Kinetics of absorption atelectasis during anesthesia: a mathematical model.

Recent computed tomography studies show that inspired gas composition affects the development of anesthesia-related atelectasis. This suggests that gas absorption plays an important role in the genesis of the atelectasis. A mathematical model was developed that combined models of gas exchange from an ideal lung compartment, peripheral gas exchange, and gas uptake from a closed collapsible cavity. It was assumed that, initially, the lung functioned as an ideal lung compartment but that, with induction of anesthesia, the airways to dependent areas of lung closed and these areas of lung behaved as a closed collapsible cavity. The main parameter of interest was the time the unventilated area of lung took to collapse; the effects of preoxygenation and of different inspired gas mixtures during anesthesia were examined. Preoxygenation increased the rate of gas uptake from the unventilated area of lung and was the most important determinant of the time to collapse. Increasing the inspired O2 fraction during anesthesia reduced the time to collapse. Which inert gas (N2 or N2O) was breathed during anesthesia had minimal effect on the time to collapse.     

Vascular release of nonheme iron in perfused rabbit lungs

In this study, we hypothesized that the lung actively releases excess iron into the circulation to regulate iron homeostasis. We measured nonheme iron (NHFe) in the perfusate of control isolated perfused rabbit lungs and lungs with ischemia-reperfusion (I/R) ventilated with normoxic (21% O(2)) or hypoxic (95% N(2)) gas mixtures. Some were perfused with bicarbonate-free (HEPES) buffer or treated with the anion exchange inhibitor DIDS. The control lungs released approximately 0.25 microg/ml of NHFe or 20% of the total lung NHFe into the vascular space that was not complexed with ferritin, transferrin, or lactoferrin or bleomycin reactive. The I/R lungs released a similar amount of NHFe during ischemia and some bleomycin-detectable iron during reperfusion. NHFe release was attenuated by approximately 50% in both control and ischemic lungs by hypoxia and by >90% in control lungs and approximately 60% in ischemic lungs by DIDS and HEPES. Reperfusion injury was not affected by DIDS or HEPES but was attenuated by hypoxia. These results indicate that biologically nonreactive nonheme iron is released rapidly by the lung into the vascular space via mechanisms that are linked to bicarbonate exchange. During prolonged ischemia, redox-active iron is also released into the vascular compartment by other mechanisms and may contribute to lung injury.     

The venous system of the terrestrial crab Ocypode cordimanus (Desmarest 1825) with particular reference to the vasculature of the lungs

The respiratory system of Ocypode cordimanus consists of seven pairs of gills, modified for aerial gas exchange, and a single pair of lungs. Each lung is formed from the inner surface of the branchiostegite and the thoracic wall of the branchial chamber. The branchiostegal surface is increased by a fleshy infolding, the branchiostegal shelf, whilst the surface area of the thoracic lung wall is enhanced by a large flaplike fold. The anatomy of the major sinus systems and the vascular supply to the lungs were investigated. Venous hemolymph is supplied to the lungs potentially from all the major body sinuses. The dorsal, ventral, hepatic, and infrabranchial sinuses are all connected anteriorly to the two eye sinuses which distribute hemolymph to the lungs. Each eye sinus gives off five branches to the branchiostegal lung surface and one to the thoracic lung wall. These afferent vessels are highly branched and interdigitate closely with efferent vessels. The two systems are connected by flat lacunae lying just beneath the respiratory epithelium and these are believed to be the site of gas exchange. The efferent vessels empty into two pulmonary veins on each side, one serving the branchiostegal lung wall and the other the thoracic wall. The two vessels on each side fuse before joining the pericardial cavity as a single trunk on each side.     

Human models of acute lung injury

Acute lung injury (ALI) is a syndrome that is characterised by acute inflammation and tissue injury that affects normal gas exchange in the lungs. Hallmarks of ALI include dysfunction of the alveolar-capillary membrane resulting in increased vascular permeability, an influx of inflammatory cells into the lung and a local pro-coagulant state. Patients with ALI present with severe hypoxaemia and radiological evidence of bilateral pulmonary oedema. The syndrome has a mortality rate of approximately 35% and usually requires invasive mechanical ventilation. ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis. Although animal models of ALI have been developed, none of them fully recapitulate the human disease. The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies. Improved animal models and the development of human in vivo and ex vivo models are therefore required. In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome.     

Indicator dilution measurements of extravascular lung water: basic assumptions and observations

Since they were introduced more than five decades ago, a variety of single-pass indicator, thermal, and osmotic dilution approaches have been developed for detecting and measuring excess fluid in the lungs. This brief review discusses why studies of the extravascular lung water (EVLW) continue to intrigue physiologists and clinicians and the likelihood that they will become sufficiently reliable for more widespread use. Emphasis is placed on the basic assumptions that underlie these measurements and limitations imposed by the nature of the data that are collected. A distinction is made between approaches that are based on compartmental models of solute and water exchange and those that represent extensions of more conventional washout procedures, which have been utilized extensively for measurements of gas volumes in the lungs. Although the compartmental approach has been used to simplify indicator dilution studies by eliminating the need for a vascular indicator, it is based on assumptions that may not be realistic. Early recirculation inevitably limits the period in which observations can be made and impairs detection of those portions of the lungs with decreased perfusion. These general principles are also used to develop a new method of analyzing osmotic transient studies. A short account is given of EVLW observations that have been made in animals and humans. Both the sensitivity and specificity of EVLW measurements in humans are uncertain, and the normal clinical range of EVLW remains in doubt.     

The influence of gas exchange on lung gas concentrations during air breathing

A model study is made of the contribution that continuing respiratory gas exchange makes to the alveolar plateau slope for O₂ during air breathing. Calculations in the model of the O₂ concentration appearing at the mouth during expiration, are performed for single breaths of air at constant flow rates 18 litres/min and 120 litres/min. At 18 litres/min the breathing period is 5 sec, the initial lung volume is 2300 ml, and the O₂ uptake rate is 300 ml STPD/min; whereas at 120 litres/min these parameters are 4 sec, 1200 ml, and 1800 ml STPD/min respectively. In each case the initial lung O₂ tension is taken to be 98 mm Hg. It is found that at 18 litres/min, the O₂ concentration difference on the alveolar plateau over the last second of expiration is 0.4 mm Hg when gas exchange is omitted and 1.2 mm Hg when gas exchange is included in the model. At 120 litres/min, this difference is zero and 5.0 mm Hg respectively. The gas exchange component predicted from a corresponding well-mixed compartment model is the same at 18 litres/min (0.8 mm Hg) but is 6.0 mm Hg at 120 litres/min.     

Kinetic measurements of gas exchange in the intact pulmonary microcirculation.

The kinetics of gas exchange are monitored in an isolated perfused lung preparation contained within a plethysmograph. The lungs are perfused with buffer, and there is no gas exchange until a 2.0-ml bolus of reactant is injected into the perfusion system. Subsequent gas exchange produces a pressure transient that is related to the corresponding volume of exchanged gas. The observed rate of volume change is the result of two separate processes: 1) the rate of gas exchange during transit through the capillary bed and 2) the distribution of vascular transit times between the point of injection and the capillary bed. The latter is assessed by a control injection containing a dissolved inert gas that is liberated in the alveoli as the bolus enters the capillary bed. Analysis of the experimental curves permits the separation of these two processes. A model of exchange kinetics indicates that this method has the capability of measuring kinetic events occurring during gas exchange in the microcirculation under physiological conditions.     

A stochastic approach for the interpretation of single pulse experiments in morphological multicompartments of renewing and exponentially growing cell populations

A general approach for the interpretation of single pulse experiments in multicompartment systems is presented. It allows an extension of the classical single compartment Barret's methodology, and has been detailed in the pipeline model case to show its capabilities. FLM, FLC, grain count curves, labelling indices and compartment size ratios of each compartment, are fitted into a coherent scheme that fully describes the statistical aspects of the phase durations including possible losses. It is shown that if the compartments are identical, irrespective of the feedback coupling between them, the system may be treated as a single compartment. It is also shown that the FLC information is necessary to identify the existence of losses in the system, and how to correct the "apparent" transit times if losses are present. The pipeline model is treated and a suggestion is made to reconcile the "British" and "American" interpretations of the erythroid system. As a corollary, simple formulae are derived in the deterministic case through a coupling matrix describing the interaction between compartments. Computer codes are described and have been implemented in the J.E.N. Thermoecology Laboratory.     

Effects of hypoxic pulmonary vasoconstriction on pulmonary gas exchange

Brimioulle, Serge, Philippe Lejeune, and Robert Naeije.Effects of hypoxic pulmonary vasoconstriction on pulmonary gasexchange. J. Appl. Physiol. 81(4):1535-1543, 1996.Several reports have suggested that hypoxicpulmonary vasoconstriction (HPV) might result in deterioration ofpulmonary gas exchange in severe hypoxia. We therefore investigated theeffects of HPV on gas exchange in normal and diseased lungs. Weincorporated a biphasic HPV stimulus-response curve observed in intactdogs (S. Brimioulle, P. Lejeune, J. L. Vachièry, M. Delcroix, R. Hallemans, and R. Naeije, J. Appl.Physiol. 77: 476-480, 1994) into a 50-compartment lung model (J. B. West, Respir.Physiol. 7: 88-110, 1969) to control the amount ofblood flow directed to each lung compartment according to the localhypoxic stimulus. The resulting model accurately reproduced the bloodgas modifications caused by HPV changes in dogs with acute lung injury.In single lung units, HPV had a moderate protective effect on alveolaroxygenation, which was maximal at near-normal alveolarPO₂ (75-80 Torr), mixed venousPO₂ (35 Torr), andPO₂ at which hemoglobin is 50%saturated (24 Torr). In simulated diseased lungs associated with40-60 Torr arterial PO₂,however, HPV increased arterial PO₂ by 15-20 Torr. We conclude that HPV can improve arterialoxygenation substantially in respiratory failure.

     

A new class of biophysical models for predicting the probability of decompression sickness in scuba diving.

Interconnected compartmental models have been used for decades in physiology and medicine to account for the observed multi-exponential washout kinetics of a variety of solutes (including inert gases) both from single tissues and from the body as a whole. They are used here as the basis for a new class of biophysical probabilistic decompression models. These models are characterized by a relatively well-perfused, risk-bearing, central compartment and one or two non-risk-bearing, relatively poorly perfused, peripheral compartment(s). The peripheral compartments affect risk indirectly by diffusive exchange of dissolved inert gas with the central compartment. On the basis of the accuracy of their respective predictions beyond the calibration regime, the three-compartment interconnected models were found to be significantly better than the two-compartment interconnected models. The former, on the basis of a number of criteria, was also better than a two-compartment parallel model used for comparative purposes. In these latter comparisons, the models all had the same number of fitted parameters (four), were based on linear kinetics, had the same risk function, and were calibrated against the same dataset. The interconnected models predict that inert gas washout during decompression is relatively fast, initially, but slows rapidly with time compared with the more uniform washout rate predicted by an independent parallel compartment model. If empirically verified, this may have important implications for diving practice.     

Quasi-static pressure-volume hysteresis in the canine respiratory system in vivo

We investigated the quasi-static pressure-volume (P-V) hysteresis of the normal canine lung in vivo by performing 15-s flow interruptions at various points throughout the breathing cycle in mechanically ventilated anesthetized paralyzed dogs. By measuring the transpulmonary pressure (Ptp) at 5 s after each interruption, we built up a quasi-static P-V loop of the lungs. We found, however, that the area of the loop was significantly smaller (by a factor of 4-6) than has been reported by others for the isolated canine lung. We also found the hysteresis loop area of the chest wall to be of similar magnitude. If we measured Ptp 10-15 s after interruption, we found it always decreased at a rate expected to result from continuing gas exchange in the lungs. We conclude that 1) the areas of the quasi-static P-V loop in vivo for the total respiratory system, as well as the lungs and chest wall separately, are significantly smaller than has been reported previously for isolated lungs and 2) continuing gas exchange in the lungs places a lower limit on the frequencies (equivalent to flow interruptions of greater than 5- to 7-s duration) at which the P-flow-V behavior of the lungs in vivo can be considered in purely mechanical terms.     

Multiscale model for pulmonary oxygen uptake and its application to quantify hypoxemia in hepatopulmonary syndrome

This paper presents a novel multiscale methodology for quantitative analysis of pulmonary gas exchange. The process of oxygen uptake in the lungs is a complex multiscale process, characterized by multiple time and length scales which are coupled nonlinearly through the processes of diffusion, convection and reaction, and the overall oxygen uptake is significantly influenced by the transport and reaction rate processes at the small-scales. Based on the separation of length scales, we characterize these disparate scales by three representative ones, namely micro (red blood cell), meso (capillary and alveolus) and macro (lung). We start with the fundamental convection-diffusion-reaction (CDR) equation that quantifies transport and reaction rates at each scale and apply spatial averaging techniques to reduce the dimensionality of these models. The resultant low-dimensional models embed each scale hierarchically within the other while retaining the important parameters of the small-scales in the averaged equations, and drastically reduce the computational efforts involved in solving them. We use our multiscale model for pulmonary gas exchange to quantify the oxygen uptake abnormalities in patients with hepatopulmonary syndrome (HPS), a disease which is characterized by coupled abnormalities in multiple length scales. Based on our multiscale modeling, we suggest a strategy to stratify patients with HPS into two categories--those who are oxygen-responsive and those who are oxygen non-responsive with intractable hypoxemia.     

Hyperpolarized 129Xe MR Imaging of Alveolar Gas Uptake in Humans

Background

One of the central physiological functions of the lungs is to transfer inhaled gases from the alveoli to pulmonary capillary blood. However, current measures of alveolar gas uptake provide only global information and thus lack the sensitivity and specificity needed to account for regional variations in gas exchange.

Methods and Principal Findings

Here we exploit the solubility, high magnetic resonance (MR) signal intensity, and large chemical shift of hyperpolarized (HP) ¹²⁹Xe to probe the regional uptake of alveolar gases by directly imaging HP ¹²⁹Xe dissolved in the gas exchange tissues and pulmonary capillary blood of human subjects. The resulting single breath-hold, three-dimensional MR images are optimized using millisecond repetition times and high flip angle radio-frequency pulses, because the dissolved HP ¹²⁹Xe magnetization is rapidly replenished by diffusive exchange with alveolar ¹²⁹Xe. The dissolved HP ¹²⁹Xe MR images display significant, directional heterogeneity, with increased signal intensity observed from the gravity-dependent portions of the lungs.

Conclusions

The features observed in dissolved-phase ¹²⁹Xe MR images are consistent with gravity-dependent lung deformation, which produces increased ventilation, reduced alveolar size (i.e., higher surface-to-volume ratios), higher tissue densities, and increased perfusion in the dependent portions of the lungs. Thus, these results suggest that dissolved HP ¹²⁹Xe imaging reports on pulmonary function at a fundamental level.     

Investigation into the foundations of the track-event theory of cell survival and the radiation action model based on nanodosimetry

This work aims at elaborating the basic assumptions behind the “track-event theory” (TET) and its derivate “radiation action model based on nanodosimetry” (RAMN) by clearly distinguishing between effects of tracks at the cellular level and the induction of lesions in subcellular targets. It is demonstrated that the model assumptions of Poisson distribution and statistical independence of the frequency of single and clustered DNA lesions are dispensable for multi-event distributions because they follow from the Poisson distribution of the number of tracks affecting the considered target volume. It is also shown that making these assumptions for the single-event distributions of the number of lethal and sublethal lesions within a cell would lead to an essentially exponential dose dependence of survival for practically relevant values of the absorbed dose. Furthermore, it is elucidated that the model equation used for consideration of repair within the TET is based on the assumption that DNA lesions induced by different tracks are repaired independently. Consequently, the model equation is presumably inconsistent with the model assumptions and requires an additional model parameter. Furthermore, the methodology for deriving model parameters from nanodosimetric properties of particle track structure is critically assessed. Based on data from proton track simulations it is shown that the assumption of statistically independent targets leads to the prediction of negligible frequency of clustered DNA damage. An approach is outlined how track structure could be considered in determining the model parameters, and the implications for TET and RAMN are discussed.

     

A model evaluation of estimates of breath-to-breath alveolar gas exchange

A mathematical model has been implemented for evaluation of methods for estimating breath-to-breath alveolar gas exchange during exercise in humans. This model includes a homogeneous alveolar gas exchange compartment, a dead space compartment, and tissue spaces for CO2 (alveolar and dead space). The dead space compartment includes a mixing portion surrounded by tissue and an unmixed (slug flow) portion which is partitioned between anatomical and apparatus contributions. A random sinusoidal flow pattern generates a breath-to-breath variation in pulmonary stores. The Auchincloss algorithm for estimating alveolar gas exchange (Auchincloss et al., J. Appl. Physiol. 21: 810-818, 1966) was applied to the model, and the results were compared with the simulated gas exchange. This comparison indicates that a compensation for changes in pulmonary stores must include factors for alveolar gas concentration change as well as alveolar volume change and thus implies the use of end-tidal measurements. Although this algorithm yields reasonable estimates of breath-to-breath alveolar gas exchange, it does not yield a "true" indirect measurement because of inherent error in the estimation of a homogeneous alveolar gas concentration at the end of expiration.     

Quantitative pulmonary anatomy of a ground-dwelling bird, the white-breasted water-hen (Amaurornis phoenicurus)

Stereological data on the lungs of ground-dwelling birds are restricted to a few, mainly galliform, species. Data are presented for the non-galliform, white-breasted water-hen. The volume densities of the main parts of the lung and exchange tissue and the surface areas and thicknesses of the components of the blood-gas pathway were estimated by point counting. The anatomical diffusing capacities of the pathway were then estimated. The main parameters determining gas exchange were normalized with body mass and compared with those of other avian species. The anatomical diffusing capacity of the water-hen was inferior to that of passerine and trochilid species, similar to that of non-passerine species reliant on continuous powered flight (mallard) or soaring and gliding (gull), superior to that of domestic galliform species, and strongly superior to that of the flightless emu. It is concluded that selection pressures evolve a lung with a capacity for gas exchange sufficient for the energetic requirements of a particular strategy.     

Pulmonary hypoplasia in mice lacking tumor necrosis factor-alpha converting enzyme indicates an indispensable role for cell surface protein shedding during embryonic lung branching morphogenesis

Many membrane-bound protein precursors, including cytokines and growth factors, are proteolytically shed to yield soluble intercellular regulatory ligands. The responsible protease, tumor necrosis factor-alpha converting enzyme (TACE/ADAM-17), is a transmembrane metalloprotease-disintegrin that cleaves multiple cell surface proteins, although it was initially identified for the enzymatic release of tumor necrosis factor-alpha (TNF-alpha). Mammalian lung growth and development are tightly controlled by cytokines and peptide growth factors. However, the biological function of the cell shedding mechanism during lung organogenesis is not understood. We therefore evaluated the role of TACE as a "sheddase" during lung morphogenesis by analyzing the developmental phenotypes of lungs in mice with an inactive TACE gene in both in vivo and ex vivo organ explant culture. Neonatal TACE-deficient mice had visible respiratory distress and their lungs failed to form normal saccular structures. These newborn mutant lungs had fewer peripheral epithelial sacs with deficient septation and thick-walled mesenchyme, resulting in reduced surface for gas exchange. At the canalicular stage of E16.5, the lungs of TACE mutant mice were impaired in branching morphogenesis, inhibited in epithelial cell proliferation and differentiation, and delayed in vasculogenesis. Embryonic TACE knockout mouse lungs (E12) branched poorly compared to wild-type lungs, when placed into serumless organ culture. Gene expression of both surfactant protein-C and aquaporin-5 were inhibited in cultured TACE-mutant embryonic lungs, indicating defects in both branching and peripheral epithelial cytodifferentiation in the absence of TACE protein. Furthermore, both the hypoplastic phenotype and the delayed cytodifferentiation in TACE-deficient lungs were rescued by exogenous addition of soluble stimulatory factors including either TNF-alpha or epidermal growth factor in embryonic lung culture. Thus, the impaired lung branching and maturation without TACE suggest a broad role for TACE in the processing of multiple membrane-anchored proteins, one or more of which is essential for normal lung morphogenesis. Taken together, our data indicate that the TACE-mediated proteolytic mechanism which enzymatically releases membrane-tethered proteins plays an indispensable role in lung morphogenesis, and its inactivation leads to abnormal lung development.     

On the maximum likelihood estimation of respiratory response slopes

Several approaches have been suggested for estimating a respiratory response slope when both x and y variables are observed with error. Recently, a maximum likelihood estimate under the assumption of a bivariate normal distribution has been proposed. A method of moments solution yields a slope estimate of y/x as long as the underlying process mean is nonzero. This paper extends the maximum likelihood approach to the case where the process mean is zero. In this case, certain additional error assumptions must be made to yield a unique estimate. These concepts are applied to the problem of estimating an effective lung volume for steady-state breath-to-breath gas exchange data during exercise.