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Background: Vigorous spontaneous effort can potentially worsen lung injury. This study hypothesized that the prone position would diminish a maldistribution of lung stress and inflation after diaphragmatic contraction and reduce spontaneous effort, resulting in less lung injury. Methods: A severe acute respiratory distress syndrome model was established by depleting surfactant and injurious mechanical ventilation in 6 male pigs ("mechanism" protocol) and 12 male rabbits ("lung injury" protocol). In the mechanism protocol, regional inspiratory negative pleural pressure swing (intrabronchial balloon manometry) and the corresponding lung inflation (electrical impedance tomography) were measured with a combination of position (supine or prone) and positive end-expiratory pressure (high or low) matching the intensity of spontaneous effort. In the lung injury protocol, the intensities of spontaneous effort (esophageal manometry) and regional lung injury were compared in the supine position versus prone position. Results: The mechanism protocol (pigs) found that in the prone position, there was no ventral-to-dorsal gradient in negative pleural pressure swing after diaphragmatic contraction, irrespective of the positive end-expiratory pressure level (-10.3 +/- 3.3 cm H2O vs. -11.7 +/- 2.4 cm H2O at low positive end-expiratory pressure, P = 0.115; -10.4 +/- 3.4 cm H2O vs. -10.8 +/- 2.3 cm H2O at high positive end-expiratory pressure, P = 0.715), achieving homogeneous inflation. In the supine position, however, spontaneous effort during low positive end-expiratory pressure had the largest ventral-to-dorsal gradient in negative pleural pressure swing (-9.8 +/- 2.9 cm H2O vs. -18.1 +/- 4.0 cm H2O, P < 0.001), causing dorsal overdistension. Higher positive end-expiratory pressure in the supine position reduced a ventral-to-dorsal gradient in negative pleural pressure swing, but it remained (-9.9 +/- 2.8 cm H2O vs. -13.3 +/- 2.3 cm H2O, P < 0.001). The lung injury protocol (rabbits) found that in the prone position, spontaneous effort was milder and lung injury was less without regional difference (lung myeloperoxidase activity in ventral vs. dorsal lung, 74.0 +/- 30.9 [mu]m [middle dot] min-1 [middle dot] mg-1 protein vs. 61.0 +/- 23.0 [mu]m [middle dot] min-1 [middle dot] mg-1 protein, P = 0.951). In the supine position, stronger spontaneous effort increased dorsal lung injury (lung myeloperoxidase activity in ventral vs. dorsal lung, 67.5 +/- 38.1 [mu]m [middle dot] min-1 [middle dot] mg-1 protein vs. 167.7 +/- 65.5 [mu]m [middle dot] min-1 [middle dot] mg-1 protein, P = 0.003). Conclusions: Prone position, independent of positive end-expiratory pressure levels, diminishes a maldistribution of lung stress and inflation imposed by spontaneous effort and mitigates spontaneous effort, resulting in less effort-dependent lung injury. What We Already Know about This Topic [ABSTRACT FROM AUTHOR]

Background: Lower tidal volumes are increasingly used in acute respiratory distress syndrome, but mortality has changed little in the last 20 yr. Therefore, in addition to ventilator settings, it is important to target molecular mediators of injury. Sepsis and other inflammatory states increase circulating concentrations of Gas6, a ligand for the antiinflammatory receptor Axl, and of a soluble decoy form of Axl. We investigated the effects of lung stretch on Axl signaling.Methods: We used a mouse model of early injury from high tidal volume and assessed the effects of inhibiting Axl on in vivo lung injury (using an antagonist R428, n = 4/group). We further determined the effects of stretch on Axl activation using in vitro lung endothelial cells.Results: High tidal volume caused mild injury (compliance decreased 6%) as intended, and shedding of the Axl receptor (soluble Axl in bronchoalveolar fluid increased 77%). The Axl antagonist R428 blocked the principal downstream Axl target (suppressor of cytokine signaling 3 [SOCS3]) but did not worsen lung physiology or inflammation. Cyclic stretch in vitro caused Axl to become insensitive to activation by its agonist, Gas6. Finally, in vitro Axl responses were rescued by blocking stretch-activated calcium channels (using guanidinium chloride [GdCl3]), and the calcium ionophore ionomycin replicated the effect of stretch.Conclusions: These data suggest that lung endothelial cell overdistention activates ion channels, and the resultant influx of Ca inactivates Axl. Downstream inactivation of Axl by stretch was not anticipated; preventing this would be required to exploit Axl receptors in reducing lung injury. [ABSTRACT FROM AUTHOR]

Background: In supine patients with acute respiratory distress syndrome, the lung typically partitions into regions of dorsal atelectasis and ventral aeration ("baby lung"). Positive airway pressure is often used to recruit atelectasis, but often overinflates ventral (already aerated) regions. A novel approach to selective recruitment of dorsal atelectasis is by "continuous negative abdominal pressure."Methods: A randomized laboratory study was performed in anesthetized pigs. Lung injury was induced by surfactant lavage followed by 1 h of injurious mechanical ventilation. Randomization (five pigs in each group) was to positive end-expiratory pressure (PEEP) alone or PEEP with continuous negative abdominal pressure (-5 cm H2O via a plexiglass chamber enclosing hindlimbs, pelvis, and abdomen), followed by 4 h of injurious ventilation (high tidal volume, 20 ml/kg; low expiratory transpulmonary pressure, -3 cm H2O). The level of PEEP at the start was ≈7 (vs. ≈3) cm H2O in the PEEP (vs. PEEP plus continuous negative abdominal pressure) groups. Esophageal pressure, hemodynamics, and electrical impedance tomography were recorded, and injury determined by lung wet/dry weight ratio and interleukin-6 expression.Results: All animals survived, but cardiac output was decreased in the PEEP group. Addition of continuous negative abdominal pressure to PEEP resulted in greater oxygenation (PaO2/fractional inspired oxygen 316 ± 134 vs. 80 ± 24 mmHg at 4 h, P = 0.005), compliance (14.2 ± 3.0 vs. 10.3 ± 2.2 ml/cm H2O, P = 0.049), and homogeneity of ventilation, with less pulmonary edema (≈10% less) and interleukin-6 expression (≈30% less).Conclusions: Continuous negative abdominal pressure added to PEEP reduces ventilator-induced lung injury in a pig model compared with PEEP alone, despite targeting identical expiratory transpulmonary pressure. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the consequences for acute lung injury and hypothesized that priming before injurious mechanical ventilation with a clinically relevant model of sepsis would be linked with greater expression of inflammatory mediators and a functional worsening of lung physiology. It measured the mediators associated with sepsis and lung injury in the plasma. It concluded that there is significant discordance among systemic and pulmonary mediators.

The article discusses a study which examined the association of continuous negative abdominal pressure using an iron lung on the augmentation of positive end-expiratory pressure in recruiting atelectatic lung. Analyzing the results of a computerized tomography suggests that continuous negative abdominal pressure was an effective adjunct to positive end-expiratory pressure for recruiting atelectasis in dependent and diaphragmatic regions.

Background: Multiple interventions have been tested in models of cardiopulmonary resuscitation (CPR) to optimize drug use, chest compressions, and ventilation. None has studied the effects of positive end-expiratory pressure (PEEP) on outcome. We hypothesized that because PEEP can reverse pulmonary atelectasis, lower pulmonary vascular resistance, and potentially improve cardiac output, its use during CPR would increase survival., Methods: Anesthetized Sprague-Dawley rats were exposed to 1 min of asphyxial cardiac arrest. Resuscitation was standardized and consisted of chest compressions, oxygen (Fio(2) 1.0), and IV epinephrine 30 microg/kg (Series 1) and 10 microg/kg (Series 2). Left ventricular function was assessed by echocardiography (Series 1), and animals were randomized to receive either 5 cm H(2)O PEEP or zero PEEP at commencement of CPR and throughout resuscitation. Survival was defined as the presence of a spontaneous circulation 60 or 120 min (Series 2) after initial resuscitation., Results: There were no baseline differences between the groups. In Series 1, administration of 5 cm H(2)O PEEP (Fio(2) 1.0 and 0.21) was associated with improved survival compared with zero PEEP (7/9 and 6/6 vs 0/9, P < 0.01 and <0.001, respectively). Application of 5 cm H(2)O PEEP (Fio(2) 1.0) increased left ventricular end-diastolic area, systemic oxygenation, and functional residual capacity. Use of PEEP during CPR did not adversely affect left ventricular systolic function or arterial blood pressure. The outcome differences were not due to increased oxygenation because the rank order of survival was 5 cm H(2)O PEEP (Fio(2) 1.0) approximately 5 cm H(2)O PEEP (Fio(2) 0.21) > zero PEEP (Fio(2) 1.0), whereas the rank order of Pao(2) was 5 cm H(2)O PEEP (Fio(2) 1.0) > 5 cm H(2)O PEEP (Fio(2) 0.21) approximately zero PEEP (Fio(2) 1.0). In an additional series in which epinephrine 10 microg/kg was used (Series 2), the survival was 100% with no beneficial effects of PEEP., Conclusion: In asphyxial cardiac arrest in a small rodent model, continuous application of PEEP (5 cm H(2)O) during and after CPR had beneficial effects on survival that were independent of oxygenation and without adverse cardiovascular effects.

Epinephrine may be detrimental in cardiac arrest. In this laboratory study we sought to characterize the effect of epinephrine and concomitant calcium channel blockade on postresuscitation myocardial performance after brief asphyxial cardiac arrest. Anesthesized rats were disconnected from mechanical ventilation, resulting in cardiac arrest. Resuscitation was attempted after 1 min with mechanical ventilation, oxygen, chest compressions, and IV medication. In experimental series 1 and 2, animals were allocated to 10 or 30 microg/kg epinephrine or 0.9% saline. In series 3, animals received 30 microg/kg of epinephrine and were randomized to 0.1 mg/kg of verapamil or to 0.9% saline. In series 1 and 3, left ventricular function was assessed using transthoracic echocardiography. In series 2, left atrial pressure was measured. Epinephrine was associated with increased mortality (0/8 [0%] in controls, 4/12 [33.3%] in 10 microg/kg animals, and 16/22 [72.8%] in 30 microg/kg animals; P < 0.05), hypertension (P < 0.001), tachycardia (P = 0.004), early transient left atrial hypertension, and dose-related reduction in left ventricular end diastolic diameter (P < 0.05). Verapamil prevented mortality associated with large-dose epinephrine (0% versus 100%) and attenuated early diastolic dysfunction and postresuscitation hypertension (P = 0.001) without systolic dysfunction. Epinephrine appears to be harmful in the setting of brief cardiac arrest after asphyxia.

Objective: Deliberate elevation of PaCO2 (therapeutic hypercapnia) protects against lung injury induced by lung reperfusion and severe lung stretch. Conversely, hypocapnic alkalosis causes lung injury and worsens lung reperfusion injury. Alterations in lung surfactant may contribute to ventilator-associated lung injury. The potential for CO2 to contribute to the pathogenesis of ventilator-associated lung injury at clinically relevant tidal volumes is unknown. We hypothesized that: 1) hypocapnia would worsen ventilator-associated lung injury, 2) therapeutic hypercapnia would attenuate ventilator-associated lung injury; and 3) the mechanisms of impaired compliance would be via alteration of surfactant biochemistry., Design: Randomized, prospective animal study., Setting: Research laboratory of university-affiliated hospital., Subjects: Anesthetized, male New Zealand Rabbits., Interventions: All animals received the same ventilation strategy (tidal volume, 12 mL/kg; positive end-expiratory pressure, 0 cm H2O; rate, 42 breaths/min) and were randomized to receive FiCO2 of 0.00, 0.05, or 0.12 to produce hypocapnia, normocapnia, and hypercapnia, respectively., Measurements and Main Results: Alveolar-arterial oxygen gradient was significantly lower with therapeutic hypercapnia, and peak airway pressure was significantly higher with hypocapnic alkalosis. However, neither static lung compliance nor surfactant chemistry (total surfactant, aggregates, or composition) differed among the groups., Conclusions: At clinically relevant tidal volume, CO2 modulates key physiologic indices of lung injury, including alveolar-arterial oxygen gradient and airway pressure, indicating a potential role in the pathogenesis of ventilator-associated lung injury. These effects are surfactant independent.