Effects of airway pressure release ventilation on multi-organ injuries in severe acute respiratory distress syndrome pig models

Abstract

Background: Extra-pulmonary multi-organ failure in patients with severe acute respiratory distress syndrome (ARDS) is a major cause of high mortality. Our purpose is to assess whether airway pressure release ventilation (APRV) causes more multi-organ damage than low tidal volume ventilation (LTV).

Methods: Twenty one pigs were randomized into control group (n = 3), ARDS group (n = 3), LTV group (n = 8) and APRV group (n = 7). Severe ARDS model was induced by repeated bronchial saline lavages. Pigs were ventilated and monitored continuously for 48 h. Respiratory data, hemodynamic data, serum inflammatory cytokines were collected throughout the study. Histological injury and apoptosis were assessed by two pathologists.

Results: After severe ARDS modeling, pigs in ARDS, LTV and APRV groups experienced significant hypoxemia and reduced lung static compliance (C_stat). Oxygenation recovered progressively after 16 h mechanical ventilation (MV) in LTV and APRV group. The results of the repeated measures ANOVA showed no statistical difference in the PaO₂/FiO₂ ratio between the APRV and LTV groups (p = 0.54). The C_stat showed a considerable improvement in APRV group with statistical significance (p < 0.01), which was significantly higher than in the LTV group since 16 h (p = 0.04). Histological injury scores showed a significantly lower injury score in the middle and lower lobes of the right lung in the APRV group compared to LTV (p_middle = 0.04, p_lower = 0.01), and no significant increase in injury scores for extra-pulmonary organs, including kidney (p = 0.10), small intestine (p = 1.0), liver (p = 0.14, p = 0.13) and heart (p = 0.20). There were no significant differences in serum inflammatory cytokines between the two groups.

Conclusion: In conclusion, in the experimental pig models of severe ARDS induced by repetitive saline lavage, APRV improved lung compliance with reduced lung injury of middle and lower lobes, and did not demonstrate more extra-pulmonary organ injuries as compared with LTV.

Keywords: Acute respiratory distress syndrome; Airway pressure release ventilation; Low tidal volume; Mechanical ventilation; Multi-organ dysfunction syndrome.

Fig. 1

Summary of the experimental design of this study

Fig. 2

Respiratory and hemodynamic variables at different time points. A PaO₂/FiO₂ ratio; B Oxygen index; C Static compliance of the respiratory system; D Mean airway pressure; E Mean arterial pressure; The p-values were calculated by repeated measurement ANOVA between the two groups; *p < 0.05 compared to the LTV group at diffeerent time point in Bonferroni post-hoc test; ns = no significance

Fig. 3

Lung tissue samples in different groups. A Control group; B ARDS group; C LTV group; D APRV group

Fig. 4

Representative light micrographs of multi-organs in different groups. A1 lung, B1 kidney, C1 intestine, D1 liver, E1 heart in the control group; A2 lung, B2 kidney, C2 intestine, D2 liver, E2 heart in the ARDS group; A3 lung, B3 kidney, C3 intestine, D3 liver, E3 heart in the LTV group; A4 lung, B4 kidney, C4 intestine, D4 liver, E4 heart in the APRV group; Histopathologic injury score in lung (A5), kidney (B5), small intestine (C5), liver (D5) and heart (E5). Black arrow in kidney = renal tubular epithelial cell edema; Red arrow in kidney = epithelial cell damage; Orange arrow in intestine = necrotic detachment of intestinal villous epithelial cells; Black arrow in liver = necrosis; Red arrow in liver = dilated liver sinuses; Yellow star in liver = fat infiltration; Green arrow = inflammatory infiltrates; Blue arrow = fibrous necrosis; small intestine: magnification 200 × ; lung, kidney, liver, heart: magnification 400 × . *p < 0.05 were calculated by Kruskal–Wallis H-test. ns = no significance

Fig. 5

Representative TUNEL staining of multi-organs in different groups. A1 lung, B1kidney, C1 intestine, D1 liver, E1 heart in the control group; A2 lung, B2 kidney, C2 intestine, D2 liver, E2 heart in the ARDS group; A3 lung, B3 kidney, C3 intestine, D3 liver, E3 heart in the LTV group; A4 lung, B4 kidney, C4 intestine, D4 liver, E4 heart in the APRV group; Apoptotic index in lung (A5), kidney (B5), small intestine (C5), liver (D5) and heart (E5); *p < 0.05; ns = no significance; kidney, small intestine: magnification 200 × ; Lung, liver, heart: magnification 400 × ; Orange in lung and kidney, pink in small intestine, green in liver and heart: TUNEL signal; Blue: DAPI. *p < 0.05 were calculated by Kruskal–Wallis H-test. ns = no significance

Fig. 6

The level of serum inflammatory cytokines. A TNF-α level in serum; B IL-1 level in serum; C IL-6 level in serum; D IL-8 level in serum; TNF-α, tumor necrosis factor alpha; IL-1, interleukin 1; IL-6, interleukin 6; IL-8, interleukin 8. The p-values were calculated by repeated measurement ANOVA between the two groups