Early effect of tidal volume on lung injury biomarkers in surgical patients with healthy lungs

Abstract

Background: The early biological impact of short-term mechanical ventilation on healthy lungs is unknown. The authors aimed to characterize the immediate tidal volume (VT)-related changes on lung injury biomarkers in patients with healthy lungs and low risk of pulmonary complications.

Methods: Twenty-eight healthy patients for knee replacement surgery were prospectively randomized to volume-controlled ventilation with VT 6 (VT6) or 10 (VT10) ml/kg predicted body weight. General anesthesia and other ventilatory parameters (positive end-expiratory pressure, 5 cm H2O, FIO2, 0.5, respiratory rate titrated for normocapnia) were managed similarly in the two groups. Exhaled breath condensate and blood samples were collected for nitrite, nitrate, tumor necrosis factor-α, interleukins-1β, -6, -8, -10, -11, neutrophil elastase, and Clara Cell protein 16 measurements, at the onset of ventilation and 60 min later.

Results: No significant differences in biomarkers were detected between the VT groups at any time. The coefficient of variation of exhaled breath condensate nitrite and nitrate decreased in the VT6 but increased in the VT10 group after 60-min ventilation. Sixty-minute ventilation significantly increased plasma neutrophil elastase levels in the VT6 (35.2 ± 30.4 vs. 56.4 ± 51.7 ng/ml, P = 0.008) and Clara Cell protein 16 levels in the VT10 group (16.4 ± 8.8 vs. 18.7 ± 9.5 ng/ml, P = 0.015). Exhaled breath condensate nitrite correlated with plateau pressure (r = 0.27, P = 0.042) and plasma neutrophil elastase (r = 0.44, P = 0.001). Plasma Clara Cell protein 16 correlated with compliance (r = 0.34, P = 0.014).

Conclusions: No tidal volume-related changes were observed in the selected lung injury biomarkers of patients with healthy lungs after 60-min ventilation. Plasma neutrophil elastase and plasma Clara Cell protein 16 might indicate atelectrauma and lung distention, respectively.

Figure 1. Nitrite, nitrate and Total nitric oxide (Total NOx = nitrite + nitrate) concentrations in exhaled breath condensate (EBC) and plasma

No statistical differences were found between the tidal volume (V_T) groups at any time point in either EBC or plasma concentrations of nitrite (A), nitrate (B) or Total NOx (C). Note the similar scale of nitrite in EBC and plasma and the approximately 20-fold concentrations of nitrate and Total NOx in plasma compared to EBC concentrations. Graphs represent mean and standard deviation (SD). Values from different time points within each group were compared with a paired t-test. The change scores of continuous variables from 0min to 60min time points were compared between the two V_T groups using an independent t-test. Significant p value was accepted as p<0.05.

Figure 2. Nitrite and nitrate concentrations in exhaled breath condensate (EBC): Individual values

The range of values at the 0min time point for nitrite (A), nitrate (B) and total nitric oxide (Total NOx = nitrite + nitrate)(C) were comparable in both groups. At the 60min time point the variability of nitrite and nitrate concentrations, and therefore of Total NOx, measured as the coefficient of variation (standard deviation/mean) was greater in the tidal volume 10 (V_T10) group compared to the V_T6 group. The increased variability in Total NOx in the V_T10 group was due to the increase in 3 patients that presented a raise predominantly in nitrate concentration, with 1 of these patients showing a simultaneous 2.5-fold increase in nitrite concentration (note the different scales for nitrite and nitrate concentrations).

Figure 3. Plasma concentrations of cytokines, neutrophil elastase and Clara cell protein-16 (CC16)

The plasma concentrations of cytokines (A), neutrophil elastase (B) and CC16 (C) were plotted at 0min and 60min time points in both tidal volume (V_T) groups. No significant differences were observed in cytokine concentrations at any time point and between the V_T groups. The mean level of neutrophil elastase significantly increased from 0min to 60min in the V_T6 group. The mean concentration of CC16 increased from 0min to 60min in the V_T10 but not in the V_T6 group. Graphs represent mean and standard deviation (SD). Comparisons between different time points were performed with a paired t-test. The change scores of continuous variables from 0min to 60min time points were compared between the two V_T groups using an independent t-test. No significant difference was observed between the V_T groups. *P < 0.05. (TNFα = Tumor Necrosis Factor α; IL= Interleukin).

Figure 3. Plasma concentrations of cytokines, neutrophil elastase and Clara cell protein-16 (CC16)

The plasma concentrations of cytokines (A), neutrophil elastase (B) and CC16 (C) were plotted at 0min and 60min time points in both tidal volume (V_T) groups. No significant differences were observed in cytokine concentrations at any time point and between the V_T groups. The mean level of neutrophil elastase significantly increased from 0min to 60min in the V_T6 group. The mean concentration of CC16 increased from 0min to 60min in the V_T10 but not in the V_T6 group. Graphs represent mean and standard deviation (SD). Comparisons between different time points were performed with a paired t-test. The change scores of continuous variables from 0min to 60min time points were compared between the two V_T groups using an independent t-test. No significant difference was observed between the V_T groups. *P < 0.05. (TNFα = Tumor Necrosis Factor α; IL= Interleukin).

Figure 4. Correlation between lung injury biomarkers and ventilatory physiology parameters

Exhaled breath condensate (EBC) nitrite concentration measurements from all samples pooled together showed a significant and positive logarithmic correlation with the airway plateau pressure (A) and plasma neutrophil elastase levels (B). Plasma Clara Cell protein 16 (CC16) concentrations showed a positive correlation with compliance (C). r represents the Pearson correlation coefficient.