Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial

Abstract

Introduction: Recent cohort studies have identified the use of large tidal volumes as a major risk factor for development of lung injury in mechanically ventilated patients without acute lung injury (ALI). We compared the effect of conventional with lower tidal volumes on pulmonary inflammation and development of lung injury in critically ill patients without ALI at the onset of mechanical ventilation.

Methods: We performed a randomized controlled nonblinded preventive trial comparing mechanical ventilation with tidal volumes of 10 ml versus 6 ml per kilogram of predicted body weight in critically ill patients without ALI at the onset of mechanical ventilation. The primary end point was cytokine levels in bronchoalveolar lavage fluid and plasma during mechanical ventilation. The secondary end point was the development of lung injury, as determined by consensus criteria for ALI, duration of mechanical ventilation, and mortality.

Results: One hundred fifty patients (74 conventional versus 76 lower tidal volume) were enrolled and analyzed. No differences were observed in lavage fluid cytokine levels at baseline between the randomization groups. Plasma interleukin-6 (IL-6) levels decreased significantly more strongly in the lower-tidal-volume group ((from 51 (20 to 182) ng/ml to 11 (5 to 20) ng/ml versus 50 (21 to 122) ng/ml to 21 (20 to 77) ng/ml; P = 0.01)). The trial was stopped prematurely for safety reasons because the development of lung injury was higher in the conventional tidal-volume group as compared with the lower tidal-volume group (13.5% versus 2.6%; P = 0.01). Univariate analysis showed statistical relations between baseline lung-injury score, randomization group, level of positive end-expiratory pressure (PEEP), the number of transfused blood products, the presence of a risk factor for ALI, and baseline IL-6 lavage fluid levels and the development of lung injury. Multivariate analysis revealed the randomization group and the level of PEEP as independent predictors of the development of lung injury.

Conclusions: Mechanical ventilation with conventional tidal volumes is associated with sustained cytokine production, as measured in plasma. Our data suggest that mechanical ventilation with conventional tidal volumes contributes to the development of lung injury in patients without ALI at the onset of mechanical ventilation.

Trial registration: ISRCTN82533884.

Figure 1

Flow diagram summarizing inclusion, allocation, and analysis. 347 patients were eligible for the study; 94 patients were excluded because of participation in another clinical trial (n = 49), use of immunosuppressive agents (n = 22), chronic obstructive pulmonary disease (n = 11), prior pneumectomy or lobectomy (n = 5), interstitial lung disease (n = 4), and pulmonary thromboembolism (n = 3); 93 patients refused informed consent, and in eight patients, participation in the trial was denied by the attending physician.

Figure 2

Serial data on mechanical ventilation parameters of patients ventilated with conventional tidal volume (solid circles) or lower tidal volumes (open circles). The number of patients was 74 versus 76 (conventional versus lower tidal volumes), 55 versus 63, and 34 versus 34, respectively, at T = 0, T = 2, and T = 4 days. *P < 0.05 (Interaction time × Group).

Figure 3

Serial data on respiratory values and lung-injury score of patients ventilated with conventional tidal volume (solid circles) or lower tidal volumes (open circles). PaO₂ partial pressure of arterial oxygen; PaCO₂ partial pressure of arterial carbon dioxide; PF = ratio of PaO₂ to fraction of inspired oxygen; LIS lung injury score. The number of patients was 74 versus 76 (conventional versus lower tidal volumes), 55 versus 63, and 34 versus 34, respectively, at T = 0, T = 2, and T = 4 days. *P < 0.05; ^#P = 0.06 (Interaction time × Group).

Figure 4

Serial data on cytokine levels in bronchoalveolar lavage fluid of patients ventilated with conventional tidal volume (solid circles) or lower tidal volumes (open circles). TNF-α = tumor necrosis factor-α; IL-1β = interleukin-1β; IL-6 = interleukin-6. The number of patients was 74 versus 76 (conventional versus lower tidal volumes), 55 versus 63, and 34 versus 34, respectively, at T = 0, T = 2, and T = 4 days. *P < 0.05; ^#P = 0.06 (Interaction time × Group).

Figure 5

Serial data on cytokine levels in lavage fluid and plasma of patients in whom ALI/ARDS developed (solid circles) and of patients in whom it did not (open circles). The number of patients was 136 versus 12 (no lung injury versus lung injury), 106 versus 12, and 61 versus 8, respectively, at T = 0, T = 2, and T = 4 days. *P < 0.05.

Figure 6

Serial data on minute volume (left graph), oxygenation index (middle graph), and lung compliance (right graph) in patients in whom lung injury developed (solid circles) and in patients in whom it did not (open circles). The number of patients was 136 versus 12 (no ALI/ARDS versus ALI/ARDS), 106 versus 12, and 61 versus eight, respectively, at T = 0, T = 2, and T = 4 days. *P < 0.05.

Figure 7

Kaplan-Meier curve of incidence of acute lung injury (left graph), percentage of patients weaned from ventilator (middle graph), and mortality (right graph) in patients mechanically ventilated with conventional tidal volume (solid circles) or lower tidal volumes (open circles).