Surfactant therapy for acute lung injury and acute respiratory distress syndrome

Abstract

This article examines exogenous lung surfactant replacement therapy and its usefulness in mitigating clinical acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Surfactant therapy is beneficial in term infants with pneumonia and meconium aspiration lung injury, and in children up to age 21 years with direct pulmonary forms of ALI/ARDS. However, extension of exogenous surfactant therapy to adults with respiratory failure and clinical ALI/ARDS remains a challenge. This article reviews clinical studies of surfactant therapy in pediatric and adult patients with ALI/ARDS, focusing on its potential advantages in patients with direct pulmonary forms of these syndromes.

FIGURE 1. Surfactant production and recycling in the normal alveolus (Panel A) and changes in surfactant metabolism in acute pulmonary injury (Panel B)

In the normal alveolus (Panel A), surfactant is synthesized and packaged into lamellar bodies in the cytoplasm of type II epithelial cells. The exocytotic lamellar body organelles secrete surfactant into the alveolar hypophase, where it forms tubular myelin and other active large lipid-protein aggregates. Surfactant lipids and proteins adsorb to the alveolar air-liquid interface as a highly-active film that lowers and varies surface tension during breathing. Surfactant activity is physiologically essential in reducing the work of breathing, stabilizing alveoli against collapse and over-distension, and lowering the hydrostatic driving force for pulmonary edema. In injured lungs (Panel B), multiple inflammatory cytokines and chemokines can influence the metabolism of alveolar surfactant (synthesis, secretion, reuptake, recycling) by altering type II pneumocyte function and responses (Panel B). Surfactant metabolism in type II cells can also be altered as a result of type I cell injury, since the former are stem cells for the alveolar epithelium. In addition, inflammation and permeability injury can lead to the presence of reactive species and other substances in the interstitium and alveoli that can interact chemically or physically with lung surfactant lipids and proteins. Examples of specific pathways by which the surface-active function of alveolar surfactant can be impaired during acute pulmonary injury are described further in Figure 2. TNF is tumor necrosis factor.

FIGURE 2. Causes of decreases in lung surfactant surface-active function during acute pulmonary injury (ALI/ARDS)

Although available amounts of surfactant may be decreased as a result of type II cell injury in some forms of ALI/ARDS, surfactant deficiency is typically much less prominent than surfactant dysfunction (reduced surface activity). Dysfunction of alveolar surfactant can result from several pathways in injured lungs, with one prominent mechanism being inactivation from biophysical interactions with inhibitor compounds like plasma/blood proteins or cellular lipids that enter the alveoli in edema fluid. Alveolar surfactant can also be chemically degraded or modified by substances present in the innate inflammatory response such as lytic enzymes (proteases, phospholipases) or reactive oxygen/nitrogen species. In addition, injury-induced depletion or compositional changes in large alveolar surfactant aggregates may lead to a decrease in overall surface-active function because such aggregates normally have the highest apoprotein content and surface activity. Modified from Reference ^, .

FIGURE 3. The effect of exogenous surfactant on mortality in infants with NRDS (adapted from)

The figure shows the results of meta-analyses of data on infant mortality from clinical trials of surfactant replacement therapy with modified bovine surfactant, porcine surfactant extract, and human amniotic fluid surfactant extract. Overall, treatment with animal-derived surfactant extracts significantly decreased the risk of neonatal mortality (typical relative risk 0.68, 95%CI 0.57, 0.82; typical risk difference −0.09, 95% CI −0.13, −0.05). The number of patients needed to be treated to prevent one neonatal death was 11 (95% CI 8, 20 Significant heterogeneity was not noted between the trials analyzed. Meta analysis also indicated that the subgroup of trials using modified bovine surfactant extract also had a significant decrease in the risk of neonatal mortality (typical relative risk 0.70, 95% CI 0.57, 0.86; typical risk difference −0.08, 95% CI −0.12, −0.03). In addition, the trial of porcine surfactant extract (European 1988) individually demonstrated a decrease in the risk of mortality (relative risk 0.61, 95% CI 0.41, 0.92).

FIGURE 4. Improvements in oxygenation index (OI) after instillation of exogenous surfactant in children with ALI/ARDS

Patients ranging in age from 1 day through 18 years in eight pediatric intensive care units were randomized to surfactant or control groups in the 1999 study of Willson et al . Surfactant-treated patients received a dose of Infasurf® of 80 mL/m² body surface (70 mg/kg body weight) by tracheal instillation during hand-ventilation with 100% oxygen (arrow). Control patients received hand-ventilation and 100% oxygen alone. Ten of 21 surfactant-treated patients received a second dose 12 or more hours after the first. Significant improvements were found in lung function in patients receiving exogenous surfactant therapy. OI is defined as: 100 × MAP × FiO₂/PaO₂, where MAP = mean airway pressure; FiO₂ = fraction of inspired oxygen; PaO₂ = arterial partial pressure of oxygen. Data are Mean ± S.D. from Willson et al .