(CHEST 1999; 116:85S-86S)
In a model of ARDS in adult rabbits, we have compared the capacity of exogenous synthetic surfactant, administered by bolus or by lavage, to reexpand the lungs and to inhibit the inflammatory process. The surfactant used contained DPPC and POPG (3:1) together with palmitic acid (15% by weight) and the peptide KLLLLKLLLLKLLLLKLLLLK ([KL.sub.4]) that mimics SP-B. This surfactant preparation, termed [KL.sub.4]-surfactant, has been evaluated in animal studies and a clinical trial in 47 patients with idiopathic respiratory distress syndrome.
Pulmonary injury was induced by partial removal of intrinsic surfactant with five lavages with 0.9% saline solution, 30 mL/kg per lavage, followed by instillation of bacterial lipopolysaccharide (LPS), 0.25 [micro]g/kg. The rabbits were ventilated with 100% [O.sub.2] Initial [Pao.sub.2] levels [is greater than] 500 mm Hg fell to [is less than] 150 within 2 h. Three to 4 h after induction of injury, at a time when inflammation in the lungs was minimal, rabbits were divided into four treatment groups: group 1 (n = 10) received a bolus of [KL.sub.4] surfactant, 100 mg/kg divided between right and left sides; group 2 (n = 6) received two BALs with [KL.sub.4]-surfactant, 2.5 and 10 mg/mL, 20 mL/kg, divided between right and left sides, leaving, after termination of the lavage, an average of 92 mg [KL.sub.4]-surfactant per kilogram in the lungs; group 3 (n = 4) received two lavages with 0.9% saline solution, 20 mL/kg, divided between right and left sides; and group 4 (n = 7) received nothing. Rabbits were killed 6 to 8 h after LPS, ie, 3 to 4 h after treatment. Rabbits in groups 3 and 4 showed no rise in [Pao.sub.2] over the 6- to 7-h period of the study and the lungs were atelectatic (Fig 1, 2). Marked inflammatory exudate, with edema fluid, polymorphonuclear leukocytes (PMNs), and RBCs, was distributed throughout the lungs. Electron photomicrographs revealed the presence of PMNs and edema in the vascular spaces and alveoli, swelling of endothelial and epithelial cells, and random sloughing of epithelial cells, leaving denuded basement membranes. Group 1 rabbits, after bolus instillation of the surfactant, showed a rise in [Pao.sub.2] over a 1- to 2-h period to [is greater than] 300 mm Hg. The lungs were partly expanded, but large zones of atelectasis were present (Fig 2). Microscopically, the expanded zones showed bubble-like cleared zones in the alveoli otherwise filled with edema fluid and PMNs, and the atelectatic areas were filled with inflammatory exudate. Rabbits treated with [KL.sub.4]-surfactant by lavage (group 2) had a rapid and sustained increase in [Pao.sub.2] to [is greater than] 300 (Fig 1). The lungs revealed a uniform expansion (Fig 2) at pressures of 4 or 0 cm [H.sub.2]O, and microscopically there was minimal inflammatory exudate in the air-expanded alveoli. Postmortem BAL fluids in untreated (group 4) vs [KL.sub.4] surfactant lavaged rabbits (group 2) showed protein concentration of 8.3 [+ or -] 0.3 vs 2.2 [+ or -] 0.3 mg/mL, myeloperoxidase of 780 [+ or -] 60 vs 160 [+ or -] 30 U/mL, and PMN levels of 8,200 [+ or -] 300 PMNs per cubic millimeter vs 1,200 [+ or -] 400. The data indicated that lavage with [KL.sub.4]-surfactant reduced the amount of inflammatory exudate. Similar data showing a reduction of pulmonary inflammation induced by intratracheal instillation of meconium was noted in rabbits treated with surfactant, but not saline solution lavage.
[Figures 1-2 ILLUSTRATION OMITTED]
To determine the response to [KL.sub.4]-surfactant lavage during maximal acute inflammation, as opposed to the early inflammation of the previous study, five rabbits were allowed to sustain inflammatory injury from the LPS for 7.0 to 7.5 h before lavage with [KL.sub.4]-surfactant. Higher concentrations of proteins in edema fluid and PMN leukocytes were present in alveoli at the time of treatment. [KL.sub.4]-surfactant lavage (same as in group 2) resulted in a slower and modestly lower rise in [Pao.sub.2] than in rabbits receiving [KL.sub.4]-surfactant lavage at 3 to 4 h after LPS. The lungs again showed uniform expansion with levels of pressure of 4 cm [H.sub.2] O, but when the pressure was removed, the lungs underwent moderate collapse. Thus, in the presence of heightened inflammatory injury, the expansion was unstable. Microscopically, considerably greater amounts of PMNs and edema were present in the alveoli, especially in dependent zones of the lungs. Analysis of the functional activity of the surfactant (both [KL.sub.4]and intrinsic surfactant) removed from the lungs at the termination of the study was performed using a bubble surfactometer. Terminal saline solution lavages were obtained and the surfactant was isolated by differential sedimentation, washed one time, and adjusted to concentrations of 3.0 mg/mL (phospholipid weight). The surface tension at minimal bubble radius values were found to be 18.0 [+ or -] 2.7 millinewtons/m as opposed to 2.4 [+ or -] 3.1 and 2.2 [+ or -] 1.6 mN/m of native rabbit and [KL.sub.4]-surfactant, respectively. The surfactant removed from the lungs during the lavage procedure had activity of 16.1 [+ or -] 4.9 mN/m, indicating a rapid partial inhibition of the exogenous surfactant under these conditions of severe pulmonary inflammation.
These results indicate that lavage of LPS-injured lungs in adult rabbits with dilute [KL.sub.4]-surfactant produced a more uniform expansion of the lung and that the lungs contained considerably less inflammatory exudate than when the [KL.sub.4]-surfactant was administered by bolus. Since the presence of inflammatory exudate in the lungs may adversely affect the clinical course and patient survival in ARDS, the lavage method of administering surfactant appears to offer advantages not experienced by the bolus method of administration. In addition, these studies indicate that treatment of highly inflamed lungs results in a less complete recovery in comparison to treatment of moderately inflamed lungs, in part owing to inactivation of the exogenously administered surfactant.
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(*) From the Department of Immunology, The Scripps Research Institute, La Jolla, CA.
Correspondence to: Charles G. Cochrane, MD, Department of Immunology, IMM12, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 920,37; e-mail: cochrane@ scripps.edu
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