Lower Tidal Volume Ventilation and Plasma Cytokine Markers of Inflammation in Patients with Acute Lung Injury

Objectives: To evaluate the association between interleukin-6, interleukin-8, and interleukin-10 and clinical outcomes including mortality in patients with acute lung injury and to determine whether lower tidal volume ventilation was associated with a decrease in plasma cytokines in patients with acute lung injury.

Design: Multiple-center, randomized trial.

Setting: Intensive care units in ten university centers.

Patients: The study included 861 patients enrolled in the National Heart, Lung and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial of lower tidal volumes compared with traditional tidal volumes for acute lung injury.

Interventions: Patients were randomized to a 6 mL/kg or a 12 mL/kg tidal volume strategy that has been previously described.

Measurements And Main Results: Baseline plasma levels of interleukin-6, interleukin-8, and interleukin-10 were each associated with an increased risk of death in both logistic regression analyses controlling for ventilator group (odds ratio 1.63 per log-10 increment, 95% confidence interval 1.33-1.98; odds ratio 2.33 per log-10 increment, 95% confidence interval 1.79-3.03; odds ratio 2.02 per log-10 increment, 95% confidence interval 1.47-2.76, respectively) and multivariate analyses controlling for ventilation strategy, Acute Physiology and Chronic Health Evaluation III score, Pao2/Fio2 ratio, creatinine, platelet count, and vasopressor use (odds ratio 1.63 per log-10 increment, 95% confidence interval 0.93-1.49; odds ratio 1.73 per log-10 increment, 95% confidence interval 1.29-2.34; odds ratio 1.23 per log-10 increment, 95% confidence interval 0.86-1.76, respectively). Interleukin-6 and interleukin-8 levels were also associated with a significant decrease in ventilator free and organ failure free days. Patients with sepsis had the highest cytokine levels and the greatest risk of death per cytokine elevation. By day 3, the 6 mL/kg strategy was associated with a greater decrease in interleukin-6 and interleukin-8 levels. There was a 26% reduction in interleukin-6 (95% confidence interval, 12-37%) and a 12% reduction in interleukin-8 (95% confidence interval, 1-23%) in the 6 mL/kg group compared with the 12 mL/kg group.

Conclusions: In patients with acute lung injury, plasma interleukin-6 and interleukin-8 levels are associated with morbidity and mortality. The severity of inflammation varies with clinical risk factor, suggesting that clinical risk factor should be considered when both developing and testing therapeutic interventions. Low tidal volume ventilation is associated with a more rapid attenuation of the inflammatory response.