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.

A large, randomized, multiple-center ventilation trial, conducted by the National Heart, Lung, and Blood Institute (NHLBI) ARDS Clinical Trials Network in patients with acute lung injury (ALI), including those with the acute respiratory distress syndrome (ARDS), established that a lower tidal volume strategy was associated with a 9% absolute reduction in mortality and more pulmonary and nonpulmonary organ failure free days. These results are consistent with animal studies demonstrating that higher tidal volumes, especially in the absence of positive end-expiratory pressure (PEEP), can cause or exacerbate lung injury and precipitate extrapulmonary organ dysfunction. The results are also consistent with a prior smaller human study of a ventilation strategy designed to reduce lung injury.

The mechanisms by which ventilation protocols afford benefit are unknown but have been hypothesized to include less barotrauma elevated levels of intrinsic PEEP resulting from an increase in respiratory rate a protective effect of hypercarbia and diminished inflammatory cytokine production. Data from the ARDS Network trials demonstrated no reduction in the incidence of pneumothorax or other obvious barotrauma no elevation in intrinsic PEEP and minimal hypercarbia. One human trial has shown a reduction of inflammatory cytokine levels using a ventilation strategy of higher PEEP combined with a lower tidal volume. In that study, both the tidal volume and PEEP differed between groups, such that the relative contribution of each of these to the decrease in inflammation could not be determined.

In an attempt to understand the mechanism of the protective effect of a lower tidal volume ventilation protocol in which both groups received a common PEEP-FIO₂ strategy, we measured plasma cytokine levels at baseline and 3 days later in a large, well-characterized population randomized to a ventilation strategy using tidal volumes of 6 or 12 mL/kg predicted body weight. Two proinflammatory cytokines, interleukin (IL)-8 and IL-6, and one regulatory cytokine, IL-10, were chosen because they were known to be increased in ALI, in previous smaller clinical trials they were variably associated with mortality, and increasing evidence suggested they were likely to be affected by mechanical ventilation. We tested two hypotheses. First, that elevated baseline levels of IL-6, IL-8, and IL-10 would have independent predictive value for mortality and other clinical outcomes. Second, we tested the hypothesis that a lower tidal volume would be associated with lower levels of these inflammatory cytokines later in the course of ALI/ARDS.