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Istituto di Fisiologia Umana I, Università di Milano, 20133 Milan; Dipartimento di Medicina Clinica e Sperimentale, Università di Padova, 35128 Padua, Italy; and Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada H2X 2P2
Submitted 3 November 2003 ; accepted in final form 10 March 2004
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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lung mechanics; viscoelasticity; recruitment-derecruitment of lung units; airway-parenchymal coupling; parenchymal inflammation
Accordingly, in the present study, we have assessed in normal, anesthetized, paralyzed, open-chest rabbits the effects of different inflation rates during low lung volume ventilation for 3–4 h on 1) lung mechanics and 2) histological indexes of lung injury and inflammation.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Airflow was measured with a heated Fleisch pneumotachograph no. 00 (HS Electronics, March-Hugstetten, Germany) connected to the tracheal cannula and a differential pressure transducer (Validyne MP45, ±2 cmH2O; Northridge, CA). The response of the pneumotachograph was linear over the experimental range of airflow. Tracheal pressure (Ptr) and systemic blood pressure were measured with pressure transducers (model 1290A; Hewlett-Packard, Palo Alto, CA) connected to the side arm of the tracheal cannula and carotid catheter, respectively. There was no appreciable shift in the signal or alteration in amplitude up to 20 Hz. The signals from the transducers were amplified (model RS3800; Gould Electronics, Valley View, OH), sampled at 200 Hz by a 14-bit analog-to-digital converter, and stored on a desktop computer. Volume changes were obtained by numerical integration of the digitized airflow signal. Arterial blood PO2, PCO2, and pH were measured by means of a blood-gas analyzer (IL 1620; Instrumentation Laboratory, Milan, Italy) on samples drawn at the beginning and end of each test session.
After completion of the surgical procedure, the rabbits were ventilated with a specially designed, computer-controlled ventilator, which delivered water-saturated air from a high-pressure source (4 atm) at a constant flow of different selected magnitudes and durations. The inspiratory and expiratory solenoid valves (model S50 and S80; Peter Paul, New Britain, CT) had a closing or opening time of 5 ms; they could be also used to occlude the airways either at end inspiration or end expiration for 5 s. The inspiratory and expiratory valves were connected to the pneumotachograph attached to the tracheal cannula by means of short, rigid tubings. A Fleisch pneumotachograph (no. 00) connected to the exhaust valve (model S50) of the inspiratory line and differential pressure transducer (Validyne MP45, ±2 cmH2O) provided the feedback signal to the computer for the fine adjustement of the proportional valve (model PSV1; Aalborg, Orangeburg, NY) setting the inflation flow. A three-way stopcock allowed the connection of the expiratory valve to either the ambient or a drum in which the pressure was set at 2.0–2.5 cmH2O by means of a flow-through system.
Two groups of nine and seven rabbits, respectively, were ventilated with high-inflation flow (groups A and C) and nine rabbits with low-inflation flow (group B). In all instances, the baseline ventilator settings consisted of fixed VT (11 ml/kg) and cycle duration of 3 s, whereas the inspiratory duration (TI) was 0.25 for groups A and C and 1.8 s for group B (Fig. 1). In groups A and C, an end-inspiratory pause of 0.75 s was applied to ensure the same mean lung volume during the respiratory cycle for all groups. During baseline ventilation, the inflation flow and TI-to-cycle duration ratio were 44 ml·kg–1·s–1 and 0.33, respectively, for groups A and C and 6.1 ml·kg–1·s–1 and 0.6 for group B. With the above settings, no intrinsic PEEP was present under any experimental condition, as evidenced by an end-expiratory pause (zero flow) and absence of Ptr changes with airway occlusion at end expiration. During the measurements, the ribs on the two sides and the diaphragm were pulled widely apart to prevent contact between lung and chest wall, except in their dependent parts. The investigation conformed to American Physiological Society guidelines for animal study.
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Measurements of lung mechanics were performed as previously described (9). Briefly, with the baseline ventilator settings kept constant, group A and B rabbits were subjected to the following sequence of PEEP and ZEEP: 1) 15 min of MV with PEEP (PEEP1); 2) 3–4 h of MV at ZEEP; and 3) 15 min of MV with PEEP (PEEP2). Lung mechanics were assessed with the rapid airway occlusion method (3, 6) during the PEEP1 and PEEP2 periods, after 
10 min (ZEEP1), and at the end of the ZEEP period (ZEEP2). Ten to fifteen minutes elapsed between measurements on ZEEP2 and PEEP2. In group C rabbits, which were ventilated as those of group A but only on PEEP, assessment of lung mechanics was made 5–10 min after the onset of MV with PEEP (PEEP1) and at the end of the 3- to 4-h PEEP period (PEEP2). Before all measurements on PEEP, the lungs were inflated three to four times to a Ptr of 25 cmH2O. Two types of measurements were carried out: 1) while VT was kept at baseline values, test breaths were intermittently performed with different inspiratory flows and TI in the range of 0.25–3 s to assess lung mechanics at end inflation; and 2) while inspiratory flow was kept at baseline values, test breaths were intermittently performed with different VT to obtain quasi-static inflation V-P curves. End-inspiratory occlusions lasting 5 s were made in all test breaths, which were performed in random order and repeated four to five times under all experimental conditions. During ventilation at ZEEP, end-inspiratory occlusions were performed only for VT 
baseline VT. During ventilation with PEEP, the expiratory valve was opened to the ambient for four to six expirations to measure the difference between the end-expiratory and the resting lung volume; these breaths were followed by two inflations with a Ptr of 20–25 cmH2O. The animals were from a single cohort, and the experiments were done in random order.
The end-inspiratory airway occlusions were followed by a rapid initial drop in Ptr and by a slow decay to an apparent plateau value (Pst). This pressure, computed as the mean pressure recorded during the last 0.5 s of occlusion, was taken to represent the quasi-static lung recoil pressure, whereas the initial drop in Ptr and the slow decay divided by inspiratory flow yielded the lung interrupter (Rint) and additional (
R) resistances, respectively. Viscoelastic parameters for resistance (Rvisc) and 
visc = Rvisc/Evisc, where Evisc is viscoelastic elastance and visc is the viscoelastic time constant, were computed by fitting the values of R and TI with the function (7)
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Histological Analysis
Lung fixation was performed in seven animals in both groups A and B and in five animals in group C. The rabbits were given heparin (355 U/kg) and papaverin (5 mg/kg) intravenously to prevent bronchospasm. The pericardium was removed, ties were placed around the descending aorta and the hilum of the right lung, and a large needle was inserted through the right ventriculum into the pulmonary artery. After three inflations to 25 cmH2O, the transpulmonary pressure was kept at 10 cmH2O, the ties were fastened, the right lung was removed, the right atrium was cut, and the left lung was perfused with saline until the lobar surfaces became white. Thereafter, lung fixation was obtained by perfusing with 4% formaldehyde and 0.1% glutardialdehyde dissolved in 0.12 M phosphate buffer. Six blocks, 1 cm thick, involving both subpleural and parahilar regions, were obtained in each animal. Each block was processed through a graded series of alcohols and embedded in paraffin. From each block, sections of 5 µm thickness were cut and stained with hematoxylin-eosin for light miscroscopy analysis. Histological evaluation was performed by a single observer who had no knowledge of the mechanical data. The following measurements were obtained: 1) mean linear intercept (Lm), which is a measure of airspace enlargement, as described by Thurlbeck (26); 2) indexes of destruction of the alveolar attachments, which are the alveolar walls that extend radially from the outer wall of the nonrespiratory bronchioles (20); and 3) polymorphonuclear leukocyte count in the alveolar walls, which is an index of parenchymal inflammation (19).
For Lm measurements, one section from each block was examined at a magnification of x125, and 40 nonoverlapping fields were analyzed on each section, giving a total of 240 fields/animal. The value of Lm was obtained as the ratio between the length (in µm) of a line passing transversely through each field and the number of alveolar walls intercepting that line, with the final result for a given animal being the average Lm of the 240 fields examined.
For alveolar-bronchiolar coupling evaluation, the percentage of abnormal alveolar attachments and the distance between attachments were assessed in 50 nonrespiratory bronchioles per animal. Any discontinuity or rupture of the alveolar walls was considered an abnormality, and such alveolar walls were called abnormal attachments. In each airway, peribronchiolar alveolar walls (normal and abnormal attachments) were counted directly in the microscopic field at a magnification of x250. The external circumference was measured by computer-aided image analysis (Casti Imaging, Venice, Italy). Two indexes were obtained for groups A and B: 1) abnormal attachments computed as the percent ratio of abnormal to total (normal and abnormal) attachments, and 2) distance between normal attachments (in µm) computed as the ratio of external circumference to number of normal attachments, whereas for group C only the former index was assessed.
Inflammatory cell counts in the lung parenchyma were performed as previously described (19). Briefly, at a magnification of x800 the number of polymorphonuclear leukocytes within the alveolar wall was computed, and the length of the alveolar wall was measured. Ten fields randomly distributed across the slide were studied, and the result was expressed as number of polymorphonuclear leukocytes per millimeter of alveolar wall. For each animal, a total of 60 fields were examined.
Statistics
Results from mechanical studies are presented as means ± SE. The least-square regression method was used to assess the parameters in Eq. 1 and of the pressure-volume relationship of the lungs. Comparisons among experimental conditions were performed with one-way ANOVA; when significant differences were found, the Bonferroni test was performed to determine significant differences between different experimental conditions. Results from histological studies are expressed as median and range, and the statistical analysis was performed using the Mann-Whitney test. The level for statistical significance was taken at P 0.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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In each animal, the values of arterial PO2 (PaO2), PCO2 (PaCO2), and pH (pHa) obtained at the beginning and at the end of the PEEP1, ZEEP1, ZEEP2, and PEEP2 sessions did not differ significantly and were thus averaged. The mean values of these parameters during PEEP1 and PEEP2 and the wet-to-dry ratio assessed at the end of the experiments were similar for all groups of rabbits (Table 1). The values of wet-to-dry ratio were similar to those of freshly excised rabbits lungs (9).
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P/t) with PEEP1 was about sevenfold larger in groups A and C than in group B (Table 2). Relative to PEEP1, P/t increased significantly with PEEP2 in both groups A and B, whereas it remained unchanged in group C.
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Viscoelastic properties.
In all animals and conditions, a unique function in the form of Eq. 1 adequately described the experimental R-TI data (r > 0.94), allowing computation of Rvisc and visc. Figure 3 depicts the group mean relationships of R to TI obtained under the various experimental conditions. With PEEP2, neither Rvisc nor visc changed significantly relative to corresponding PEEP1 values in all groups of rabbits (Table 5). On an individual basis, Rvisc was, however, increased significantly in four and two animals of groups A and B, respectively. No significant changes of either Rvisc or visc were observed in any animal of group C.
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Relative to PEEP1, with ZEEP1 there was a similar increase of PaCO2 and decrease of PaO2 and pHa in both group A and group B (Table 1). With further ventilation on ZEEP (ZEEP2), there was a small but significant increase of PaO2, whereas pHa and PaCO2 remained essentially unchanged (Table 1). Because this occurred in both group A and group B, the values of PaO2, PaCO2, and pHa were similar among the animals of the two groups also with ZEEP2.
The average values of P/t increased markedly on ZEEP in both group A and group B, and a further significant increase occurred with prolonged ventilation on ZEEP (Table 2).
Elastance.
According to the Vo values in Table 3, baseline tidal ventilation on ZEEP occurred in the range of 0–33% Vo. There was both an immediate and a progressive increase in Est with ventilation on ZEEP (Table 4) in animals ventilated with high (group A) and low inflation flows (group B). These changes were, however, significantly larger in group A than in group B, both at ZEEP1 (250 ± 17 vs. 185 ± 13 cmH2O/l; P < 0.001) and ZEEP2 (328 ± 14 vs. 258 ± 6 cmH2O/l; P < 0.001). Moreover, the quasi-static V-P relationship, which on PEEP was slightly concave toward the pressure axis, became sigmoidal (Fig. 2). Although Est on PEEP was significantly lower than that at baseline VT for any VT below baseline VT, on ZEEP it was significantly larger than that at baseline VT with VT of 4.4 and 8.9 ml (Est = 11.7 ± 1.6 and 5.3 ± 1.1 cmH2O/l, respectively; P < 0.001) and lower with a VT of 18 ml (Est = –4.7 ± 0.9 cmH2O/l; P < 0.001).
Rint. The mean values of Rint obtained on ZEEP1 and ZEEP2 during ventilation with high and low inflation flows are shown in Table 4. In both groups of animals, there was an immediate and a progressive increase of Rint. With ZEEP1, the increase of Rint, relative to that with PEEP1, amounted to 148 ± 16 and 63 ± 10% in group A and group B, whereas with ZEEP2 and relative to PEEP2 it amounted to 177 ± 25 and 157 ± 25% in the two groups of rabbits, respectively. Hence, there was a significant increase of Rint with prolonged ventilation on ZEEP in animals ventilated with high and low inflation flows, but the increase in Rint was significantly larger in group A than in group B, on both ZEEP1 (20 ± 2 vs. 9 ± 1 cmH2O·s·l–1; P < 0.001) and ZEEP2 (55 ± 7 vs. 36 ± 5 cmH2O·s·l–1; P = 0.022).
Viscoelastic properties.
Figure 3 depicts the relationships of R to TI pertaining to groups A and B obtained with ZEEP1 and ZEEP2, with the group mean values of Rvisc and visc being reported in Table 5. Both Rvisc and visc did not differ significantly between the two groups of animals under any conditions. With ZEEP1, Rvisc increased significantly relative to that with PEEP1 in group A (change in Rvisc = 97 ± 24 cmH2O·s·l–1; P < 0.001) and in group B (change in Rvisc = 58 ± 12 cmH2O·s·l–1; P < 0.001), and a further significant increase occurred between ZEEP1 and ZEEP2 in group A (change in Rvisc = 29 ± 9 cmH2O·s·l–1; P < 0.001) and group B (change in Rvisc = 50 ± 15 cmH2O·s·l–1; P < 0.001). In contrast, visc remained essentially the same under all conditions. The effects of ZEEP on Rvisc were qualitatively similar to those of Est reported above (Table 4). Indeed, there was a highly significant correlation between changes in Est and Rvisc, both expressed relative to the corresponding values during PEEP1, observed in all animals with ZEEP1 and ZEEP2 (Fig. 4).
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Figure 5 illustrates the infiltration of polymorphonuclear leukocytes that occurred in the alveolar septa of rabbits ventilated on ZEEP with high or low inflation flows, whereas Fig. 6 shows the different degrees of airway-parenchyma uncoupling, as it could be inferred from the presence of abnormal alveolar-bronchiolar attachments. The results of measurements of airspace enlargement (Lm), peribronchiolar alveolar wall destruction (percentage of abnormal attachments, distance between normal attachments), and cell counts in the lung parenchyma (cells/mm of alveolar wall) are shown in Table 6 for all groups of rabbits. The values of Lm, percentage of abnormal attachments, and distance between normal attachments were similar in groups A and B. When parenchymal inflammation was analyzed, the number of polymorphonuclear leukocytes within the alveolar wall was significantly larger in group A than in group B (P = 0.018). On the other hand, both the number of polymorphonuclear leukocytes within the alveolar wall and the percentage of abnormal alveolar-bronchiolar attachments were markedly smaller in group C, whereas the values of Lm were essentially the same in all groups (Table 6). No signs of focal alveolar collapse, edema, hemorrhages, and epithelial desquamation in alveoli (25) were present in all groups of rabbits.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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In line with previous results (9), during MV with PEEP, there was no evidence of airway closure since the static inflation V-P curve of the lung was concave to the pressure axis, as shown in Fig. 2 (11). In contrast, at ZEEP, the inflation V-P curve became sigmoidal, its initial part being convex to the pressure axis, reflecting progressive reopening of the small airway (<1 mm in diameter) (12). Thus, during MV on ZEEP, there was cyclic airway opening and closing, which should be responsible for the observed histological alterations as well as the increase in Rint on PEEP2 relative to PEEP1. Moreover, the convexity of the initial part of the quasistatic inflation V-P curve on ZEEP was more pronounced in animals ventilated with high inflation flow (Fig. 2), with the ratio between Est with the lowest inflation volume (4 ml/kg) and baseline VT being significantly larger in group A than in group B (1.34 ± 0.06 vs. 1.18 ± 0.05; P = 0.032). This suggests that, during ventilation with high inflation flow, more airways were involved in cyclic opening and closing with concurrent greater mechanical and histological damage (Tables 4 and 6).
On ZEEP, in both group A and group B, there was a significant increase of Est, Rint, and Rvisc relative to PEEP1, which was significantly greater after 3–4 h (ZEEP2) than after 5–10 min (ZEEP1) of ventilation on ZEEP (Tables 4 and 5). Similar results have been obtained in a previous study (9) on open-chest rabbits ventilated with inflation flows (9 ml·kg–1·s–1 ), which were close to those of group B. A progressive increase of total lung resistance and dynamic elastance during MV at low lung volumes has been previously reported in normal open-chest rabbits (24).
Two mechanisms may account for the increase of Est and Rvisc that occurs on ZEEP relative to PEEP, as well as for their progressive increase with time, namely an increase of lung stiffness due to larger surface forces and a decrease of ventilated tissue caused by airway closure and/or alveolar collapse. An increase of surface forces with time at low end-expiratory transpulmonary pressure and lung volume has been advocated to explain the changes of lung compliance in the absence of detectable airway closure (29, 30). It could also explain the increase in Rvisc, especially on ZEEP2, since most of Rvisc should reside in the air-liquid interface (2). A reduction in ventilated tissue due to airway closure or alveolar collapse should cause proportional changes of Est and Rvisc, while leaving visc unaffected, as was in fact the case (Tables 4 and 5 and Fig. 4). On the basis of theoretical considerations, diffuse alveolar collapse has been predicted to take place at low lung volumes (22, 23), but visible areas of atelectasis did not occur in the present animals. Accordingly, it is likely that increased surface tension and small airway closure are the main mechanisms leading to increased Est and Rvisc during ventilation on ZEEP, with a possible contribution from microatelectasis. Persistent small-airway closure and dependent air trapping should have been evenly distributed throughout the lung, because on visual inspection lung expansion in both group A and group B was apparently uniform on ZEEP as on PEEP. Hence, overdistension of recruited lung units on ZEEP was likely similar during ventilation with low and high inflation flow or even smaller under the latter condition if more airways were involved in cyclic opening and closing (see above).
The increase in airway resistance with acute reductions in lung volume has been ascribed to the concomitant decrease in lung recoil (13). Under the present conditions, however, the lung recoil at baseline VT (i.e., the lung volume at which Rint was assessed) was larger during ZEEP than during PEEP and larger on ZEEP2 than on ZEEP1 (Fig. 2), whereas Rint was larger on ZEEP than on PEEP and larger on ZEEP2 than on ZEEP1 (Table 4). The increase in Rint was not due to the changes in arterial blood gases or pH with ZEEP (Table 1), with the hypercapnia and acidosis observed on ZEEP having, if any, a bronchodilating effect (8). Moreover, hypercapnic acidosis has been reported to exert a protective effect on ventilator-induced lung injury (4). The increase in Rint should be instead related to 1) reduction of ventilated tissue due to small airway closure; 2) uncoupling between peripheral airways and lung parenchyma, as suggested by the occurrence of a large number of abnormal alveolar attachments and increased distance between attachments (Table 6), such that the airway caliber was reduced despite increased lung recoil; and 3) increased bronchomotor tone due to release of inflammatory mediators, as indicated by the presence of polymorphonuclear leukocytes (Table 6). Because the number of abnormal alveolar attachments and the distance between attachments were not significantly different between groups A and B and the amount of gas trapping was possibly larger in group B, the greater increase of Rint on ZEEP with high inflation flow was probably due to a greater contribution of the last mechanisms.
After return of group A and B rabbits to PEEP (PEEP2), Rvisc as well as Est reversed to the initial (PEEP1) values (Tables 4 and 6), whereas Rint remained significantly (P < 0.001) larger (Table 4). The increase in Rint on PEEP2 could not be related to changes in arterial blood gases or pH, because the latter were not significant (Table 1), or to changes in the elastic recoil, because the quasistatic V-P curve, as well as Est, were almost the same on PEEP1 and PEEP2 in all groups of rabbits (Fig. 1 and Table 4). Absence of parenchymal alterations was further indicated by the Lm values (Table 6) that were similar to those of group C rabbits and within the range of those obtained in normal rabbit lungs at corresponding distending pressure (5). Hence, the increase in Rint with PEEP2 was due to changes in the mechanical coupling between peripheral airways and lung parenchyma, as reflected by abnormal alveolar attachments and increased distance between attachments and increased bronchomotor tone with release of mediators by inflammatory cells (Table 6). Indeed, both the percentage of abnormal attachments and the number of inflammatory cells in the alveolar septa were markedly larger in groups A and B than in group C, which did not exhibit any significant change in Rint from PEEP1 to PEEP2 (Tables 4 and 6). Finally, the increased Rint could have also been, in part, related to changes in the mechanical properties of the peripheral airways themselves, since in normal open-chest rabbits evidence of peripheral airway injury, with epithelial necrosis and sloughing, have been found after prolonged ventilation on ZEEP in lungs that were fixed by intratracheal infusion of formalin at a distending pressure of 20 cmH2O (9).
The increase in Rint between PEEP1 and PEEP2 was markedly larger in group A than in group B (Table 4). Assuming that the increase of Rint was due to peripheral airway resistance (9) and that, under normal conditions, peripheral airway resistance contributes 20% of Rint (13), peripheral airway resistance with PEEP1 should have amounted to 3 cmH2O·s·l–1 in all groups of animals and the increase with PEEP2 to 15 and 8 cmH2O·s·l–1 in groups A and B, respectively. Compared with ventilation with low inflation flows (group B), ventilation with high inflation flow, and hence higher P/t (Table 2), should have caused larger stresses in the lung parenchyma surrounding occluded airways (14). Moreover, opening of small airways with rapid inflations could have required pressures substantially larger than critical pressures due to latent opening time (1). This could have, in turn, produced a more marked disruption of the mechanical linkage between parenchyma and small airways, as well as more pronounced alveolar epithelial cell injury (27, 28) with inflammatory reaction and release of brochomotor mediators. The present results (Table 6) indicate that the latter mechanisms were the main cause of the larger increase in Rint during low-volume ventilation with high inflation flows.
Recruitment of polymorphonuclear leukocytes in the alveolar walls during low-volume ventilation and their greater increase with high inflation flows should be of interest in connection with a recently described type of ventilator-induced lung injury called biotrauma (10). Parenchymal overdistension and shear forces generated during repetitive opening and closure of lung units can exacerbate or even initiate significant lung injury and inflammation. However, the relationship among mechanical stimuli, lung injury, and cellular inflammatory response is not fully understood. In particular, the interaction between inflammatory cells and structural cells in the pathogenesis of lung injury has not yet been clarified. There is evidence that MV can lead to release of mediators that prime polymorphonuclear leukocytes, which may represent the major effector cells in the generation of tissue injury, especially considering their potential interaction with other candidate cells, such as alveolar epithelial cells (an additional potential source of inflammatory mediators), contributing to the upregulation of the inflammatory response (10, 27). The finding of an increased number of polymorphonuclear leukocytes within the alveolar walls suggests that the interaction between these inflammatory cells and alveolar epithelial cells could play a crucial role in the pathogenesis of ventilator-induced lung injury.
In the open-chest rabbits in the present study, histological lesions and signs of inflammation were found throughout the lungs because pleural surface pressure was essentially uniform. With a closed chest, however, the lesions should be mainly located in the dependent lung zones, where airway closure occurs preferentially because of lower transpulmonary pressure (15). In this condition, breathing with high inspiratory flows causes redistribution of the inspired volume toward the dependent regions (18), likely increasing the number of airways subjected to cyclic opening and closing, as well as the stress exerted by the expanding parenchyma on closed airways. Based on the present results, it seems likely that, also with a closed chest, the mechanical and histological damage in the dependent lung zones should be greater with rapid than with slow inspirations.
In conclusion, the present study confirms our previous results in normal, open-chest rabbits (9) that after 3–4 h of MV at low lung volume, there is an increase of Rint, which persists after restoration of normal end-expiratory volumes. In addition, the present results show that this increase in Rint is associated with an alteration of alveolar-bronchiolar coupling and lung inflammation, as reflected by the number of polymorphonuclear leukocytes in the alveolar septa and that the latter effects are greater with fast than with slow lung inflations.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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), volume changes (
