Showing papers by "Gordon R. Bernard published in 1984"

Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function.

Abstract: Oxygen free radicals released during endotoxemia may contribute to the lung injury of the adult respiratory distress syndrome (ARDS). As this syndrome occurs frequently after gram-negative sepsis in humans, we studied the effect of intravenous N-acetylcysteine (NAC), a free radical scavenger, upon the endotoxin (E)-induced model of ARDS in awake sheep. In vivo studies demonstrated that NAC attenuates the endotoxin-induced rise in pulmonary artery pressure (62 +/- 3 torr with E control vs. 43 +/- 3 torr for E + NAC), and markedly diminishes the rise in lymph flow at 1 h (8.5 +/- 1.2 vs 4.5 +/- 0.6 ml/15 min) and 4 h (5.0 +/- 0.6 vs. 3.3 +/- 0.4 ml/15 min), respectively, for E control vs. E + NAC. NAC also markedly attenuated the alterations in lung mechanics after endotoxemia. Dynamic compliance at 2 h after endotoxemia was 44 +/- 6% of base line for E vs. 76 +/- 10% of base line for E + NAC. Resistance to airflow across the lung at 1 h postendotoxin was 811 +/- 280% of base line for E vs. 391 +/- 233% of base line for E + NAC. NAC substantially reduced the 1 h postendotoxin rise in lymph concentrations of thromboxane B2 (8.29 +/- 3.28 vs. 2.75 +/- 1.93 ng/ml for E vs. E + NAC) and 6-keto-prostaglandin-F1 alpha (0.91 +/- 0.27 vs. 0.23 +/- 0.12 ng/ml for E vs. E + NAC). In addition, in vitro studies were performed which revealed NAC to be a potent free radical scavenger in both biologic and nonbiologic free radical generating systems. NAC decreased phorbol-stimulated granulocyte aggregation in a concentration-dependent manner in vitro. Minimal effects were observed, however, upon leukocyte degranulation at the concentrations of NAC achieved during the in vivo tests. Thus, NAC significantly attenuated all monitored pathophysiologic changes in the endotoxin model of ARDS in sheep, possibly by its ability to scavenge toxic oxygen free radicals. A direct impairment of the ability of inflammatory cells to generate oxygen radicals cannot be ruled out.

Effects of left atrial pressure elevation and histamine infusion on lung lymph in awake sheep

Abstract: To study the mechanism by which infused histamine increases lung fluid and solute exchange, the effects of left atrial pressure elevation (using a Foley catheter positioned at the mitral valve orifice) on lung lymph flow and protein content were studied in the presence and absence of histamine infusion in nine chronically instrumented unanesthetized sheep. In six sheep, histamine infusion (1-3 micrograms X kg-1 X min-1) was begun 2 h before increasing left atrial pressure by 10 and 20 cmH2O for 3 h each. Control experiments were performed on the same sheep to study the effects of left atrial pressure elevation alone and histamine infusion alone. Left atrial pressure elevation in the presence of histamine infusion did not cause a disproportionate increase in lung lymph flow nor was the lymph-to-plasma protein concentration ratio (L/P) different from left atrial pressure elevation alone. This argues against the presence of increased microvascular permeability at the time of these elevations. In three sheep, left atrial pressure was elevated by 20 cmH2O, and then histamine was infused at 2 micrograms X kg-1 X min-1. Histamine infusion caused a transient increase in L/P and a large increase in lymph flow, findings like those we have previously taken to represent an increase in microvascular permeability. However, L/P decreased to values comparable to those seen with elevated left atrial pressure alone. These observations suggest that histamine infusion may have a biphasic effect on lung lymph. There is an early (1-3 h) transient increase in lymph protein clearance that could result from a transient increase in permeability followed by a sustained increase in microvascular surface area. The early response is difficult to interpret because the changes are transient and could be affected by alterations outside the lung.

Effect of aerosol histamine on lung lymph in awake sheep.

Abstract: This study examined the effect of aerosol histamine on lung lymph in the awake sheep. Eleven sheep were chronically instrumented for measurement of lung lymph, lung mechanics, and vascular pressures. Aerosol histamine was given by use of a Collison nebulizer and delivered via a tracheostomy tube. Five breaths of a 30 mg/ml histamine solution caused lung lymph flow (QL) to increase from a base line of 5.5 +/- 0.5 (SE) ml/h to 14.3 +/- 1.5 (P less than 0.05) and the lymph-to-plasma protein concentration ratio (L/P) to increase from 0.63 +/- 0.02 to 0.72 +/- 0.02 (P less than 0.05). The concentration of aerosol histamine required to change QL by 30% (ED130QL) was determined by giving increasing concentrations of aerosol histamine every 15 min. The mean ED130QL was 22.2 mg/ml. The dose of histamine required to increase QL by 30% did not correlate (r = 0.04, n = 7) with the dose required to decrease dynamic compliance by 35%. The increase in QL lasted 100 +/- 19 min. Hourly exposure to five breaths of 30 mg/ml for 5 h caused a sustained increase in QL in two sheep and a waning effect in two sheep. The combination of aerosol histamine and elevated microvascular pressure (achieved by inflating a Foley catheter situated in the left atrium) caused changes in QL and L/P not totally consistent with the hypothesis that histamine increased pulmonary vascular permeability. Increased vascular permeability in the bronchial circulation was considered a likely explanation of the data.