Early airway pressure release ventilation prevents ARDS-a novel preventive approach to lung injury

Abstract

Acute respiratory distress syndrome (ARDS) afflicts 200,000 patients annually with a mortality rate of 30% to 60% despite wide use of low tidal volume (LTV) ventilation, the present standard of care. High-permeability alveolar edema and instability occur early in the development of ARDS, before clinical signs of lung injury, and represent potential targets for therapy. We hypothesize that early application of a protective ventilation strategy (airway pressure release ventilation [APRV]) will stabilize alveoli and reduce alveolar edema, preventing the development of ARDS. Yorkshire pigs (30-40 kg) were anesthetized and subjected to two-hit injury: (a) intestinal ischemia-reperfusion, (b) peritoneal sepsis, or sham surgery. Following surgery, pigs were randomized into APRV (n = 4), according to current published guidelines for APRV; LTV ventilation (n = 3), using the current published ARDS Network guidelines (6 mL/kg); or sham (n = 5). The clinical care of all pigs was administered per the Surviving Sepsis Campaign guidelines. Animals were killed, and necropsy performed at 48 h. Arterial blood gases were measured to assess for the development of clinical lung injury. Lung tissue epithelial cadherin (E-cadherin) was measured to assess alveolar permeability. Bronchoalveolar lavage fluid (BALF) surfactant protein A was measured to assess alveolar stability. Lung edema content and histopathology were analyzed at 48 h. Airway pressure release ventilation pigs did not develop ARDS. In contrast, pigs in the LTV ventilation met ARDS criteria (PaO2/FIO2 ratio) (APRV: baseline = 471 ± 16; 48 h = 392 ± 8; vs. LTV ventilation: baseline = 551 ± 28; 48 h = 138 ± 88; P < 0.001). Airway pressure release ventilation preserved alveolar epithelial integrity demonstrated by higher levels of E-cadherin in lung tissue as compared with LTV ventilation (P < 0.05). Surfactant protein A levels were higher in BALF from the APRV group, suggesting APRV preserved alveolar stability. Quantitative histologic scoring showed improvements in all stigmata of ARDS in the APRV group versus the LTV ventilation (P < 0.05). Airway pressure release ventilation had significantly lower lung edema (wet-dry weight) than LTV ventilation (P < 0.05). Protective ventilation with APRV immediately following injury prevents development of ARDS. Reduction in lung edema, preservation of lung E-cadherin, and surfactant protein A abundance in BALF suggest that APRV attenuates lung permeability, edema, and surfactant degradation. Protective ventilation could change the clinical paradigm from supportive care for ARDS with LTV ventilation to preventing development of ARDS with APRV.

Figure 1. Pulmonary Data

A. PaO₂/FiO₂ Ratio- APRV maintains a normal P/F ratio throughout 48 h study with no significant difference from uninjured Sham animals. LTV develop ALI (P/F < 300) by 19 h and ARDS (PF<250) by 33 h, ventilation strategy does not alter steady progression of increasing hypoxemia (p<0.001 vs APRV & Sham). B. Static Compliance (C_stat)- The APRV shows significant increase in C_stat after transition from volume-cycled mode to APRV (p<0.001 vs Sham & LTV). Sham maintained a normal C_stat level throughout the course of the study. In contrast the LTV group developed progressive decreases in C_stat to less than 50% of baseline. C. Mean Airway Pressure (P_mean)- Sham group maintained normal P_mean throughout 48-h significantly different from both APRV and LTV (p<0.001). P_mean was significantly higher in APRV than both Sham and LTV after transition from conventional ventilation at 1-h. Due to stepwise increases in PEEP per the ARDSnet protocol the P_mean were identical from 39-h to 48-h for LTV & APRV. D. Pressure Time Profile (P/T_P)- APRV group had significantly higher P/T_P than both other groups as soon as the transition was made from volume cycled ventilation (p<0.001 vs Sham & LTV). In the LTV group P/T_P remained low and didn’t change over the 48-h course of the study. Sham group animals also had low P/T_P, which was not significantly different from the LTV group throughout the study.

Figure 2. Gross Pathology

Representative specimens of gross lungs from LTV and APRV groups are shown. A. APRV Whole Lung- animals exhibited normal, pink, homogenously well-inflated lung tissue with no evidence of inflammation, no evidence of atelectasis and appeared to be inflated nearly to total lung capacity. B. APRV Cut Surface- The cut surface of the representative APRV lung specimen shows no bronchial nor septal edema. C. LTV Whole Lung- The lungs were predominantly atelectatic with heterogenous parenchymal inflammation. D. LTV Cut Surface- The cut surface shows gel-like edema filling the interlobular septae of the lung in the LTV group and airway edema in the bronchial openings.

Figure 3. Histology

Photomicrographs of representative lung sections of specimens from each treatment group at 40x magnification. F = fibrinous deposit in the air compartment. Arrow = blood in alveolus. Arrowhead = congested alveolar capillary. Bracket = thickened alveolar wall. A. Sham- animals received 48 hours of mechanical ventilation without PS+I/R injury. Specimen exhibits stigmata of lung injury including fibrinous deposits, blood in alveolus, congested capillaries, and thickened alveolar walls. B. LTV- animals received PS+I/R injury and LTV ventilation after onset of ALI. Specimen exhibits stigmata of lung injury including fibrinous deposits, blood in alveolus, congested capillaries, leukocyte infiltration, and thickened alveolar walls. C. APRV- Animals received APRV one hour following PS+I/R injury. Specimen shows normal pulmonary architecture, alveoli are well expanded, thin walled and there are no exudates.

Figure 4. Bronchoalveolar Lavage and Lung Tissue Analysis

A. Epithelial Cadherin in Lung tissue- APRV had significantly greater E-Cadherin abundance in lung tissue than LTV (p<0.05). B. Surfactant Protein A in BALF- APRV had significantly higher SP-A abundance in BALF than LTV (P<0.05). C. Interleukin- 6 in BALF- APRV had significantly lower IL-6 in BALF than LTV (p<0.05)