Rationale: In the original 1974 in vivo study of ventilator-induced lung injury, Webb and Tierney reported that high Vt with zero positive end-expiratory pressure caused overwhelming lung injury, subsequently shown by others to be due to lung shear stress. Objectives: To reproduce the lung injury and edema examined in the Webb and Tierney study and to investigate the underlying mechanism thereof. Methods: Sprague-Dawley rats weighing approximately 400 g received mechanical ventilation for 60 minutes according to the protocol of Webb and Tierney (airway pressures of 14/0, 30/0, 45/10, 45/0 cm H₂O). Additional series of experiments (20 min in duration to ensure all animals survived) were studied to assess permeability (n = 4 per group), echocardiography (n = 4 per group), and right and left ventricular pressure (n = 5 and n = 4 per group, respectively). Measurements and Main Results: The original Webb and Tierney results were replicated in terms of lung/body weight ratio (45/0 > 45/10 ≈ 30/0 ≈ 14/0; P < 0.05) and histology. In 45/0, pulmonary edema was overt and rapid, with survival less than 30 minutes. In 45/0 (but not 45/10), there was an increase in microvascular permeability, cyclical abolition of preload, and progressive dilation of the right ventricle. Although left ventricular end-diastolic pressure decreased in 45/10, it increased in 45/0. Conclusions: In a classic model of ventilator-induced lung injury, high peak pressure (and zero positive end-expiratory pressure) causes respiratory swings (obliteration during inspiration) in right ventricular filling and pulmonary perfusion, ultimately resulting in right ventricular failure and dilation. Pulmonary edema was due to increased permeability, which was augmented by a modest (approximately 40%) increase in hydrostatic pressure. The lung injury and acute cor pulmonale is likely due to pulmonary microvascular injury, the mechanism of which is uncertain, but which may be due to cyclic interruption and exaggeration of pulmonary blood flow.

Rationale: Asphyxiated neonates with hypoxic ischemic encephalopathy (HIE) are at risk of myocardial dysfunction; however, echocardiography studies are limited and little is known about the relationship between hemodynamics and brain injury. Objectives: To analyze the association between severity of myocardial dysfunction and adverse outcome as defined by the composite of death and/or abnormal magnetic resonance imaging. Methods: Neonates with HIE undergoing therapeutic hypothermia were enrolled. Participants underwent echocardiography at 24 hours, 72 hours (before rewarming), and 96 hours (after rewarming). Cerebral hemodynamics were monitored by near-infrared spectroscopy and middle cerebral artery Doppler. Measurements and Main Results: Fifty-three patients with a mean gestation and birthweight of 38.8 ± 2.0 weeks and 3.33 ± 0.6 kg, respectively, were recruited. Thirteen patients (25%) had mild encephalopathy, 27 (50%) had moderate encephalopathy, and 13 (25%) had severe encephalopathy. Eighteen patients (34%) had an adverse outcome. Severity of cardiovascular illness (P < 0.001) and severity of neurologic insult (P = 0.02) were higher in neonates with adverse outcome. Right ventricle (RV) systolic performance at 24 hours was substantially lower than published normative data in all groups. At 24 hours, lower tricuspid annular plane systolic excursion (P = 0.004) and RV fractional area change (P < 0.001), but not pulmonary hypertension, were independently associated with adverse outcome on logistic regression. High brain regional oxygen saturation (P = 0.007) and low middle cerebral artery resistive index (P = 0.04) were associated with RV dysfunction on post hoc analysis. Conclusions: RV dysfunction is associated with the risk of adverse outcome in asphyxiated patients with HIE undergoing hypothermia. Echocardiography may be a valuable diagnostic and prognostic tool in this vulnerable population.

Rationale: Ventilator management in acute respiratory distress syndrome usually focuses on setting parameters, but events occurring at ventilator disconnection are not well understood. Objectives: To determine if abrupt deflation after sustained inflation causes lung injury. Methods: Male Sprague-Dawley rats were ventilated (low Vt, 6 ml/kg) and randomized to control (n = 6; positive end-expiratory pressure [PEEP], 3 cm H2O; 100 min) or intervention (n = 6; PEEP, 3–11 cm H2O over 70 min; abrupt deflation to zero PEEP; ventilation for 30 min). Lung function and injury was assessed, scanning electron microscopy performed, and microvascular leak timed by Evans blue dye (n = 4/group at 0, 2, 5, 10, and 20 min after deflation). Hemodynamic assessment included systemic arterial pressure (n = 6), echocardiography (n = 4), and right (n = 6) and left ventricular pressures (n = 6). Measurements and Main Results: Abrupt deflation after sustained inflation (vs. control) caused acute lung dysfunction (compliance 0.48 ± 1.0 vs. 0.82 ± 0.2 m/cm H2O, oxygen saturation as measured by pulse oximetry 67 ± 23.5 vs. 91 ± 4.4%; P < 0.05) and injury (wet/dry ratio 6.1 ± 0.6 vs. 4.6 ± 0.4; P < 0.01). Vascular leak was absent before deflation and maximal 5–10 minutes thereafter; injury was predominantly endothelial. At deflation, left ventricular preload, systemic blood pressure, and left ventricular end-diastolic pressure increased precipitously in proportion to the degree of injury. Injury caused later right ventricular failure. Sodium nitroprusside prevented the increase in systemic blood pressure and left ventricular end-diastolic pressure associated with deflation, and prevented injury. Injury did not occur with gradual deflation. Conclusions: Abrupt deflation after sustained inflation can cause acute lung injury. It seems to be mediated by acute left ventricular decompensation (caused by increased left ventricular preload and afterload) that elevates pulmonary microvascular pressure; this directly injures the endothelium and causes edema, which is potentiated by the surge in pulmonary perfusion.