Dependence of lung injury on inflation rate during low-volume ventilation in normal open-chest rabbits.

Lung mechanics and morphometry were assessed in two groups of nine normal open-chest rabbits mechanically ventilated (MV) for 3-4 h at zero end-expiratory pressure (ZEEP) with physiological tidal volumes (Vt; 11 ml/kg) and high (group A) or low (group B) inflation flow (44 and 6.1 ml x kg(-1) x s(-1), respectively). Relative to initial MV on positive end-expiratory pressure (PEEP; 2.3 cmH(2)O), MV on ZEEP increased quasi-static elastance and airway and viscoelastic resistance more in group A (+251, +393, and +225%, respectively) than in group B (+180, +247, and +183%, respectively), with no change in viscoelastic time constant. After restoration of PEEP, quasi-static elastance and viscoelastic resistance returned to control, whereas airway resistance, still relative to initial values, remained elevated more in group A (+86%) than in group B (+33%). In contrast, prolonged high-flow MV on PEEP had no effect on lung mechanics of seven open-chest rabbits (group C). Gas exchange on PEEP was equally preserved in all groups, and the lung wet-to-dry ratios were normal. Relative to group C, both groups A and B had an increased percentage of abnormal alveolar-bronchiolar attachments and number of polymorphonuclear leukocytes in alveolar septa, the latter being significantly larger in group A than in group B. Thus prolonged MV on ZEEP with cyclic opening-closing of peripheral airways causes alveolar-bronchiolar uncoupling and parenchymal inflammation with concurrent, persistent increase in airway resistance, which are worsened by high-inflation flow.     

Dependence of lung injury on surface tension during low-volume ventilation in normal open-chest rabbits.

To evaluate the role of pulmonary surfactant in the prevention of lung injury caused by mechanical ventilation (MV) at low end-expiratory volumes, lung mechanics and morphometry were assessed in three groups of eight normal, open-chest rabbits ventilated for 3-4 h at zero end-expiratory pressure (ZEEP) with physiological tidal volumes (Vt = 10 ml/kg). One group was left untreated (group A); the other two received surfactant intratracheally (group B) or aerosolized dioctylsodiumsulfosuccinate (group C) before MV on ZEEP. Relative to initial MV on positive end-expiratory pressure (PEEP; 2.3 cmH(2)O), quasi-static elastance (Est) and airway (Rint) and viscoelastic resistance (Rvisc) increased on ZEEP in all groups. After restoration of PEEP, only Rint (124%) remained elevated in group A, only Est (36%) was significantly increased in group B, whereas in group C, Est, Rint, and Rvisc were all markedly augmented (274, 253, and 343%). In contrast, prolonged MV on PEEP had no effect on lung mechanics of eight open-chest rabbits (group D). Lung edema developed in group C (wet-to-dry ratio = 7.1), but not in the other groups. Relative to group D, both groups A and C, but not B, showed histological indexes of bronchiolar injury, whereas all groups exhibited an increased number of polymorphonuclear leukocytes in alveolar septa, which was significantly greater in group C. In conclusion, administration of exogenous surfactant largely prevents the histological and functional damage of prolonged MV at low lung volumes, whereas surfactant dysfunction worsens the functional alterations, also because of edema formation and, possibly, increased inflammatory response.     

Effects of mechanical ventilation at low lung volume on respiratory mechanics and nitric oxide exhalation in normal rabbits.

Lung mechanics, exhaled NO (NOe), and TNF-alpha in serum and bronchoalveolar lavage fluid were assessed in eight closed and eight open chest, normal anesthetized rabbits undergoing prolonged (3-4 h) mechanical ventilation (MV) at low volume with physiological tidal volumes (10 ml/kg). Relative to initial MV on positive end-expiratory pressure (PEEP), MV at low volume increased lung quasi-static elastance (+267 and +281%), airway (+471 and +382%) and viscolelastic resistance (+480 and +294%), and decreased NOe (-42 and -25%) in closed and open chest rabbits, respectively. After restoration of PEEP, viscoelastic resistance returned to control, whereas airway resistance remained elevated (+120 and +31%) and NOe low (-25 and -20%) in both groups of rabbits. Elastance remained elevated (+23%) only in closed-chest animals, being associated with interstitial pulmonary edema, as reflected by increased lung wet-to-dry weight ratio with normal albumin concentration in bronchoalveolar lavage fluid. In contrast, in 16 additional closed- and open-chest rabbits, there were no changes of lung mechanics or NOe after prolonged MV on PEEP only. At the end of prolonged MV, TNF-alpha was practically undetectable in serum, whereas its concentration in bronchoalveolar lavage fluid was low and similar in animals subjected or not subjected to ventilation at low volume (62 vs. 43 pg/ml). These results indicate that mechanical injury of peripheral airways due to their cyclic opening and closing during ventilation at low volume results in changes in lung mechanics and reduction in NOe and that these alterations are not mediated by a proinflammatory process, since this is expressed by TNF-alpha levels.     

Cytokine release, small airway injury, and parenchymal damage during mechanical ventilation in normal open-chest rats.

Lung morpho-functional alterations and inflammatory response to various types of mechanical ventilation (MV) have been assessed in normal, anesthetized, open-chest rats. Measurements were taken during protective MV [tidal volume (Vt) = 8 ml/kg; positive end-expiratory pressure (PEEP) = 2.6 cmH(2)O] before and after a 2- to 2.5-h period of ventilation on PEEP (control group), zero EEP without (ZEEP group) or with administration of dioctylsodiumsulfosuccinate (ZEEP-DOSS group), on negative EEP (NEEP group), or with large Vt (26 ml/kg) on PEEP (Hi-Vt group). No change in lung mechanics occurred in the Control group. Relative to the initial period of MV on PEEP, airway resistance increased by 33 +/- 4, 49 +/- 9, 573 +/- 84, and 13 +/- 4%, and quasi-static elastance by 19 +/- 3, 35 +/- 7, 248 +/- 12, and 20 +/- 3% in the ZEEP, NEEP, ZEEP-DOSS, and Hi-Vt groups. Relative to Control, all groups ventilated from low lung volumes exhibited histologic signs of bronchiolar injury, more marked in the NEEP and ZEEP-DOSS groups. Parenchymal and vascular injury occurred in the ZEEP-DOSS and Hi-Vt groups. Pro-inflammatory cytokine concentration in the bronchoalveolar lavage fluid (BALF) was similar in the Control and ZEEP group, but increased in all other groups, and higher in the ZEEP-DOSS and Hi-Vt groups. Interrupter resistance was correlated with indexes of bronchiolar damage, and cytokine levels with vascular-alveolar damage, as indexed by lung wet-to-dry ratio. Hence, protective MV from resting lung volume causes mechanical alterations and small airway injury, but no cytokine release, which seems mainly related to stress-related damage of endothelial-alveolar cells. Enhanced small airway epithelial damage with induced surfactant dysfunction or MV on NEEP can, however, contribute to cytokine production.     

Effect of PEEP on respiratory mechanics in anesthetized paralyzed humans.

With the use of the technique of rapid airway occlusion during constant flow inflation, respiratory mechanics were studied in eight anesthetized paralyzed supine normal humans during zero (ZEEP) and positive end-expiratory pressure (PEEP) ventilation. PEEP increased the end-expiratory lung volume by 0.49 liter. The changes in transpulmonary and esophageal pressure after flow interruption were analyzed in terms of a seven-parameter "viscoelastic" model. This allowed assessment of static lung and chest wall elastance (Est,L and Est,W), partitioning of overall resistance into airway interrupter (Rint,L) and tissue resistances (delta RL and delta RW), and computation of lung and chest wall "viscoelastic constants." With increasing flow, Rint,L increased, whereas delta RL and delta RW decreased, as predicted by the model. Est,L, Est,W, and Rint,L decreased significantly with PEEP because of increased lung volume, whereas delta R and viscoelastic constants of lung and chest wall were independent of PEEP. The results indicate that PEEP caused a significant decrease in Rint,L, Est,L, and Est,W, whereas the dynamic tissue behavior, as reflected by delta RL and delta RW, did not change.     

Positive end-expiratory pressure prevents lung mechanical stress caused by recruitment/derecruitment.

This study tests the hypotheses that a recruitment maneuver per se yields and/or intensifies lung mechanical stress. Recruitment maneuver was applied to a model of paraquat-induced acute lung injury (ALI) and to healthy rats with (ATEL) or without (CTRL) previous atelectasis. Recruitment was done by using 40-cmH(2)O continuous positive airway pressure for 40 s. Rats were, then, ventilated for 1 h at zero end-expiratory pressure (ZEEP) or positive end-expiratory pressure (PEEP; 5 cmH(2)O). Atelectasis was generated by inflating a sphygmomanometer around the thorax. Additional groups did not undergo recruitment but were ventilated for 1 h under ZEEP. Lung resistive and viscoelastic pressures and static elastance were computed before and immediately after recruitment, and at the end of 1 h of ventilation. Lungs were prepared for histology. Type III procollagen (PCIII) mRNA expression in lung tissue was analyzed by RT-PCR. Lung mechanics improved after recruitment in the CTRL and ALI groups. One hour of ventilation at ZEEP increased alveolar collapse, static elastance, and lung resistive and viscoelastic pressures. Alveolar collapse was similar in ATEL and ALI, and recruitment opened the alveoli in both groups. ALI showed higher PCIII expression than ATEL or CTRL groups. One hour of ventilation at ZEEP did not increase PCIII expression but augmented it significantly in the three groups when applied after recruitment. However, PEEP ventilation after recruitment avoided any increment in PCIII expression in all groups. In conclusion, recruitment followed by ZEEP was more deleterious in ALI than in mechanical ATEL, although ZEEP alone did not elevate PCIII expression. Ventilation with 5-cmH(2)O PEEP prevented derecruitment and aborted the increase in PCIII expression.     

Effect of PEEP on the mechanics of the respiratory system in ARDS patients.

In patients with adult respiratory distress syndrome (ARDS) we studied the effect of positive end-expiratory pressure (PEEP) on respiratory mechanics. We used the technique of rapid airway occlusion during constant flow (V) inflation to partition the total respiratory system resistance (Rrs) into the interrupter resistance (Rint,rs) and the additional resistance (delta Rrs) due to viscoelastic pressure dissipations and time constant inequalities. We also measured static (Est,rs) and dynamic (Edyn,rs) elastance of the respiratory system. The procedure was carried out in nine ARDS patients at different inspiratory V and inflation volumes (delta V) at PEEP of 0, 5, 10, and 15 cmH2O. We found that during baseline ventilation (delta V = 0.7 liter and V = 1 l/s), Est,rs, Edyn,rs, and Rint,rs did not change significantly with PEEP, whereas delta Rrs and Rrs increased significantly only with PEEP of 15 cmH2O. The increase of delta Rrs and Rrs with PEEP was positively correlated with the concomitant changes in end-expiratory lung volume (P < 0.001). At all levels of PEEP, under iso-delta V conditions, delta Rrs decreased with increasing V, whereas at a fixed V, delta Rrs increased with increasing delta V. A four-parameter model of the respiratory system failed to fully describe respiratory dynamics in the ARDS patients, probably due to nonlinearities.     

Involvement of ANF in the acute antidiuresis during PEEP ventilation

To investigate the potential role of natriuretic factor (ANF) on changes on renal excretory function in response to increased intrathoracic pressure, seven patients were studied during three successive 60-min periods of 1) mechanical ventilation (MV) and zero end-expiratory pressure (ZEEP), 2) MV with 12 cmH2O positive end-expiratory pressure (PEEP), and 3) MV with the same level of PEEP while lower-body positive pressure (LBPP) was applied to restore venous return and increase central blood volume without fluid loading. Hemodynamics, renal excretory function parameters, and plasma immunoreactive atrial natriuretic factor (irANF) levels were recorded at the end of each period. Compared with ZEEP, PEEP induced a significant reduction of diuresis (from 134 +/- 17 to 59 +/- 13 ml/h, P less than 0.01) and natriuresis (from 8.37 +/- 3.5 to 3.83 +/- 2 mmol/h, P less than 0.01), whereas plasma irANF fell from 520 +/- 292 to 155 +/- 40 pg/ml (P less than 0.01) and transmural right atrial pressure decreased from 3.9 +/- 0.5 to 2.4 +/- 0.3 mmHg (P less than 0.01). Opposite changes were observed during application of LBPP, which restored diuresis and plasma irANF to near control ZEEP values, despite continuation of PEEP. Changes in renal excretory function parameters thus paralleled changes in right atrial pressure and plasma irANF. We suggest that changes in plasma irANF in response to hemodynamic variations induced by changes in intrathoracic pressure may contribute to alterations of renal excretory function during PEEP.     

Hormonal interactions and renal function during mechanical ventilation and ANF infusion in humans

To investigate the influence of atrial natriuretic factor (ANF) on renal function during mechanical ventilation (MV), we examined the renal and hormonal responses to synthetic human ANF infusion in eight patients during MV with zero (ZEEP) or 10 cmH2O positive end-expiratory pressure (PEEP). Compared with ZEEP, MV with PEEP was associated with a reduction in diuresis (V) from 208 +/- 51 to 68 +/- 11 ml/h (P less than 0.02), in natriuresis (UNa) from 12.4 +/- 3.3 to 6.2 +/- 2.1 mmol/h (P less than 0.02), and in fractional excretion of sodium (FENa) from 1.07 +/- 0.02), 0.21 to 0.67 +/- 0.17% (P less than 0.02) and with an increase in plasma renin activity (PRA) from 4.83 +/- 1.53 to 7.85 +/- 3.02 ng.ml-1.h-1 (P less than 0.05). Plasma ANF levels markedly decreased during PEEP in four patients but showed only minor changes in the other four patients, and mean plasma ANF levels did not change (163 +/- 33 pg/ml during ZEEP and 126 +/- 30 pg/ml during PEEP). Glomerular filtration rate and renal plasma flow were unchanged. Infusion of ANF (5 ng.kg-1.min-1) during PEEP markedly increased V and UNa by 110 +/- 61 and 107 +/- 26%, respectively, whereas PRA decreased from 7.85 +/- 3.02 to 4.40 +/- 1.5 ng.ml-1.min-1 (P less than 0.05). In response to a 10 ng.kg-1.min-1 ANF infusion, V increased to 338 +/- 79 ml/h during ZEEP but only to 134 +/- 45 ml/h during PEEP (P less than 0.02), whereas UNa increased, respectively, to 23.8 +/- 5.3 and 11.3 +/- 3.3 mmol/h (P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in proteoglycans and lung tissue mechanics during excessive mechanical ventilation in rats

Excessive mechanical ventilation results in changes in lung tissue mechanics. We hypothesized that changes in tissue properties might be related to changes in the extracellular matrix component proteoglycans (PGs). The effect of different ventilation regimens on lung tissue mechanics and PGs was examined in an in vivo rat model. Animals were anesthetized, tracheostomized, and ventilated at a tidal volume of 8 (VT(8)), 20, or 30 (VT(30)) ml/kg, positive end-expiratory pressure of 0 (PEEP(0)) or 1.5 (PEEP(1.5)) cmH(2)O, and frequency of 1.5 Hz for 2 h. The constant-phase model was used to derive airway resistance, tissue elastance, and tissue damping. After physiological measurements, one lung was frozen for immunohistochemistry and the other was reserved for PG extraction and Western blotting. After 2 h of mechanical ventilation, tissue elastance and damping were significantly increased in rats ventilated at VT(30)PEEP(0) compared with control rats (ventilated at VT(8)PEEP(1.5)). Versican, basement membrane heparan sulfate PG, and biglycan were all increased in rat lungs ventilated at VT(30)PEEP(0) compared with control rats. At VT(30)PEEP(0), heparan sulfate PG and versican staining became prominent in the alveolar wall and airspace; biglycan was mostly localized in the airway wall. These data demonstrate that alterations in lung tissue mechanics with excessive mechanical ventilation are accompanied by changes in all classes of extracellular matrix PG.     

Pulmonary and chest wall mechanics in anesthetized paralyzed humans

Pulmonary and chest wall mechanics were studied in 18 anesthetized paralyzed supine humans by use of the technique of rapid airway occlusion during constant-flow inflation. Analysis of the changes in transpulmonary pressure after flow interruption allowed partitioning of the overall resistance of the lung (RL) into two compartments, one (Rint,L) reflecting airway resistance and the other (delta RL) representing the viscoelastic properties of the pulmonary tissues. Similar analysis of the changes in esophageal pressure indicates that chest wall resistance (RW) was due entirely to the viscoelastic properties of the chest wall tissues (delta RW = RW). In line with previous measurements of airway resistance, Rint,L increased with increasing flow and decreased with increasing volume. The opposite was true for both delta RL and delta RW. This behavior was interpreted in terms of a viscoelastic model that allowed computation of the viscoelastic constants of the lung and chest wall. This model also accounts for frequency, volume, and flow dependence of elastance of the lung and chest wall. Static and dynamic elastances, as well as delta R, were higher for the lung than for the chest wall.     

Analysis of behavior of the respiratory system in ARDS patients: effects of flow, volume, and time

The effects of inspiratory flow (V) and inflation volume (delta V) on the mechanical properties of the respiratory system in eight ARDS patients were investigated using the technique of rapid airway occlusion during constant-flow inflation. We measured interrupter resistance (Rint,rs), which in humans represents airway resistance, the additional resistance (delta Rrs) due to viscoelastic pressure dissipations and time constant inequalities, and static (Est,rs) and dynamic (Edyn,rs) elastance. The results were compared with a previous study on 16 normal anesthetized paralyzed humans (D'Angelo et al. J. Appl. Physiol. 67: 2556-2564, 1989). We observed that 1) resistance and elastance were higher in ARDS patients; 2) with increasing V, Rint,rs and Est,rs did not change, delta Rrs decreased progressively, and Edyn,rs increased progressively; 3) with increasing delta V, Rint,rs decreased slightly, delta Rrs increased progressively, and Est,rs and Edyn,rs showed an initial decrease followed by a secondary increase noted only in the ARDS patients. The above findings could be explained in terms of a model incorporating a standard resistance in parallel with a standard elastance and a series spring-and-dashpot body that represents the stress adaptation units within the tissues of the respiratory system.     

Mechanisms of recruitment in oleic acid-injured lungs.

Lung recruitment strategies, such as the application of positive end-expiratory pressure (PEEP), are thought to protect the lungs from ventilator-associated injury by reducing the shear stress associated with the repeated opening of collapsed peripheral units. Using the parenchymal marker technique, we measured regional lung deformations in 13 oleic acid (OA)-injured dogs during mechanical ventilation in different postures. Whereas OA injury caused a marked decrease in the oscillation amplitude of dependent lung regions, even the most dependent regions maintained normal end-expiratory dimensions. This is because dependent lung is flooded as opposed to collapsed. PEEP restored oscillation amplitudes only at pressures that raised regional volumes above preinjury levels. Because the amount of PEEP necessary to promote dependent lung recruitment increased the end-expiratory dimensions of all lung regions (nondependent AND dependent ones) compared with their preinjury baseline, the "price" for recruitment is a universal increase in parenchymal stress. We conclude that the mechanics of the OA-injured lung might be more appropriately viewed as a partial liquid ventilation problem and not a shear stress and airway collapse problem and that the mechanisms of PEEP-related lung protection might have to be rethought.     

Desmin modulates lung elastic recoil and airway responsiveness

Desmin is a structural protein that is expressed in smooth muscle cells of both airways and alveolar ducts. Therefore, desmin could be well situated to participate in passive and contractile force transmission in the lung. We hypothesized that desmin modulates lung compliance, lung recoil pressure, and airway contractile response. To test this hypothesis, respiratory system complex impedance (Zin,rs) at different positive end-expiratory pressure (PEEP) levels and quasi-static pressure-volume data were obtained in desmin-null and wild-type mice at baseline and during methacholine administration. Airways and lung tissue properties were partitioned by fitting Zin,rs to a constant-phase model. Relative to controls, desmin-null mice showed 1) lower values for lung stiffness and recoil pressure at baseline and induced airway constriction, 2) greater negative PEEP dependence of H and airway resistance under baseline conditions and cholinergic stimulation, and 3) airway hyporesponsiveness. These results demonstrate that desmin is a load-bearing protein that stiffens the airways and consequently the lung and modulates airway contractile response.     

Respiratory mechanics and lung development in the rat from early age to adulthood.

The purpose of the present study was to establish how the dependence of respiratory mechanics on lung inflation changes during development. We studied seven groups of rats from 10 days to 3 mo of age at five levels of positive end-expiratory pressure (PEEP) from 0 to 7 hPa (1 hPa = 0.1 kPa approximately 1 cmH(2)O). At each PEEP level, we measured respiratory system resistance and elastance at both 0.9 and 4.8 Hz to partition the mechanical properties into its airway and tissue components. Elastance increased more rapidly with PEEP in the younger animals, which we interpret as reflecting a more pronounced strain stiffening of the younger parenchyma. However, the decrease in airway resistance with PEEP was more pronounced in the older animals. Morphometric analysis showed that mean tissue density decreased and total alveolar surface area increased with age. Our data suggest that the mechanical interdependence between airways and parenchyma is weaker in very young animals compared with mature animals. This may play a role in the hyperresponsiveness of immaturity.     

Atrial natriuretic factor and renal sodium excretion during ventilation with PEEP in hypervolemic dogs.

Controlled mandatory ventilation with positive end-expiratory pressure (PEEP) reduces renal sodium excretion. To examine whether atrial natriuretic factor (ANF) is involved in the renal response to alterations in end-expiratory pressure in hypervolemic dogs, experiments were performed on anesthetized dogs with increased blood volume. Changing from PEEP to zero end-expiratory pressure (ZEEP) increased sodium excretion by 145 +/- 61 from 310 +/- 61 mumol/min and increased plasma immunoreactive (ir) ANF by 104 +/- 27 from 136 +/- 21 pg/ml. Changing from ZEEP to PEEP reduced sodium excretion by 136 +/- 36 mumol/min and reduced plasma irANF by 98 +/- 22 pg/ml. To examine a possible causal relationship, ANF (6 ng.min-1.kg body wt-1) was infused intravenously during PEEP to raise plasma irANF to the same level as during ZEEP. Sodium excretion increased by 80 +/- 36 from 290 +/- 78 mumol/min as plasma irANF increased by 96 +/- 28 from 148 +/- 28 pg/ml. We conclude that alterations in end-expiratory pressure lead to great changes in plasma irANF and sodium excretion in dogs with increased blood volume. Comparison of the effects of altering end-expiratory pressure and infusing ANF indicates that a substantial part of the changes in sodium excretion during variations in end-expiratory pressure can be attributed to changes in plasma irANF.     

Effect of regional lung inflation on ventilation heterogeneity at different length scales during mechanical ventilation of normal sheep lungs

Heterogeneous, small-airway diameters and alveolar derecruitment in poorly aerated regions of normal lungs could produce ventilation heterogeneity at those anatomic levels. We modeled the washout kinetics of (13)NN with positron emission tomography to examine how specific ventilation (sV) heterogeneity at different length scales is influenced by lung aeration. Three groups of anesthetized, supine sheep were studied: high tidal volume (Vt; 18.4 ± 4.2 ml/kg) and zero end-expiratory pressure (ZEEP) (n = 6); low Vt (9.2 ± 1.0 ml/kg) and ZEEP (n = 6); and low Vt (8.2 ± 0.2 ml/kg) and positive end-expiratory pressure (PEEP; 19 ± 1 cmH(2)O) (n = 4). We quantified fractional gas content with transmission scans, and sV with emission scans of infused (13)NN-saline. Voxel (13)NN-washout curves were fit with one- or two-compartment models to estimate sV. Total heterogeneity, measured as SD[log(10)(sV)], was divided into length-scale ranges by measuring changes in variance of log(10)(sV), resulting from progressive filtering of sV images. High-Vt ZEEP showed higher sV heterogeneity at <12- (P < 0.01), 12- to 36- (P < 0.01), and 36- to 60-mm (P < 0.05) length scales compared with low-Vt PEEP, with low-Vt ZEEP in between. Increased heterogeneity was associated with the emergence of low sV units in poorly aerated regions, with a high correlation (r = 0.95, P < 0.001) between total heterogeneity and the fraction of lung with slow washout. Regional mean fractional gas content was inversely correlated with regional sV heterogeneity at <12- (r = -0.67), 12- to 36- (r = -0.74), and >36-mm (r = -0.72) length scales (P < 0.001). We conclude that sV heterogeneity at length scales <60 mm increases in poorly aerated regions of mechanically ventilated normal lungs, likely due to heterogeneous small-airway narrowing and alveolar derecruitment. PEEP reduces sV heterogeneity by maintaining lung expansion and airway patency at those small length scales.     

Different ventilation strategies alter surfactant responses in preterm rabbits.

The effect of ventilation strategy on in vivo function of different surfactants was evaluated in preterm rabbits delivered at 27 days gestational age and ventilated with either 0 cmH2O positive end-expiratory pressure (PEEP) at tidal volumes of 10-11 ml/kg or 3 cmH2O PEEP at tidal volumes of 7-8 ml/kg after treatment with one of four different surfactants: sheep surfactant, the lipids of sheep surfactant stripped of protein (LH-20 lipid), Exosurf, and Survanta. The use of 3 cmH2O PEEP decreased pneumothoraces in all groups except for the sheep surfactant group where pneumothoraces increased (P < 0.01). Ventilatory pressures (peak pressures - PEEP) decreased more with the 3 cmH2O PEEP, low-tidal-volume ventilation strategy for Exosurf-, Survanta-, and sheep surfactant-treated rabbits (P < 0.05), whereas ventilation efficiency indexes (VEI) improved only for Survanta- and sheep surfactant-treated rabbits with 3 cmH2O PEEP (P < 0.01). Pressure-volume curves for sheep surfactant-treated rabbits were better than for all other treated groups (P < 0.01), although Exosurf and Survanta increased lung volumes above those in control rabbits (P < 0.05). The recovery of intravascular radiolabeled albumin in the lungs and alveolar washes was used as an indicator of pulmonary edema. Only Survanta and sheep surfactant decreased protein leaks in the absence of PEEP, whereas all treatments decreased labeled albumin recoveries when 3 cmH2O PEEP was used (P < 0.05). These experiments demonstrate that ventilation style will alter a number of measurements of surfactant function, and the effects differ for different surfactants.     

Volume dependence of airway and tissue impedances in mice.

We measured respiratory input impedance (1-25 Hz) in mice and obtained parameters for airway and tissue mechanics by model fitting. Lung volume was varied by inflating to airway opening pressure (Pao) between 0 and 20 cm H2O. The expected pattern of changes in respiratory mechanics with increasing lung volume was seen: a progressive fall in airway resistance and increases in the coefficients of tissue damping and elastance. A surprising pattern was seen in hysteresivity (eta), with a plateau at low lung volumes (Pao < 10 cm H2O), a sharp fall occurring between 10 and 15 cm H2O, and eta approaching a second (lower) plateau at higher lung volumes. Studies designed to elucidate the mechanism(s) behind this behavior revealed that this was not due to chest wall properties, differences in volume history at low lung volume, time dependence of volume recruitment, or surface-acting forces. Our data are consistent with the notion that at low lung volumes the mechanics of the tissue matrix determine eta, whereas at high lung volumes the properties of individual fibers (collagen) become more important.     

Mechanics, nonlinearity, and failure strength of lung tissue in a mouse model of emphysema: possible role of collagen remodeling.

Enlargement of the respiratory air spaces is associated with the breakdown and reorganization of the connective tissue fiber network during the development of pulmonary emphysema. In this study, a mouse (C57BL/6) model of emphysema was developed by direct instillation of 1.2 IU of porcine pancreatic elastase (PPE) and compared with control mice treated with saline. The PPE treatment caused 95% alveolar enlargement (P = 0.001) associated with a 29% lower elastance along the quasi-static pressure-volume curves (P < 0.001). Respiratory mechanics were measured at several positive end-expiratory pressures in the closed-chest condition. The dynamic tissue elastance was 19% lower (P < 0.001), hysteresivity was 9% higher (P < 0.05), and harmonic distortion, a measure of collagen-related dynamic nonlinearity, was 33% higher in the PPE-treated group (P < 0.001). Whole lung hydroxyproline content, which represents the total collagen content, was 48% higher (P < 0.01), and alpha-elastin content was 13% lower (P = 0.16) in the PPE-treated group. There was no significant difference in airway resistance (P = 0.7). The failure stress at which isolated parenchymal tissues break during stretching was 40% lower in the PPE-treated mice (P = 0.002). These findings suggest that, after elastolytic injury, abnormal collagen remodeling may play a significant role in all aspects of lung functional changes and mechanical forces, leading to progressive emphysema.