Three-dimensional model of surfactant replacement therapy

Abstract

Surfactant replacement therapy (SRT) involves instillation of a liquid-surfactant mixture directly into the lung airway tree. It is widely successful for treating surfactant deficiency in premature neonates who develop neonatal respiratory distress syndrome (NRDS). However, when applied to adults with acute respiratory distress syndrome (ARDS), early successes were followed by failures. This unexpected and puzzling situation is a vexing issue in the pulmonary community. A pressing question is whether the instilled surfactant mixture actually reaches the adult alveoli/acinus in therapeutic amounts. In this study, to our knowledge, we present the first mathematical model of SRT in a 3D lung structure to provide insight into answering this and other questions. The delivery is computed from fluid mechanical principals for 3D models of the lung airway tree for neonates and adults. A liquid plug propagates through the tree from forced inspiration. In two separate modeling steps, the plug deposits a coating film on the airway wall and then splits unevenly at the bifurcation due to gravity. The model generates 3D images of the resulting acinar distribution and calculates two global indexes, efficiency and homogeneity. Simulating published procedural methods, we show the neonatal lung is a well-mixed compartment, whereas the adult lung is not. The earlier, successful adult SRT studies show comparatively good index values implying adequate delivery. The later, failed studies used different protocols resulting in very low values of both indexes, consistent with inadequate acinar delivery. Reasons for these differences and the evolution of failure from success are outlined and potential remedies discussed.surfactant replacement therapy | pulmonary drug delivery | biological fluid mechanics | respiratory distress syndrome | biological transport processes S ince the early 1980s, surfactant replacement therapy (SRT) has been successful in applications to prematurely born neonates to treat their lack of surfactant production, which normally initiates late in gestation (1). Because surfactant reduces the surface tension between the air and the lung's liquid lining, its deficiency creates high surface tensions and collapsed, stiff lungs making them difficult to inflate. The resulting clinical entity of labored breathing and poor oxygenation is called neonatal respiratory distress syndrome (NRDS), or hyaline membrane disease, and is a risk of premature birth increasing with decreasing gestational age. The incidence is ∼1% of all births, equating to 40,000 cases annually in the United States (2). The mortality associated with NRDS dropped from 4,997 deaths in 1980 to 861 in 2005, and SRT played an important role in this success (3).SRT has also been tried in adults whose surfactant systems are compromised by acute respiratory distress syndrome (ARDS). ARDS results from overwhelming infections, mechanical injuries, and other insults either directly or indirectly to the lung. ARDS cases in the United States total 190,600 annually wit...

Splitting of a two-dimensional liquid plug at an airway bifurcation

“…We observed that the presence of a transverse gravitational field induces asymmetries in plug splitting, which are mitigated by an increase in the driving gas flow rate. This is in agreement with previous experimental and analytical models introduced by Zheng et al (2005) and Filoche et al (2015). We measured the asymmetry of the splitting using the splitting ratio, R S , and generated sufficient numerical data to allow for a nonlinear least-squares fit to that could be used to predict an approximate splitting ratio for a given roll angle and capillary number.…”

“…Note that the experimental and theoretical results from Zheng et al (2005) are for dry walls in the daughters and the two-dimensional model presented here and the one-dimensional model in Filoche et al (2015) have wet walls in the daughters. Since the Bond number used to generate the results presented in figure 5 and table 1, and the nonlinear fitting is Bo = 2.5 and the Bond number used in the dataset from Zheng et al (2005) is Bo = 1.26, we must adjust the roll angle before we can compare results.…”

“…To assess the accuracy of our model, we compare the results from the twodimensional model with the experimental and one-dimensional results from the LB-400-X dataset in Zheng et al (2005) and the one-dimensional model from Filoche et al (2015). Note that the experimental and theoretical results from Zheng et al (2005) are for dry walls in the daughters and the two-dimensional model presented here and the one-dimensional model in Filoche et al (2015) have wet walls in the daughters.…”

“…A major result of that analysis was to offer an explanation of why SRT applied to adults began with successful clinical trials (Gregory et al 1997), but later experienced failed clinical studies (Spragg et al 2004(Spragg et al , 2011 possibly due to alterations of the fluid mechanical parameters. A goal of this work is to develop an improved plug splitting model that can be incorporated into the organ-level model used in Filoche et al (2015).…”

“…In Filoche et al (2015), a one-dimensional analytical model was used to generate a three-dimensional, organ-level model of SRT. In addition, numerical models on the effects of inertia (Fujioka & Grotberg 2004), gravity (Jensen et al 1987;, material properties (Zamankhan et al 2012) and surfactant (Fujioka & Grotberg 2005) on the propagation of liquid plugs through two-dimensional channels and axisymmetric tubes have been performed.…”