Liquid-filled Lungs Research Articles

From intra- to extra-uterine: early phase design of a transfer to extra-uterine life support through medical simulation.

Extra-uterine life support technology could provide a more physiologic alternative for the treatment of extremely premature infants, as it allows further fetal growth and development ex utero. Animal studies have been carried out which involved placing fetuses in a liquid-filled incubator, with oxygen supplied through an oxygenator connected to the umbilical vessels. Hence, by delaying lung exposure to air, further lung development and maturation can take place. This medical intervention requires adjustments to current obstetric procedures to maintain liquid-filled lungs through a so-called transfer procedure. Our objective was to develop obstetric device prototypes that allow clinicians to simulate this birth procedure to safely transfer the infant from the mother's uterus to an extra-uterine life support system. To facilitate a user-centered design, implementation of medical simulation during early phase design of the prototype development was used. First, the requirements for the procedure and devices were established, by reviewing the literature and through interviewing direct stakeholders. The initial transfer device prototypes were tested on maternal and fetal manikins in participatory simulations with clinicians. Through analysis of recordings of the simulations, the prototypes were evaluated on effectiveness, safety and usability with latent conditions being identified and improved. This medical simulation-based design process resulted in the development of a set of surgical prototypes and allowed for knowledge building on obstetric care in an extra-uterine life support context.

Expiratory Flow Limitation during Gravitational Drainage of Perfluorocarbons from Liquid-Filled Lungs

Flow limitation during pressure-driven expiration in liquid-filled lungs was examined in intact, euthanized New Zealand white rabbits. The aim of this study was to further characterize expiratory flow limitation during gravitational drainage of perfluorocarbon liquids from the lungs, and to study the effect of perfluorocarbon type and negative mouth pressure on this phenomenon. Four different perfluorocarbons (PP4, perfluorodecalin, perfluoro-octyl-bromide, and FC-77) were used to examine the effects of density and kinematic viscosity on volume recovered and maximum expiratory flow. It was demonstrated that flow limitation occurs during gravitational drainage when the airway pressure is < or = -15 cm H(2)O, and that this critical value of pressure did not depend on mouth pressure or perfluorocarbon type. The perfluorocarbon properties affect the volume recovered, maximum expiratory flow, and the time to drain, with the most viscous perfluorocarbon (perfluorodecalin) taking the longest time to drain and resulting in lowest maximum expiratory flow. Perfluoro-octyl-bromide resulted in the highest recovered volume. The findings of this study are relevant to the selection of perfluorocarbons to reduce the occurrence of flow limitation and provide adequate minute ventilation during total liquid ventilation.

Location of Flow Limitation in Liquid-Filled Rabbit Lungs

The effects of end-inspiratory lung volume (EILV) and expiratory flow rate (Q) on the location of flow limitation in liquid-filled lungs were investigated by measuring pressure along the airways and by radiographic imaging. The lungs of New Zealand white rabbits were filled with perfluorocarbon to the randomly selected EILV of 20, 30, or 40 ml/kg, and the volume was actively drained at one of three Q: 2.5, 5.0, or 7.5 ml/s. The minimum pressures recorded by a movable catheter at locations along the airways show that flow limitation occurred in the main bronchi and trachea, and was independent of EILV and Q. The minimum pressure at the trachea was -80 mm Hg compared with values that were more positive than -10 mm Hg at a location 3 cm distal to the carina for all EILV and Q combinations. This location was confirmed by the lung images. The airway diameters gradually decreased with time, until flow limitation occurred. In airways distal to the collapse, there was not a significant decrease in diameter. Based on these data, we conclude that flow limitation in liquid-filled lungs occurs in the trachea and main bronchi and its location is independent of EILV or Q.

Flow Limitation in Liquid-Filled Lungs: Effects of Liquid Properties

Flow limitation in liquid-filled lungs is examined in intact rabbit experiments and a theoretical model. Flow limitation ("choked" flow) occurs when the expiratory flow reaches a maximum value and further increases in driving pressure do not increase the flow. In total liquid ventilation this is characterized by the sudden development of excessively negative airway pressures and airway collapse at the choke point. The occurrence of flow limitation limits the efficacy of total liquid ventilation by reducing the minute ventilation. In this paper we investigate the effects of liquid properties on flow limitation in liquid-filled lungs. It is found that the behavior of liquids with similar densities and viscosities can be quite different. The results of the theoretical model, which incorporates alveolar compliance and airway resistance, agrees qualitatively well with the experimental results. Lung compliance and airway resistance are shown to vary with the perfluorocarbon liquid used to fill the lungs. Surfactant is found to modify the interfacial tension between saline and perfluorocarbon, and surfactant activity at the interface of perfluorocarbon and the native aqueous lining of the lungs appears to induce hysteresis in pressure-volume curves for liquid-filled lungs. Ventilation with a liquid that results in low viscous resistance and high elastic recoil can reduce the amount of liquid remaining in the lungs when choke occurs, and, therefore, may be desirable for liquid ventilation.

Feasibility of lung cancer hyperthermia using breathable perfluorochemical (PFC) liquids. Part II: Ultrasound hyperthermia

Enhanced local control of disease in lung cancer has been shown to improve survival, and controlled clinical trials of hyperthermia adjunctive to radiotherapy in other cancers have shown improved disease control and survival over radiotherapy alone. The challenge of lung hyperthermia, however, persists. This investigation sought to demonstrate the feasibility of localized lung hyperthermia at depth via therapeutic ultrasound. The method is based on using breathable perfluorochemical liquids as acoustic coupling media in the lung, liquids that have also been shown to enable controlled liquid-filled lung convective hyperthermia (LCHT). The ability to use both lung convective hyperthermia and liquid-filled lung ultrasound hyperthermia (LUHT) provides potential flexibility in heating patterns for the hyperthermic treatment of lung cancer with concurrent radiotherapy and/or chemotherapy. Using custom ultrasound transducers designed and built for these studies, the acoustic properties of three candidate perfluorochemicals were characterized over a range of temperatures, gas contents and ultrasound frequencies and acoustic intensities. Both sound speed and attenuation were measured in the neat liquids and in isolated lungs filled with the perfluorochemicals. Successful ultrasound hyperthermia at depth was demonstrated in vivo in sheep lung lobes in intraoperative conditions. In addition, the use of ultrasound diagnostic imaging was explored as a tool for use in conjunction with lung ultrasound hyperthermia.

Feasibility of lung cancer hyperthermia using breathable perfluorochemical (PFC) liquids. Part I: Convective hyperthermia

Clinical studies have shown that hyperthermia in combination with radiotherapy and/or chemotherapy may be effective in the treatment of advanced cancer. No method of lung hyperthermia, however, has been accepted as standard or superior. This investigation sought to demonstrate in animals the thermal and physiologic feasibility of lung hyperthermia induced using heated breathable perfluorochemical (PFC) liquids, a method termed liquid-filled lung convective hyperthermia (LCHT). The ability to use LCHT is rooted in the development of both PFC liquid ventilation, now in clinical development with the PFC perflubron (LiquiVent®), and a PFC blood substitute also in late Phase III trials (Oxygent™). As LCHT background, the PFC technologies and biology are first reviewed. The physical properties of a variety of PFCs were evaluated for LCHT and it was concluded that more than one liquid is suitable based on such properties. Using total liquid ventilation type devices, LCHT was shown to deliver successfully localized (lobar) lung heating in sheep, and bilateral whole lung heating and whole-body hyperthermia in rabbits, cats and lambs. During LCHT, lung parenchymal temperatures were uniform (<1°C) across heated regions. In addition, based on patterns relating lung tissue temperatures to inspiratory and expiratory PFC liquid temperatures in the endotracheal tube, LCHT may minimize invasive thermometry requirements in the lung. Based on acute experiments, it was concluded that LCHT appears feasible and may simplify lung hyperthermia. It was recommended that potentially synergistic combinations of LCHT with other whole-body hyperthermia or local heating modalities, and with chemotherapeutic lung drug delivery, also be explored in the future.

Terminology of three-dimensional and four-dimensional ultrasound imaging of the fetal heart and other moving body parts.

Terminology of three-dimensional and four-dimensional ultrasound imaging of the fetal heart and other moving body parts.

Measurements of differential diffusion in a liquid-filled lung model

A noninvasive method for obtaining quantitative images of differential diffusion in liquid-filled lung models is presented. The method utilizes planar fluorescence imaging to obtain differences in concentration fields and was tested on an oscillatory flow of water in a Y-shaped tube. Differences as large as 36% were measured between the concentration fields of two dyes having a factor of 15 difference in their diffusion coefficient. The method is applicable to the study of differential diffusion in any internal flow. The relevance to recent clinical studies of liquid phase respiration (Greenspan et al. 1990) is discussed.

Time course of hypoxic pulmonary vasoconstriction: a rabbit model of regional hypoxia.

There is disagreement in the literature about the time required for hypoxic constriction of pulmonary vessels to reach its full intensity. Some studies suggest that only minutes are required, others that several hours are needed. We examined the time course over 6 h of changes in pulmonary shunt (as a fraction of cardiac output) following induction of unilateral hypoxia by collapse or liquid filling of the left lung in 47 anesthetized rabbits. The time course was examined at four degrees of lung inflation: during collapse and at airway pressures of 0.3 kPa, 0.6 kPa, and 0.9 kPa. The respective volumes (mean +/- SD) of the liquid-filled lung were estimated to be 6.4 +/- 1.0, 12.8 +/- 2.5, and 15.8 +/- 1.6 ml/kg body weight (BW). During sustained hypoxia (the period from 150 to 360 min after inducing hypoxia), shunt declined at a slow linear rate of 2.37 x 10(-4)/min, which was independent of lung inflation (p = 0.65 analysis of variance [ANOVA]) and significantly different from zero (p < 0.001). The stability of cardiac output in this animal model, as measured sequentially by thermodilution, was confirmed in a further 20 animals. The experiments provide evidence for a slow intensification of blood-flow diversion at a rate that does not depend upon the degree of lung inflation. Whether this change is a feature of hypoxic constriction itself, or some modulation of it, remains unclear.

Dynamic elastance and tissue resistance of isolated liquid-filled rat lungs

The effect of the surface forces of the alveolar air-liquid interface on the dynamic behavior of lung tissue was investigated in five isolated liquid-filled rat lungs. The lungs were subjected to 0.04-Hz sinusoidal oscillation (1.5-ml tidal volume) at lung volume (VL) levels ranging from volume at zero pressure (V0) + 4 ml to V0 + 10 ml. Oscillations were performed at each VL after inflation of the lungs from V0. Alveolar pressure (PA) was measured with an alveolar capsule attached to the visceral pleura. Dynamic elastance (Edyn), tissue resistance (Rti), and hysteresivity [eta = Rti omega/Edyn, where omega is angular frequency (2 pi x frequency)] were computed from PA and VL changes. Edyn was 59.6 +/- 4.3 Pa/ml at V0 + 4 ml and varied little up to V0 + 7 ml. Thereafter, Edyn increased markedly with VL, reaching 102 +/- 16 Pa/ml at V0 + 10 ml. No significant difference was found between elastance computed from PA and that computed from pressure recorded at the airway opening. Rti was 35.2 +/- 3.6 Pa.s.ml-1 and exhibited a VL dependence similar to that of Edyn. As a result, eta was 0.16 and did not vary significantly in the explored VL range. We conclude that PA can be reliably measured in the liquid-filled lung by means of alveolar capsules. In the liquid-filled lung, Edyn was smaller than and eta was similar to values reported for air-filled lungs. Hence, surface tension accounts for a considerable part of elastance and Rti of the air-filled lung within the volume range of normal breathing.

Effects of lung volume and surface forces on maximal airway smooth muscle shortening

The effects of lung volume and surface forces on airway smooth muscle shortening were studied in isolated perfused rat lungs. The lungs were inflated via the trachea with gas or Krebs solution (n = 12 each) to volumes equivalent to gas inflation pressures of 5 (low), 15 (medium), and 25 (high) cmH2O (n = 4 each). At each volume, two of the four lungs were perfused with methacholine (10(-2) M) and then all were perfused with Formalin for fixation. The amount of smooth muscle shortening present in transverse sections of the airways was determined by comparing the observed outer perimeter of the smooth muscle layer with its calculated relaxed perimeter. In the control lungs, mean shortening was < or = 10% in all groups except the liquid-filled lungs at low lung volumes [33 +/- 12% (SD)]. In the methacholine-stimulated lungs, mean shortening was between 45 and 56% at medium and low lung volumes in gas- and liquid-filled lungs, respectively, and approximated the degree of shortening required to cause airway closure. At high lung volume, less shortening was observed in the methacholine-stimulated lungs, either liquid (34 +/- 17%) or gas filled (16 +/- 19%; P < 0.05 compared with liquid filled). The effects of lung volume in liquid-filled lungs and the differences in response between gas- and liquid-filled lungs demonstrate, respectively, that both lung tissue recoil and surface forces act to oppose shortening of maximally stimulated smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathophysiology of congenital diaphragmatic hernia. V. Effect of exogenous surfactant therapy on gas exchange and lung mechanics in the lamb congenital diaphragmatic hernia model

The aim of this study was to assess the impact of surfactant deficiency on the pathophysiology of congenital diaphragmatic hernia (CDH). Pregnant ewes were operated on at 80 days of gestation for creation of a diaphragmatic hernia in the lambs. Twenty-one lambs survived to be delivered by cesarean section and were studied. Compliance was improved when surface tension effects were removed by saline solution in lungs of both control animals and lambs with CDH; however, the lungs of the lambs with CDH still had significantly impaired compliance. In a second series of experiments, two groups were studied: a surfactant-treated and a control, nontreated group. Surfactant was given prophylactically into the liquid-filled lungs before the first breath. All lambs were paralyzed and sedated and their lungs mechanically ventilated with 100% oxygen for 30 minutes; gas exchange was then assessed, pressure-volume data were obtained, and compliance was calculated. Surfactant significantly improved gas exchange; arterial oxygen pressure increased from 39 ± 11.4 to 316 ± 53.6 mm Hg, arterial carbon dioxide pressure decreased from 148 to 63 mm Hg, and pH increased from 6.87 to 7.16 ( p < 0.001). Lung volume at 25 cm H 2O, functional residual capacity, and compliance were all increased ( p < 0.02). Thus, in the CDH lamb model, pulmonary mechanics are impaired by both parenchymal and surfactant abnormalities. Both lung mechanics and gas exchange are markedly improved by exogenous surfactant therapy. (J P EDIATR 1994;124:289-93)

Alveolar transepithelial potential difference and ion transport in adult rat lung

The complex morphology of the mammalian lung complicates characterization of solute transport across the intact alveolar epithelium. We impaled the subpleural alveolar epithelium with microelectrodes and measured the transepithelial potential difference (PD) of the liquid-filled vascular-perfused left lobe of the rat lung. When the air space was filled entirely with Krebs-Ringer-bicarbonate, the PD was 4.7 mV (lumen negative). The PD was not affected significantly by agents that modify either Na+ or Cl- transport, but replacement of luminal Cl- with gluconate resulted in a fourfold hyperpolarization, a response also noted for large airways. When the airways were blocked by an immiscible nonconducting fluorocarbon, basal PD was not different from unblocked lobes (4.0 mV) but was inhibited 73% by luminal amiloride. Cl(-)-free Krebs-Ringer-bicarbonate blocked in the alveoli with fluorocarbon did not induce hyperpolarization. This result suggests that 1) Cl- permselectivity of the alveolar epithelium is less than that of large airway epithelium and 2) airway PD dominates the voltage across the liquid-filled lung, even when measurements are made from alveoli. When airways are blocked by fluorocarbon, the PD across the alveolar epithelium is largely dependent on Na+ flow through a path with amiloride-sensitive channels.

Respiratory mechanics in adult rats hypercapnic in the neonatal period

Because chronic hypoxia in the neonatal period has long-term effects on the mechanical properties of the respiratory system (S. Okubo and J. P. Mortola, J. Appl. Physiol. 66: 1772-1778, 1989), we asked whether similar effects would occur after neonatal exposure to hypercapnia. Three groups of rats were used. The first was exposed to 7% CO2 in normoxia from day 1 to 7 after birth and then returned to normocapnia (NB-CO2). The second was exposed to the same level and duration of hypercapnia from day 36 to 42, i.e., approximately 2 wk after weaning (AD-CO2). The third was raised in normoxia and normocapnia (control). At approximately 50 days, i.e., 1-2 wk after puberty, the passive mechanical properties of the respiratory system, lung, and chest were measured during artificial ventilation in the anesthetized and paralyzed animal. No differences were observed between AD-CO2 and control. NB-CO2 had higher compliance of the lung (approximately +40%) and respiratory system (+32%) than control or AD-CO2. Average values of resistance of the total respiratory system, lung, and chest wall were consistently lower in NB-CO2 than in control and AD-CO2, although the magnitude and statistical significance of the decrease depended on the method of measurement. In a separate group of NB-CO2, lung compliance was measured during spontaneous breathing, and it averaged 34% more than in control. The exponential constant of the deflation quasi-static pressure-volume curve of the liquid-filled lungs was also significantly higher than in control.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose dependency of intratracheal elastase-induced changes in pressure volume curve and morphometry in rat lungs.

We studied the dose-dependency of the lung pressure-volume curve (n = 37) and morphometry (n = 30) with intratracheally administered elastase. Four weeks after elastase was instilled at dosages of 20 (EL-20), 40, 80, and 100 U/100 g wt., chord compliance between 50 and 70% of total lung capacity (TLC) (C50-70) and that between 80 and 100% TLC (C80-100) were measured. After a significant initial reduction, the weight of the EL-80 group recovered to the control level, whereas the weight curve of the EL-100 significantly decreased below that of the EL-80. Lung volumes of all the elastase-treated groups were significantly larger than those of control. Air-filled lung volumes monotonously increased when the elastase dose was increased from 20 to 80 U/100 g wt. In contrast lung volume of the EL-100 was significantly lower than that of the EL-80. On the other hand, liquid-filled lung volumes monotonously increased from 20 to 100 U/100 g wt. C80-100 was significantly smaller in the EL-100 than in the EL-80. The mean linear intercept increased and alveolar surface area decreased monotonously over the dose range tested. We conclude that there is a critical dose of elastase below which lung volume is increased and above which the increase is suppressed when elastase is administered intratracheally to Wistar rats.

Elastic properties of air- and liquid-filled lung parenchyma.

Pressure-volume measurements and the punch indentation test are used to obtain the bulk modulus (kappa) and the shear modulus (mu) of lung parenchyma of air- and liquid-filled rabbit lungs. Plots of kappa and mu vs. transpulmonary pressure obtained from these measurements indicate that there is very little difference between the elastic behavior of the air- and liquid-filled lung, suggesting that the mechanism of resisting deformation in both cases is similar. On the other hand, from plots of kappa and mu vs. lung volume, it appears that the elastic moduli are higher in the air-filled lung than in the liquid-filled lung at the same volume. These differences, referred to as kappa gamma and mu gamma, as well as the difference in transpulmonary pressures (P gamma), are presumably due to the additional elastic recoil of the air-filled lung provided by alveolar surface tension (gamma). No conclusion could be reached about the shape of the kappa gamma vs. P gamma curve. However, the mu gamma vs. P gamma relationship appears to be approximately linear, with a slope of approximately 0.5. This result agrees qualitatively with the model (T. A. Wilson and H. Bachofen, J. Appl. Physiol. 52: 1064-1070, 1982) in which the part of the parenchyma that provides P gamma is pictured as mechanically analogous to an open cell liquid foam, having mu gamma = 0.4P gamma (J. Appl. Mech. Trans. ASME 51: 229-231, 1984), but it is statistically significant only at high lung volumes.

The progressive onset of spontaneous and induced fetal breathing

Intratracheal pressure (ITP max) and respiratory drive (dITP/dt) from the occluded, liquid-filled trachea of term fetal lambs in utero were measured for each breath at the onset of fetal breathing (1) during spontaneous breathing, (2) during sciatic nerve stimulation, (3) during induced hypercapnia, and (4) following naloxone administration. These responses were characterized by linear increase of ITP max and dITP/dt following which these parameters became stable. The rate of rise of ITP max and dITP/dt was lowest and similar during spontaneous breathing and sciatic stimulation, but increased incrementally with hypercapnia and naloxone. Mechanical factors could not account for these responses in the liquid-filled lung, nor did appreciable chemical changes occur during this period. These results suggest that progressive breathing responses at the onset of fetal breathing may stem from gradual recruitment of central respiratory neurons, and that the rate of rise of such recruitment depends on facilitation by natural arousal, somatosensory stimulation and hypercapnia as well as on release from natural endorphin inhibition.

Water and Electrolytes of Rat Lung: Effects of Fluid-Filling, Perfusion, and Metabolic Inhibitor Treatment

The left lobe of the rat lung was filled through the bronchus with Krebs Bicarbonate Ring-er solution (KBR) with 70,000 mol wt 14C-dextran. Electrolytes and water in slices of the lobe were measured. The volume of liquid trapped in the airspace estimated from the volume of distribution of dextran was equivalent to the gravimetrically determined difference in water content (1.2 1/kg dry wt or 21% of slice water) between slices of gas and KBR-filled lobes. Additional Na+ and Cl− in slices of liquid-filled lobes were accounted for by the NaCl in a volume of KBR equal to the volume of residual airspace fluid. Perfusion of liquid-filled lobes with KBR with 6% colloid for 1 hr did not affect tissue water (4.4 1/kg dry wt), electrolytes (Na+ = 406, K+ = 336, Cl− = 388 mEq/kg dry wt) or Q02 (7 μl/mg dry wt., hr). The permeability coefficient for dextran movement between the airspace and perfusion fluid was 6 × 10−10 cm/sec. The tissue compartment of slices from lobes perfused with 1% colloid in KBR was 22% larger. Na+ and Cl− increased but K+ and Pdextran were unchanged. These results suggest the formation of interstitial edema. Addition of ouabain (10−3M) or NaCN and iodoacetamide (10−3M each) to the perfusion fluid resulted in the loss of about 150 mEq/kg dry wt of tissue K+ and a gain of an equal amount of Na+. Tissue Cl− and water did not change. Exchange of Na+ for cell K+ is suggested. We conclude that the slice technique can be used to monitor changes in the composition and volume of liquid compartments of the parenchyma of liquid-filled lungs.

Increased alveolar epithelial permeability with acid aspiration: the effects of high-dose steroids.

Using the in vivo, liquid-filled dog lung model, we found that aspriation of acid with a pH of 2.5 or less led to increased alveolar epithelial permeability for albumin (molecular weight, 69,000 daltons; molecular radius, 35 a) and exogenously administered, polydispersed dextrans (molecular weight, 150,000 to 170,000 daltons: approximately molecular radius, 100 a). This increased permeability occurred with a large-volume (3 to 5 ml/kg) or small-volume (1 to 1.5 ml/kg) aspirate and with acid nebulization (1 to 1.5 ml/kg). When animals were either pretreated (30 min before aspiration) or post-treated (30 min after aspiration) with 30 mg of methylprednisolone/kg of body weight, there was no improvement in the increased permeability associated with acid aspiration. We conclude that, acutely, steroids have no effect on the increased alveolar epithelial permeability associated with acid aspiration.

Effects of Acid Aspiration on Pulmonary Alveolar Epithelial Membrane Permeability

Employing a modification of the in vivo model of a liquid-filled canine lung, we measured the movement of substances of specific sizes (albumin, 69,000 daltons with a molecular radius of 35 A; and dextran with a molecular weight of 150,000 to 170,000 and an approximate molecular radius of 100 A) from the pulmonary capillary blood to the liquid-filled lung. A solution with a specific pH (1.5 to 4.5) was instilled into the left lung of the animals at a dosage of 3 to 5 ml/kg of body weight. For both albumin and dextran with a molecular weight of 150,000 to 170,000, the time for 50 percent equilibration between the specific substance in the blood and the same substance in the pulmonary liquid decreased significantly with instillation of pulmonary liquid with a pH of 1.5 and 2.5 but did not with a pH of 3.5 or above (P less than 0.05). In addition, since histamine has been implicated as a possible humoral mediator leading to increased permeability of alveolar membranes, the levels of histamine were measured in pulmonary liquids and blood in all groups. Levels of histamine in the pulmonary liquid (but not blood) were significantly higher in animals with instillation of liquids with a pH of 1.5 and 2.5 compared to all other groups.