Perlman Lung Mechanics Lab

Biomechanics • Pulmonary Physiology • Surface Tension • Surfactant Biophysics

Research Findings

In respiratory distress model, intravenous suflorhodamine B reduces surface tension, improves oxygenation and reduces VILI

In a respiratory distress model, intravenous SRB passes through the alveolar capillary barrier in the same locations as edema liquid, thus lowers T specifically in injured lung regions. Intravenous SRB marginally reduces global permeability, at the expense of marginally increasing permeability in already-injured regions; markedly improves oxygenation; and reduces VILI. Intravenous SRB has strong potential as a therapy that would help respiratory distress patients, including novel coronavirus patients, avoid mechanical ventilation and survive.

• Wu, Nguyen, Perlman. Intravenous sulforhodamine B reduces alveolar surface tension, improves oxygenation, and reduces ventilation injury in a respiratory distress model. J Appl Physiol, 130: 1305-1315, 2021.

Suflorhodamine B reduces surface tension under ARDS conditions

Substances purported to raise T in ARDS—cell debris, secretory phospholipase A₂ (sPLA₂), acid and mucins—are tested alone, with exogenous surfactant and with SRB. The substances are all shown to raise T in situ in the alveolus. Exogenous surfactant and SRB counter the T-elevation caused by cell debris and sPLA₂, with exogenous surfactant requiring lung ventilation to be effective. Neither exogenous surfactant nor SRB is effective against acid or mucins, thus neither may be effective in aspiration-induced ARDS.

• Nguyen, Perlman. Sulforhodamine B and exogenous surfactant effects on alveolar surface tension under acute respiratory distress syndrome conditions. J Appl Physiol 129: 1505-1530, 2020.

A low-cost mechanical ventilator for a mass respiratory failure scenario A ventilator constructed with polyvinyl chloride tubing and a single electrical component, an automated garden hose valve, uses variable-resistance valves and water columns to individualize maximal (peak inspiratory, PIP) and minimial (PEEP) ventilation pressures for multiple patients. •Jardim-Neto, Perlman. A low-cost off-the-shelf pressure-controlled mechanical ventilator for a mass respiratory failure scenario. Br J Anaesth 125: e438-e440, 2020.

Surface tension-dependent stress concentrations affect ventilation injury A conceptual analysis of experimental and theoretical evidence for static and dynamic mechanical mechanisms, at the alveolar scale, through which elevated T exacerbates VILI; potential causes of elevated T in ARDS; and T-dependent means of reducing VILI. Also considered are possible means of reducing T and of improving the efficacy of recruitment maneuvers during mechanical ventilation of ARDS patients. •Perlman. The contribution of surface tension-dependent alveolar septal stress concentrations to ventilation-induced lung injury in the acute respiratory distress syndrome. Frontiers in Physiology 11: 388, 2020.

Tracheal surfactant instillation raises alveolar surface tension
		Tracheal surfactant instillation washes airway mucins to the alveoli, where the mucins unexpectedly raise T. Further, in a model of acid-aspiration induced acute respiratory distress syndrome (ARDS), even surfactant delivered mucin-free to the alveolus fails to reduce T. These findings may help explain the inefficacy of exogenous surfactant therapy as a treatment for ARDS.
•Nguyen, Perlman. Tracheal acid or surfactant instillation raises alveolar surface tension. J Appl Physiol 125: 1357-1367, 2018.

Accelerated deflation can clear alveoli, under right conditions

In healthy lungs with normal T, accelerated deflation during ventilation can increase momentum transfer to and eject liquid out of flooded alveoli. This phenomenon occurs when breath volume and PEEP are moderate—high enough to increase tissue stiffness and thus generate significant momentum transfer, but not so high as to raise T, and thus the T-dependent pressure barrier, to a prohibitive degree. Ejected liquid appears to redistribute across the regional liquid lining layer such that the fraction of flooded alveoli decreases, which should decrease the number of septa separating aerated from flooded alveoli and, in turn, decrease VILI. A model disease state is generated by first causing hydrostatic edema, which does not alter T, and then ventilating gently for 50 cycles, which increases T 52% above normal. In this model with elevated T, accelerated deflation still ejects liquid from flooded alveoli. However, the high T keeps the liquid aggregated such that it jumps en masse to a nearby alveolus and the fraction of flooded alveoli is not reduced.

•Wu, Nguyen, Perlman. Accelerated deflation promotes homogeneous airspace liquid redistribution in the edematous lung. J Appl Physiol 122: 739-751, 2017.

Sulforhodamine B reduces surface tension below normal in healthy lungs

With our new surface-tension determination technique, we found that the dye sulforhodamine B (SRB), when facilitated by the presence of albumin, improves the efficacy of native surfactant and lowers surface tension, T, 27% below normal in healthy lungs. Thus not only does albumin not raise T in the lungs, albumin may help lower T. Further, according to the Laplace relation, pressure should be greater at the sides than in the center of flooded alveoli, to a degree proportional to T. Thus there is a T-dependent pressure barrier trapping liquid in flooded alveoli. Administration of SRB-plus-albumin reduces ventilation injury, as assessed by VILI assay, and, by reducing the T-dependent pressure barrier, promotes clearance of flooded alveoli.

•Kharge, Wu, Perlman. Sulforhodamine B interacts with albumin to lower surface tension and protect against ventilation injury of flooded alveoli. J Appl Physiol 118: 355-364, 2015.

With flooding, five gentle ventilation breaths permanently increase barrier permeability

We previously showed that septa between aerated and flooded alveoli are a site of stress concentration. Here, we show that ventilation of a region with heterogeneous alveolar flooding, in which many such septa are present, causes a sustained increase in permeability of the alveolar-capillary barrier. The degree of increase in permeability, which constitutes a VILI assay, is proportional to surface tension, breath volume and, in the absence of any collapsed alveoli, positive end-expiratory pressure (PEEP). Even the most-protective ventilation increases barrier permeability.

•Wu, Kharge, Perlman. Lung ventilation injures areas with discrete alveolar flooding, in a surface-tension dependent fashion. J Appl Physiol 117: 788-796, 2014.

Plasma proteins do not raise surface tension in the lungs
		A new technique is introduced — surface tension is calculated from the Laplace relation following servo-nulling measurement of liquid phase pressure and confocal microscopic determination of interfacial curvature. In tests of albumin solution and blood plasma, plasma proteins are not found to raise surface tension in the lungs unless lung volume is reduced markedly below the physiologic range.
•Kharge, Wu, Perlman. Surface tension in situ in flooded alveolus unaltered by albumin. J Appl Physiol 117: 440-451, 2014.

Experimental-computational determination of alveolar septal modulus
		Septal modulus is calculated from experimentally determined strain and computationally determined stress. The computational model is based on the classic study of Mead et al., showing that septa transmit pleural pressure into the interior of the lungs.
•Perlman, Wu. In situ determination of alveolar septal strain, stress and effective Young's modulus: an experimental/computational approach. Am J Physiol - Lung Cell Mol Physiol 307: L302-L310, 2014.

Imaging methods do not alter mechanics Lung mechanics are not altered by perfusion, use of a cover slip or use of a coverslip plus light vacuum pressure. •Wu, Perlman. In situ methods for assessing alveolar mechanics. J Appl Physiol 112: 519-526, 2012.

Stress concentrations between aerated and flooded alveoli Septa that separate aerated and flooded alveoli bow into flooded alveoli, thus are over-distended and a site of stress concentration. The degree of over-distension is proportional to surface tension. As these septa are a likely site of ventilation-induced lung injury (VILI), this study suggests that VILI should be proportional to surface tension. •Perlman, Lederer, Bhattacharya. The micromechanics of alveolar edema. Am J Respir Cell Mol Biol 44: 34-39, 2011.

A low cost ventilator for one or more patients, with individualized settings

The low cost ventilator is extended with multiple, parallel circuits to individualize maximal (peak inspiratory, PIP) and minimial (PEEP) ventilation pressures for multiple patients. May be employed as a stand-alone ventilator or, in combination with a commercial ventilator, as a multi-patient circuit.

• Jardim-Neto, Perlman. Preprint available on medRxiv.