Alveolar instability (atelectrauma) is not identified by arterial oxygenation predisposing the development of an occult ventilator-induced lung injury.

BACKGROUND: Improperly set mechanical ventilation (MV) with normal lungs can advance lung injury and increase the incidence of acute respiratory distress syndrome (ARDS). A key mechanism of ventilator-induced lung injury (VILI) is an alteration in alveolar mechanics including alveolar instability or recruitment/derecruitment (R/D). We hypothesize that R/D cannot be identified by PaO2 (masking occult VILI), and if protective ventilation is not applied, ARDS incidence will increase. METHODS: Sprague-Dawley rats (n = 8) were anesthetized, surgically instrumented, and placed on MV. A thoracotomy was performed and an in vivo microscope attached to the pleural surface of the lung with baseline dynamic changes in alveolar size during MV recorded. Alveolar instability was induced by intra-tracheal instillation of Tween and alveolar R/D identified as a marked change in alveolar size from inspiration to expiration with increases in positive end-expiratory pressure (PEEP) levels. RESULTS: Despite maintaining a clinically acceptable PaO2 (55-80 mmHg), the alveoli remained unstable with significant R/D at low PEEP levels. Although PaO2 consistently increased with an increase in PEEP, R/D did not plateau until PEEP was >9 cmH2O. CONCLUSIONS: PaO2 remained clinically acceptable while alveolar instability persisted at all levels of PEEP (especially PEEP <9 cmH2O). Therefore, PaO2 levels cannot be used reliably to guide protective MV strategies or infer that VILI is not occurring. Using PaO2 to set a PEEP level necessary to stabilize the alveoli could underestimate the potential for VILI. These findings highlight the need for more accurate marker(s) of alveolar stability to guide protective MV necessary to prevent VILI.

Airway pressure release ventilation reduces conducting airway micro-strain in lung injury.

BACKGROUND: Improper mechanical ventilation can exacerbate acute lung damage, causing a secondary ventilator-induced lung injury (VILI). We hypothesized that VILI can be reduced by modifying specific components of the ventilation waveform (mechanical breath), and we studied the impact of airway pressure release ventilation (APRV) and controlled mandatory ventilation (CMV) on the lung micro-anatomy (alveoli and conducting airways). The distribution of gas during inspiration and expiration and the strain generated during mechanical ventilation in the micro-anatomy (micro-strain) were calculated. STUDY DESIGN: Rats were anesthetized, surgically prepared, and randomized into 1 uninjured control group (n = 2) and 4 groups with lung injury: APRV 75% (n = 2), time at expiration (TLow) set to terminate appropriately at 75% of peak expiratory flow rate (PEFR); APRV 10% (n = 2), TLow set to terminate inappropriately at 10% of PEFR; CMV with PEEP 5 cm H2O (PEEP 5; n = 2); or PEEP 16 cm H2O (PEEP 16; n = 2). Lung injury was induced in the experimental groups by Tween lavage and ventilated with their respective settings. Lungs were fixed at peak inspiration and end expiration for standard histology. Conducting airway and alveolar air space areas were quantified and conducting airway micro-strain was calculated. RESULTS: All lung injury groups redistributed inspired gas away from alveoli into the conducting airways. The APRV 75% minimized gas redistribution and micro-strain in the conducting airways and provided the alveolar air space occupancy most similar to control at both inspiration and expiration. CONCLUSIONS: In an injured lung, APRV 75% maintained micro-anatomic gas distribution similar to that of the normal lung. The lung protection demonstrated in previous studies using APRV 75% may be due to a more homogeneous distribution of gas at the micro-anatomic level as well as a reduction in conducting airway micro-strain.

Mechanical breath profile of airway pressure release ventilation: the effect on alveolar recruitment and microstrain in acute lung injury.

IMPORTANCE: Improper mechanical ventilation settings can exacerbate acute lung injury by causing a secondary ventilator-induced lung injury. It is therefore important to establish the mechanism by which the ventilator induces lung injury to develop protective ventilation strategies. It has been postulated that the mechanism of ventilator-induced lung injury is the result of heterogeneous, elevated strain on the pulmonary parenchyma. Acute lung injury has been associated with increases in whole-lung macrostrain, which is correlated with increased pathology. However, the effect of mechanical ventilation on alveolar microstrain remains unknown. OBJECTIVE: To examine whether the mechanical breath profile of airway pressure release ventilation (APRV), consisting of a prolonged pressure-time profile and brief expiratory release phase, reduces microstrain. DESIGN, SETTING, AND PARTICIPANTS: In a randomized, nonblinded laboratory animal study, rats were randomized into a controlled mandatory ventilation group (n = 3) and an APRV group (n = 3). Lung injury was induced by polysorbate lavage. A thoracotomy was performed and an in vivo microscope was placed on the lungs to measure alveolar mechanics. MAIN OUTCOMES AND MEASURES: In the controlled mandatory ventilation group, multiple levels of positive end-expiratory pressure (PEEP; 5, 10, 16, 20, and 24 cm H2O) were tested. In the APRV group, decreasing durations of expiratory release (time at low pressure [T(low)]) were tested. The T(low) was set to achieve ratios of termination of peak expiratory flow rate (T-PEFR) to peak expiratory flow rate (PEFR) of 10%, 25%, 50%, and 75% (the smaller this ratio is [ie, 10%], the more time the lung is exposed to low pressure during the release phase, which decreases end-expiratory lung volume and potentiates derecruitment). Alveolar perimeters were measured at peak inspiration and end expiration using digital image analysis, and strain was calculated by normalizing the change in alveolar perimeter length to the original length. Macrostrain was measured by volume displacement. RESULTS: Higher PEEP (16-24 cm H2O) and a brief T(low) (APRV T-PEFR to PEFR ratio of 75%) reduced microstrain. Microstrain was minimized with an APRV T-PEFR to PEFR ratio of 75% (mean [SEM], 0.05 [0.03]) and PEEP of 16 cm H2O (mean [SEM], 0.09 [0.08]), but an APRV T-PEFR to PEFR ratio of 75% also promoted alveolar recruitment compared with PEEP of 16 cm H2O (mean [SEM] total inspiratory area, 52.0% [2.9%] vs 29.4% [4.3%], respectively; P < .05). Whole-lung strain was correlated with alveolar microstrain in tested settings (P < .05) except PEEP of 16 cm H2O (P > .05). CONCLUSIONS AND RELEVANCE: Increased positive-end expiratory pressure and reduced time at low pressure (decreased T(low)) reduced alveolar microstrain. Reduced microstrain and improved alveolar recruitment using an APRV T-PEFR to PEFR ratio of 75% may be the mechanism of lung protection seen in previous clinical and animal studies.

Airway pressure release ventilation prevents ventilator-induced lung injury in normal lungs.

IMPORTANCE: Up to 25% of patients with normal lungs develop acute lung injury (ALI) secondary to mechanical ventilation, with 60% to 80% progressing to acute respiratory distress syndrome (ARDS). Once established, ARDS is treated with mechanical ventilation that can paradoxically elevate mortality. A ventilation strategy that reduces the incidence of ARDS could change the clinical paradigm from treatment to prevention. OBJECTIVES: To demonstrate that (1) mechanical ventilation with tidal volume (VT) and positive end-expiratory pressure (PEEP) settings used routinely on surgery patients causes ALI/ARDS in normal rats and (2) preemptive application of airway pressure release ventilation (APRV) blocks drivers of lung injury (ie, surfactant deactivation and alveolar edema) and prevents ARDS. DESIGN, SETTING, AND SUBJECTS: Rats were anesthetized and tracheostomy was performed at State University of New York Upstate Medical University. Arterial and venous lines, a peritoneal catheter, and a rectal temperature probe were inserted. Animals were randomized into 3 groups and followed up for 6 hours: spontaneous breathing ventilation (SBV, n = 5), continuous mandatory ventilation (CMV, n = 6), and APRV (n = 5). Rats in the CMV group were ventilated with Vt of 10 cc/kg and PEEP of 0.5 cm H2O. Airway pressure release ventilation was set with a P(High) of 15 to 20 cm H2O; P(Low) was set at 0 cm H2O. Time at P(High) (T(High)) was 1.3 to 1.5 seconds and a T(Low) was set to terminate at 75% of the peak expiratory flow rate (0.11-0.14 seconds), creating a minimum 90% cycle time spent at P(High). Bronchoalveolar lavage fluid and lungs were harvested for histopathologic analysis at necropsy. RESULTS: Acute lung injury/ARDS developed in the CMV group (mean [SE] PaO2/FiO2 ratio, 242.96 [24.82]) and was prevented with preemptive APRV (mean [SE] PaO2/FIO2 ratio, 478.00 [41.38]; P < .05). Airway pressure release ventilation also significantly reduced histopathologic changes and bronchoalveolar lavage fluid total protein (endothelial permeability) and preserved surfactant proteins A and B concentrations as compared with the CMV group. CONCLUSIONS AND RELEVANCE: Continuous mandatory ventilation in normal rats for 6 hours with Vt and PEEP settings similar to those of surgery patients caused ALI. Preemptive application of APRV blocked early drivers of lung injury, preventing ARDS. Our data suggest that APRV applied early could reduce the incidence of ARDS in patients at risk.

Preemptive application of airway pressure release ventilation prevents development of acute respiratory distress syndrome in a rat traumatic hemorrhagic shock model.

BACKGROUND: Once established, the acute respiratory distress syndrome (ARDS) is highly resistant to treatment and retains a high mortality. We hypothesized that preemptive application of airway pressure release ventilation (APRV) in a rat model of trauma/hemorrhagic shock (T/HS) would prevent ARDS. METHODS: Rats were anesthetized, instrumented for hemodynamic monitoring, subjected to T/HS, and randomized into two groups: (a) volume cycled ventilation (VC) (n = 5, tidal volume 10 mL/kg; positive end-expiratory pressure 0.5 cmH(2)O) or (b) APRV (n = 4, P(high) = 15-20 cmH(2)O; T(high) = 1.3-1.5 s to achieve 90% of the total cycle time; T(low) = 0.11-0.14 s, which was set to 75% of the peak expiratory flow rate; P(low) = 0 cmH(2)O). Study duration was 6 h. RESULTS: Airway pressure release ventilation prevented lung injury as measured by PaO(2)/FIO(2) (VC 143.3 ± 42.4 vs. APRV 426.8 ± 26.9, P < 0.05), which correlated with a significant decrease in histopathology as compared with the VC group. In addition, APRV resulted in a significant decrease in bronchoalveolar lavage fluid total protein, increased surfactant protein B concentration, and an increase in epithelial cadherin tissue expression. In vivo microscopy demonstrated that APRV significantly improved alveolar patency and stability as compared with the VC group. CONCLUSIONS: Our findings demonstrate that preemptive mechanical ventilation with APRV attenuates the clinical and histologic lung injury associated with T/HS. The mechanism of injury prevention is related to preservation of alveolar epithelial and endothelial integrity. These data support our hypothesis that preemptive APRV, applied using published guidelines, can prevent the development of ARDS.

Early stabilizing alveolar ventilation prevents acute respiratory distress syndrome: a novel timing-based ventilatory intervention to avert lung injury.

BACKGROUND: Established acute respiratory distress syndrome (ARDS) is often refractory to treatment. Clinical trials have demonstrated modest treatment effects, and mortality remains high. Ventilator strategies must be developed to prevent ARDS. HYPOTHESIS: Early ventilatory intervention will block progression to ARDS if the ventilator mode (1) maintains alveolar stability and (2) reduces pulmonary edema formation. METHODS: Yorkshire pigs (38-45 kg) were anesthetized and subjected to a "two-hit" ischemia-reperfusion and peritoneal sepsis. After injury, animals were randomized into two groups: early preventative ventilation (airway pressure release ventilation [APRV]) versus nonpreventative ventilation (NPV) and followed for 48 hours. All animals received anesthesia, antibiotics, and fluid or vasopressor therapy as per the Surviving Sepsis Campaign. Titrated for optimal alveolar stability were the following ventilation parameters: (1) NPV group--tidal volume, 10 mL/kg + positive end-expiratory pressure - 5 cm/H2O volume-cycled mode; (2) APRV group--tidal volume, 10 to 15 mL/kg; high pressure, low pressure, time duration of inspiration (Thigh), and time duration of release phase (Tlow). Physiological data and plasma were collected throughout the 48-hour study period, followed by BAL and necropsy. RESULTS: APRV prevented the development of ARDS (p < 0.001 vs. NPV) by PaO2/FIO2 ratio. Quantitative histological scoring showed that APRV prevented lung tissue injury (p < 0.001 vs. NPV). Bronchoalveolar lavage fluid showed that APRV lowered total protein and interleukin 6 while preserving surfactant proteins A and B (p < 0.05 vs. NPV). APRV significantly lowered lung water (p < 0.001 vs. NPV). Plasma interleukin 6 concentrations were similar between groups. CONCLUSION: Early preventative mechanical ventilation with APRV blocked ARDS development, preserved surfactant proteins, and reduced pulmonary inflammation and edema despite systemic inflammation similar to NPV. These data suggest that early preventative ventilation strategies stabilizing alveoli and reducing pulmonary edema can attenuate ARDS after ischemia-reperfusion and sepsis.