Carrie E. Perlman

Micromechanics of Alveolar Edema

The decrease of lung compliance in pulmonary edema underlies ventilator-induced lung injury. However, the cause of the decrease in compliance is unknown. We tested the hypothesis that in pulmonary edema, the mechanical effects of liquid-filled alveoli increase tissue stress in adjacent air-filled alveoli. By micropuncture of isolated, perfused rat lungs, we established a single-alveolus model of pulmonary edema that we imaged using confocal microscopy. In this model, we viewed a liquid-filled alveolus together with its air-filled neighbor at different transpulmonary pressures, both before and after liquid-filling. Instilling liquid in an alveolus caused alveolar shrinkage. As a result, the interalveolar septum was stretched, causing the neighboring air-filled alveolus to bulge. Thus, the air-filled alveolus was overexpanded by virtue of its adjacency to a liquid-filled alveolus. Confocal microscopy at different depths of the liquid-filled alveolus revealed a meniscus. Lung inflation to near-total lung capacity (TLC) demonstrated decreased compliance of the air-filled but not liquid-filled alveolus. However, at near TLC, the air-filled alveolus was larger than it was in the pre-edematous control tissue. In pulmonary edema, liquid-filled alveoli induce mechanical stress on air-filled alveoli, reducing the compliance of air-filled alveoli, and hence overall lung compliance. Because of increased mechanical stress, air-filled alveoli may be susceptible to overdistension injury during mechanical ventilation of the edematous lung.

Hemodynamic effects of attachment modes and device design of a thoracic artificial lung.

A thoracic artificial lung (TAL) was designed to treat respiratory insufficiency, acting as a temporary assist device in acute cases or as a bridge to transplant in chronic cases. We developed a computational model of the pulmonary circulatory system with the TAL inserted. The model was employed to investigate the effects of parameter values and flow distributions on power generated by the right ventricle, pulsatility in the pulmonary system, inlet flow to the left atrium, and input impedance. The ratio of right ventricle (RV) power to cardiac output ranges between 0.05 and 0.10 W/(L/min) from implantation configurations of low impedance to those of high impedance, with a control value of 0.04 W/(L/min). Addition of an inlet compliance to the TAL reduces right heart power (RHP) and impedance. A compliant TAL housing reduces flow pulsatility in the fiber bundle, thus affecting oxygen transfer rates. An elevated bundle resistance reduces flow pulsatility in the bundle, but at the expense of increased right heart power. The hybrid implantation mode, with inflow to the TAL from the proximal pulmonary artery (PA), outflow branches to the distal PA and the left atrium (LA), a band around the PA between the two anastomoses, and a band around the outlet graft to the LA, is the best compromise between hemodynamic performance and preservation of some portion of the nonpulmonary functions of the natural lungs.

Hemodynamic and gas transfer properties of a compliant thoracic artificial lung

A compliant thoracic artificial lung (TAL) has been developed for acute respiratory failure or as a bridge to transplantation. The development goal was to increase TAL compliance, lower TAL impedance, and improve right ventricular function during use. Prototypes were tested in vitro and in vivo in eight pigs between 67 and 79 kg to determine hemodynamic and gas transfer properties. The in vitro compliance was 16.2 ± 4.4 ml/mm Hg at pressures < 7.8 mm Hg and 4.3 ± 1.1 ml/mm Hg above 7.8 mm Hg. In vivo, this compliance significantly reduced blood flow pulsatility from 1.7 at the inlet to 0.36 at the outlet. Device resistance was 1.9 and 1.8 mm Hg/(L/min) at a flow rate of 4 L/min in vitro and in vivo, respectively. Approximately 75% of the resistance was at the inlet and outlet. In vivo TAL O2 and CO2 transfer rates were 188 and 186 ml/min, respectively, at 4 L/min of blood and gas flow, and average outlet O2 saturations exceeded 98% for average flow rates up to and including the maximum tested, 5.3 L/min. The new design has a markedly improved compliance and excellent gas transfer but also possesses inlet and outlet resistances that must be reduced in future designs.

In vivo hemodynamic responses to thoracic artificial lung attachment

A thoracic artificial lung (TAL) was attached to the pulmonary circulation in a porcine model. Proximal main pulmonary artery (PA) blood flow, in part or whole, was diverted to the TAL, and TAL outlet blood flow was split between the distal main PA and left atrium (LA). The right ventricle (RV) drove blood flow through the combined TAL/natural lung (NL) pulmonary system. Selective banding placed the TAL in parallel with the NLs, in series with the NLs, or in an intermediary hybrid configuration. Parallel TAL attachment lowered pulmonary system impedance, raised cardiac output (CO), and provided the greatest TAL blood flow rate, but reduced the NL blood flow rate which is important for pulmonary embolic clearance and metabolic blood processing. Hybrid or series TAL attachment raised pulmonary system impedance, lowered CO, increased RV oxygen consumption, and reduced RV oxygen supply. Redesign of the PA anastomoses, TAL inlet graft, and TAL entrance and exit would significantly improve hemodynamics and RV function with TAL attachment. Mean LA pressure increased throughout the experiment, which may indicate damage caused by graft attachment to the LA. Pulmonary resistance–flow rate curves may enable clinical prediction of tolerable TAL attachment configurations.

Surface tension in situ in flooded alveolus unaltered by albumin

In the acute respiratory distress syndrome, plasma proteins in alveolar edema liquid are thought to inactivate lung surfactant and raise surface tension, T. However, plasma protein-surfactant interaction has been assessed only in vitro, during unphysiologically large surface area compression (%ΔA). Here, we investigate whether plasma proteins raise T in situ in the isolated rat lung under physiologic conditions. We flood alveoli with liquid that omits/includes plasma proteins. We ventilate the lung between transpulmonary pressures of 5 and 15 cmH2O to apply a near-maximal physiologic %ΔA, comparable to that of severe mechanical ventilation, or between 1 and 30 cmH2O, to apply a supraphysiologic %ΔA. We pause ventilation for 20 min and determine T at the meniscus that is present at the flooded alveolar mouth. We determine alveolar air pressure at the trachea, alveolar liquid phase pressure by servo-nulling pressure measurement, and meniscus radius by confocal microscopy, and we calculate T according to the Laplace relation. Over 60 ventilation cycles, application of maximal physiologic %ΔA to alveoli flooded with 4.6% albumin solution does not alter T; supraphysiologic %ΔA raise T, transiently, by 51 ± 4%. In separate experiments, we find that addition of exogenous surfactant to the alveolar liquid can, with two cycles of maximal physiologic %ΔA, reduce T by 29 ± 11% despite the presence of albumin. We interpret that supraphysiologic %ΔA likely collapses the interfacial surfactant monolayer, allowing albumin to raise T. With maximal physiologic %ΔA, the monolayer likely remains intact such that albumin, blocked from the interface, cannot interfere with native or exogenous surfactant activity.

Blood flow pulsatility effects upon oxygen transfer in artificial lungs.

This report discusses theoretical effects of blood flow pulsatility upon the rate of oxygen transfer in artificial lungs, demonstrates the effects with in vitro tests upon commercial oxygenators, and applies the theory to these oxygenators and to a thoracic artificial lung. Steady flow gas transfer theory is applied to pulsatile flow by using the instantaneous value of flow rate at each instant of time, that is, quasi-steady gas transfer. The theory suggests that the local rate of oxygen transfer for a given device and blood composition is proportional to the flow rate to a power less than unity and to the hemoglobin saturation level. It predicts, for some cases, overall reduced rates of gas transfer for pulsatile flow relative to those at steady flow for the same mean blood flow rates. In vitro bovine blood tests, using pediatric oxygenators, a pulsatile pump, and an adjustable compliance chamber, indicate a significant average 10% reduction of oxygen transfer for pulsatile flow relative to steady flow. The application of the theory to the oxygenators predicts gas transfer values that are in agreement with those measured during the experiments. The results have implications in the design of implantable thoracic artificial lungs, which should include a compliant section to dampen the cardiac pulse. A relatively small compliance (0.2 ml/mm Hg) at the thoracic artificial lung inlet is sufficient to obtain approximately 95% of steady flow oxygen transfer.

Lung ventilation injures areas with discrete alveolar flooding, in a surface tension-dependent fashion

With proteinaceous-liquid flooding of discrete alveoli, a model of the edema pattern in the acute respiratory distress syndrome, lung inflation over expands aerated alveoli adjacent to flooded alveoli. Theoretical considerations suggest that the overexpansion may be proportional to surface tension, T. Yet recent evidence indicates proteinaceous edema liquid may not elevate T. Thus whether the overexpansion is injurious is not known. Here, working in the isolated, perfused rat lung, we quantify fluorescence movement from the vasculature to the alveolar liquid phase as a measure of overdistension injury to the alveolar-capillary barrier. We label the perfusate with fluorescence; micropuncture a surface alveolus and instill a controlled volume of nonfluorescent liquid to obtain a micropunctured-but-aerated region (control group) or a region with discrete alveolar flooding; image the region at a constant transpulmonary pressure of 5 cmH2O; apply five ventilation cycles with a positive end-expiratory pressure of 0-20 cmH2O and tidal volume of 6 or 12 ml/kg; return the lung to a constant transpulmonary pressure of 5 cmH2O; and image for an additional 10 min. In aerated areas, ventilation is not injurious. With discrete alveolar flooding, all ventilation protocols cause sustained injury. Greater positive end-expiratory pressure or tidal volume increases injury. Furthermore, we determine T and find injury increases with T. Inclusion of either plasma proteins or Survanta in the flooding liquid does not alter T or injury. Inclusion of 2.7-10% albumin and 1% Survanta together, however, lowers T and injury. Contrary to expectation, albumin inclusion in our model facilitates exogenous surfactant activity.

In situ methods for assessing alveolar mechanics

Lung mechanics are an important determinant of physiological and pathophysiological lung function. Recent light microscopy studies of the intact lung have furthered the understanding of lung mechanics but used methodologies that may have introduced artifacts. To address this concern, we employed a short working distance water immersion objective to capture confocal images of a fluorescently labeled alveolar field on the costal surface of the isolated, perfused rat lung. Surface tension held a saline drop between the objective tip and the lung surface, such that the lung surface was unconstrained. For comparison, we also imaged with O-ring and coverslip; with O-ring, coverslip, and vacuum pressure; and without perfusion. Under each condition, we ventilated the lung and imaged the same region at the endpoints of ventilation. We found use of a coverslip caused a minimal enlargement of the alveolar field; additional use of vacuum pressure caused no further dimensional change; and absence of perfusion did not affect alveolar field dimension. Inflation-induced expansion was unaltered by methodology. In response to inflation, percent expansion was the same as recorded by all four alternative methods.

In situ determination of alveolar septal strain, stress and effective Young's modulus: an experimental/computational approach

Alveolar septa, which have often been modeled as linear elements, may distend due to inflation-induced reduction in slack or increase in tissue stretch. The distended septum supports tissue elastic and interfacial forces. An effective Youngs modulus, describing the inflation-induced relative displacement of septal end points, has not been determined in situ for lack of a means of determining the forces supported by septa in situ. Here we determine such forces indirectly according to Mead, Takishima, and Leiths classic lung mechanics analysis (J Appl Physiol 28: 596-608, 1970), which demonstrates that septal connections transmit the transpulmonary pressure, PTP, from the pleural surface to interior regions. We combine experimental septal strain determination and computational stress determination, according to Mead et al., to calculate effective Youngs modulus. In the isolated, perfused rat lung, we label the perfusate with fluorescence to visualize the alveolar septa. At eight PTP values around a ventilation loop between 4 and 25 cmH2O, and upon total deflation, we image the same region by confocal microscopy. Within an analysis region, we measure septal lengths. Normalizing by unstressed lengths at total deflation, we calculate septal strains for all PTP > 0 cmH2O. For the static imaging conditions, we computationally model application of PTP to the boundary of the analysis region and solve for septal stresses by least squares fit of an overdetermined system. From group septal strain and stress values, we find effective septal Youngs modulus to range from 1.2 × 10(5) dyn/cm(2) at low P(TP) to 1.4 × 10(6) dyn/cm(2) at high P(TP).

Hemodynamic consequences of thoracic artificial lung attachment configuration: a computational model.

A thoracic artificial lung (TAL) is being developed to assist treatment of acute and chronic pulmonary dysfunction. The TAL is attached directly to the pulmonary circulation. Depending on pathophysiology, the TAL may be attached in series with the natural lungs (NLs), in parallel with the NLs, or in an intermediate, hybrid configuration. We developed a computational model to study hemodynamic consequences of TAL attachment configuration under pathologic conditions. The pulmonary and systemic circulations, heart, and TAL are modeled as interconnected compliances and conductances, some valved. Time-varying cardiac compliance drives the system and generates pressures and flow rates. The model includes blood pressure feedback from the sympathetic nervous system, renin-angiotensin system, and renal volume control mechanism. We used previously published results from porcine experiments to verify model accuracy. We modeled normal physiology and four disease states. A hybrid configuration with 100% cardiac output through the TAL and 40% through the NLs would deliver maximal blood flow, 3.6 to 4.6 l/min, to the TAL and be tolerated by the right ventricle. Additionally, the model suggests that reducing the large “minor loss” resistances at the graft anastomoses to the pulmonary artery would improve the hemodynamics of all TAL attachment configurations.