This study compared pathophysiological and biochemical indexes of acute lung injury in a saline-lavaged rabbit model with different ventilatory strategies: a control group consisting of moderate tidal volume (V(T)) (10-12 ml/kg) and low positive end-expiratory pressure (PEEP) (4-5 cmH(2)O); and three protective groups: 1) low V(T) (5-6 ml/kg) high PEEP, 2-3 cmH(2)O greater than the lower inflection point; 2) low V(T) (5-6 ml/kg), high PEEP (8-10 cmH(2)O); and 3) high-frequency oscillatory ventilation (HFOV). The strategy using PEEP > inflection point resulted in hypotension and barotrauma. HFOV attenuated the decrease in pulmonary compliance, the lung inflammation assessed by polymorphonuclear leukocyte infiltration and tumor necrosis factor-alpha concentration in the alveolar space, and pathological changes of the small airways and alveoli. Conventional mechanical ventilation using lung protection strategies (low V(T) high PEEP) only attenuated the decrease in oxygenation and pulmonary compliance. Therefore, HFOV may be a preferable option as a lung protection strategy.

Inflammatory chemical mediators, platelet-activating factor (PAF), thromboxane (TX) B2, and 6-keto-prostaglandin (PG)F1 alpha, were extracted from lung lavage fluid after conventional mechanical ventilation (CMV) and high frequency oscillatory ventilation (HFOV) to clarify the relation between mode of ventilation and lung injury in surfactant-depleted rabbit lungs. Anesthetized adult rabbits were tracheostomized, and surfactant depletion was induced by repeated saline lavage. Lung lavage for measurement of mediators was performed after 4 h of CMV at an FIO2 of 1.0 and a mean airway pressure of 15 cm H2O or HFOV (15 Hz) at an FIO2 of 1.0 or 0.21 and a mean airway pressure of 15 cm H2O. The number of total cells and polymorphonuclear leukocytes (PMN) and the levels of PAF, TXB2, and 6-keto-PGF1 alpha were measured by radioimmunoassay. Total respiratory compliance (Crs) was measured by the passive flow-volume curve method. The numbers of PMN, and the levels of PAF and TXB2 in lung lavage fluid were significantly greater during CMV than during HFOV. HFOV resulted in decreased production of PAF and TXB2 in a surfactant-depleted rabbit lung. Crs was significantly less during CMV than during HFOV. These results suggest that HFOV could prevent the release of such inflammatory chemical mediators and result in less lung injury than CMV.

The effects of conventional mechanical ventilation (CMV) and high-frequency oscillatory ventilation (HFO) on intraalveolar expression of the tumor necrosis factor-alpha (TNF-alpha) gene were studied in surfactant-depleted rabbits. After lung lavage with saline, 13 rabbits were administered either CMV (n = 6) or HFO (n = 7) for 1 h at an FiO2 of 1.0 and a mean airway pressure of 13 cm H2O. Lung lavage was then repeated. The rabbits' RNA was extracted from the lavage cells, and mRNA for TNF-alpha was quantitated by reverse-transcription polymerase chain reaction using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an internal standard. At 1 h of ventilation, PaO2 was slightly lower with CMV than HFO, while lavage cell counts and cytology were similar between the two groups. The ratio of TNF-alpha mRNA to GAPDH mRNA increased with CMV (control, 0.48 +/- 0.04 [SE] versus 1 h, 1.02 +/- 0.14, p < 0.01) but did not change with HFO (0.55 +/- 0.07 versus 0.73 +/- 0.09). In a separate series of experiments, ten surfactant-depleted rabbits continued to be ventilated for 4 h either by CMV (n = 5) or HFO (n = 5). Conventional mechanical ventilation resulted in a progressive hypoxemia, decreased lung compliance, increased number of neutrophils in lung lavage fluid, and substantial morphological changes including hyaline membrane formation and neutrophil accumulation, whereas HFO was associated with minimal changes in such physiological and pathological abnormalities. These results suggest that activation of alveolar macrophages and production of proinflammatory cytokines may play a pivotal role in the early stage of ventilator-induced lung injury, and that ventilator mode (CMV or HFO) substantially modulates macrophage activation and hence the degree of lung injury.

The effect of applying a high-frequency small-volume sinusoidal oscillation at the airway was investigated in anesthetized apneic beagle dogs (mean wt 11 kg, mean VDphys 6.6 +/- 0.6 ml/kg). Oscillations generated by a piston in a cylinder were transmitter to the lungs through an uncuffed endotracheal tube (4.5 mm ID, 6.0 mm OD), which allowed a substantial leak back through the vocal cords. A bias flow of fresh gas presented inspired air to the midtracheal level. The minimum distal airway pressure (measured at the end of the endotracheal tube) was maintained between 0 and 2 cmH2O. Peak airway pressures were 4-8 cmH2O. The optimal frequency for CO2 elimination was 15 Hz. Using volumes of 1.9 ml/kg (range 1.7-2.3) at this frequency the mean PaCO2 was 33.1 +/- 0.5 Torr. In four dogs breathing 100% O2 the PaO2 was 594 +/- 9 Torr during spontaneous ventilation and 580 +/- 9 Torr after 5 h of uninterrupted oscillation. In four experiments using room air the PaO2 was 95 +/- 5 Torr during spontaneous respiration and 106 +/- 1 Torr after 5 h of oscillation. In an additional seven studies there was no difference in mean cardiac output between oscillation and conventional mechanical ventilation. This study demonstrates that high-frequency small-volume oscillations can maintain gas exchange for many hours presumably by markedly enhancing the diffusivity of gases in the lung.

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To evaluate the role of tumor necrosis factor (TNF)-alpha in the pathogenesis of ventilator-induced lung injury, we 1) measured TNF-alpha production in the lung caused by conventional mechanical ventilation (CMV) and 2) evaluated the protective effect of anti-TNF-alpha antibody (Ab) in saline-lavaged rabbit lungs. After they received saline lung lavage, rabbits were intratracheally instilled with 1 mg/kg of polyclonal anti-TNF-alpha Ab in the high-dose group (n = 6), 0.2 mg/kg of anti-TNF-alpha Ab in the low-dose group (n = 6), serum IgG fraction in the Ab control group (n = 6), and saline in the saline control group (n = 7). Animals then underwent CMV for 4 h. Levels of TNF-alpha in lung lavage fluid were significantly higher after CMV than before in both control groups. Pretreatment with intratracheal instillation of high and low doses of anti-TNF-alpha Ab improved oxygenation and respiratory compliance, reduced the infiltration of leukocytes, and ameliorated pathological findings. CMV led to TNF-alpha production in the lungs, and intratracheal instillation of anti-TNF-alpha Ab attenuated CMV-induced lung injury in this model.

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The effect of steady-state increases in abdominal pressure (Pab) on cardiac performance was studied in seven acutely instrumented swine with pneumoperitoneum (PP). The animal was placed on volume-preset ventilation, and PP was created by air insufflation. Cardiac output (CO), right atrial (Pra), left atrial (Pla), pericardial (Ppe), and abdominal inferior vena cava pressures (Pivc) were measured while Pab was increased from baseline to 7.5, 15, and 30 mmHg (PP7.5, PP15, and PP30, respectively). Cardiac function curves of the right and left ventricle (RV and LV, respectively) were compared between baseline and PP30. CO presented biphasic changes, with an inital slight increase at PP7.5 followed by a fall at PP30. A significant discrepancy was observed between Pra and Pivc at PP15 and PP30, consistent with development of a "vascular waterfall." Transmural Pla (Pla - Ppe) showed parallel changes with CO, whereas transmural Pra (Pra - Ppe) exhibited a sustained increase. The RV cardiac-function curve was more depressed than was that of the LV at PP30; this suggests an increased RV afterload produced by the elevated airway pressure. These results support the hypothesis that our previously proposed concept of abdominal vascular zone conditions (M. Takata, R. A. Wise, and J. L. Robotham. J. Appl. Physiol. 69: 1961-1972, 1990) is also applicable to steady-state hemodynamic analyses. The abdominal zones appear to play an important role in determining CO, with increases in Pab, by modulating systemic venous return and the LV preload. Simultaneous measurements of Pra and Pivc may provide useful information in the hemodynamic care of patients with elevated Pab.