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Surfactant Lavage Treatment in a Model of Respiratory Distress Syndrome^*

^* 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 92037; e-mail: cochrane{at}scripps.edu

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 (KL₄) that mimics SP-B.¹ This surfactant preparation, termed KL₄-surfactant, has been evaluated in animal studies² and a clinical trial in 47 patients with idiopathic respiratory distress syndrome.³

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 µg/kg. The rabbits were ventilated with 100% O₂. Initial PaO₂ levels > 500 mm Hg fell to < 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 KL₄-surfactant, 100 mg/kg divided between right and left sides; group 2 (n = 6) received two BALs with KL₄-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 KL₄-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 PaO₂ 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 PaO₂ over a 1- to 2-h period to > 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 KL₄-surfactant by lavage (group 2) had a rapid and sustained increase in PaO₂ to > 300 (Fig 1) . The lungs revealed a uniform expansion (Fig 2) at pressures of 4 or 0 cm H₂O, and microscopically there was minimal inflammatory exudate in the air-expanded alveoli. Postmortem BAL fluids in untreated (group 4) vs KL₄-surfactant lavaged rabbits (group 2) showed protein concentration of 8.3 ± 0.3 vs 2.2 ± 0.3 mg/mL, myeloperoxidase of 780 ± 60 vs 160 ± 30 U/mL, and PMN levels of 8,200 ± 300 PMNs per cubic millimeter vs 1,200 ± 400. The data indicated that lavage with KL₄-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.⁴

View larger version (24K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Rabbits received bronchoalveolar saline solution lavages, followed by intratracheal administration of LPS to induce pulmonary injury as noted in text. Rabbits were followed up for 3.6 h before treatment with lavage with saline solution or dilute KL4-surfactant as defined in text, or for 7 h, in order to allow development of maximal inflammation before KL4-surfactant lavage.

View larger version (81K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Photographs of lungs of injured rabbits, untreated, or after treatment with KL4-surfactant by bolus or lavage. Lungs of injured rabbits that were untreated (left) or lavaged with saline solution (not shown) were nearly totally collapsed. Lungs of injured rabbits receiving treatment with a bolus of KL4-surfactant (center) showed regions of expansion and atelectasis, while injured lungs lavaged with dilute KL4-surfactant (right) showed generalized, uniform expansion.

These results indicate that lavage of LPS-injured lungs in adult rabbits with dilute KL₄-surfactant produced a more uniform expansion of the lung and that the lungs contained considerably less inflammatory exudate than when the KL₄-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.

References

1. Cochrane, CG, Revak, SD (1991) Pulmonary surfactant protein B (SP-B): structure-function relationships. Science 254,566-568[Abstract/Free Full Text]
2. Revak, SD, Merritt, TA, Cochrane, CG, et al (1996) Efficacy of synthetic peptide-containing surfactant in the treatment of respiratory distress syndrome in preterm infant rhesus monkeys. Pediatr Res 39,715-724[ISI][Medline]
3. Cochrane, CG, Revak, SD, Merritt, TA, et al (1996) The efficacy and safety of KL₄-surfactant in preterm infants with RDS. Am J Respir Crit Care Med 153,404-410[Abstract]
4. Cochrane, CG, Revak, SD, Merritt, TA, et al (1998) Bronchoalveolar lavage with KL₄-surfactant in models of meconium aspiration syndrome. Pediatr Res 44,1-11[ISI][Medline]

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