiratory system resistance and increase in lung compliance between 2-month-old and 24-month-old mice. Recently, Herbert et al [ 10 ] mechanically ventilated 2-month-old and 20-month-old male mice and established that older mice had increased lung compliance and were more prone to ventilator-induced edema and mortality.…”

Mathematical modeling of ventilator-induced lung inflammation

“…Pressure-Controlled Ventilator-Induced Lung Injury Model: We mechanically ventilated young (2-3 mo) and old (20-25 mo) C57BL/6J wild-type mice using a Scireq FlexiVent computer-driven small-animal ventilator (Montreal, Canada) and previously cited methods (Herbert et al, 2016) with slight modifications. Mice were anesthetized, tracheotomized, and then ventilated for 5 minutes using a low pressure-controlled strategy (peak inspiratory pressure (PIP): 15 cmH20, respiratory rate (RR): 125 breaths/min, positive end-expiratory pressure (PEEP): 3 cmH20).…”

Inflammation and Monocyte Recruitment Due to Aging and Mechanical Stretch in Alveolar Epithelium are Inhibited by the Molecular Chaperone 4-Phenylbutyrate

“…Epidemiological studies also suggest that age is a predictive factor in the severity of VILI; however, the exact molecular mechanisms between age and VILI are still unknown (16, 55, 63). In rodent models of VILI, we and others have shown that age increases susceptibility to ventilator-induced edema, injury, and mortality (1, 36). In general, advanced age is also known to promote an increasingly dysregulated innate immune/inflammatory response to injury with an overall shift towards a proinflammatory state that is known as inflammaging (23).…”