ABSTRACT. We studied the effect of positive pressure mechanical ventilation on the pulmonary clearance (k) of 99mtechnetium diethylenetriamine pentaacetate (99mTc-DTPA) in lambs. Twelve lambs were anesthetized and ventilated with air at 25 breathslmin and with end expiratory airway pressure at 2 cm H20 for a minimum period of 8 h. Four lambs received normal pressure ventilation with peak airway pressure at 17 f 3 cm Hz0 and eight received high pressure ventilation with peak airway pressure at 41 f 2 cm H20. Three 99mTc-DTPA clearance studies were done in each lamb; at the start and after 4 and 8 h of mechanical ventilation. All clearance measurements were made at normal peak airway pressure 16 f 3 cm H20. Baseline clearance rate, k, (n = 12) was 1.2 f 0.5% (SD). During normal pressure ventilation, k increased from 1.0 2 0.5 to 2.2 f 0.8% after 4 h and to 2.7 f 0.8% after 8 h. During high pressure ventilation, k increased from 1.4 f 0.4 to 3.6 f 1.3% after 4 h and to 4.8 f 1.2% after 8 h. To see if 8 h of mechanical ventilation was associated with other evidence of lung epithelial injury, we determined the movement of IlZ5 labeled albumin from the interstitium into the airspace, lung water content, lung histology, and lung lavage constituents in the lambs at the end of the study. All variables were similar between ventilated and four unventilated lambs, except the percentage of alveolar macrophages recovered by lavage, which was more in the ventilated lambs. We conclude that positive pressure mechanical ventilation results in a continuous increase in the pulmonary clearance of 99mTc-DTPA and the duration and magnitude of positive pressure applied tended to increase the value of k. ventilation (I), it is apparent that ventilator-induced barotrauma can also occur in the absence of acute lung injury (2, 3). Hyperventilation with assisted mechanical ventilation is frequently used as a therapeutic maneuver to reduce pulmonary vascular resistance in newborn infants with pulmonary hypertension (4) and to reduce cerebral edema in newborn and pediatric patients in the intensive care unit. In these cases where hyperventilation is used to produce hypocarbia and alkalosis, the lung parenchyma may be structually normal to begin with, but subsequently become injured from prolonged barotrauma (5). High peak airway pressures have been shown in animals to injure both the airway (6) and alveolar epithelium (7,8), as well as the capillary endothelium (9).The measurement of the pulmonary clearance of aerosolized solutes such as 99mTc-DTPA has been used in the assessment of the integrity of the pulmonary epithelium. In a variety of lung diseases such as adult respiratory distress syndrome (lo), interstitial lung disease (1 I), and Pneumocystis carinii infection (12) where damage to the pulmonary epithelium is present, the detection of an accelerated clearance rate of 99mTc-DTPA has been attributed to an increase in pulmonary epithelial permeability. However, other maneuvers such as an increase in lung volume (1 3) and acute exposure ...