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J Appl Physiol 88: 705-712, 2000;
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Vol. 88, Issue 2, 705-712, February 2000

Ventilation heterogeneity does not change following pulmonary microembolism

John Y. C. Tsang1, David Frazer2, and Michael P. Hlastala2

1 University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, Vancouver, British Columbia, Canada V6Z 1Y6; and 2 Departments of Physiology and Biophysics and Medicine, University of Washington, Seattle, Washington 98195


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

By using the multiple-breath helium washout technique, ventilation heterogeneity (VH) after embolic injury in the lung can be quantitatively partitioned into the conductive and acinar components. Total VH, represented by the normalized slope of the phase III alveolar plateau, SnIII (total), was studied for 120 min in three groups of anesthetized and paralyzed mongrel dogs. Group 1 (n = 3) received only normal saline and served as controls. Group 2 (n = 4) received repeated infusions of polystyrene beads (250 µm) into the right atrium at 10, 40, 80, and 120 min. Group 3 (n = 3) was similarly treated, except that the embolic beads used were 1,000 µm in diameter. The data show that, despite repeated embolic injury by polystyrene beads of different diameters, there was no significant increase in total VH. The acinar component of SnIII, which represents VH in the distal airways, accounts for over 90% of the total VH. The conductive component of SnIII, which represents VH between larger conductive airways, remains relatively constant and a minor component. We conclude that pulmonary microembolism does not result in significant redistribution of ventilation.

conduction; diffusion; multiple-breath helium washout technique; normalized slope of phase III alveolar plateau


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

HYPOXEMIA IS A COMMON FEATURE after acute pulmonary embolism (10, 40). Previous studies have suggested that the mechanisms for the impairment of gas exchange are related to ventilation-perfusion mismatch, increase in physiological dead space, bronchoconstriction, and pulmonary edema (9, 22). With the use of the multiple inert gas elimination technique, the relationships between ventilation and perfusion in pulmonary embolism have been well described (11), but the separate changes in either ventilation or perfusion cannot be specifically distinguished because of the nature of the methodology. For example, creation of a region of low ventilation-to-perfusion ratio (VA/Q) can be caused by increases in perfusion to a region or by decreases in ventilation to that same region. To study specifically the changes in the distribution of ventilation after embolic injury in the lung, the multiple-breath helium washout (MBHW) technique (8) was chosen for our present investigation.

Levy and Simmons (21) have reported that, after acute embolic injury in the lung, there are significant differences in the CO2 tension in the embolized vs. the nonembolized regions. Consequently, alveolar ventilation gradually shifts away from the embolized areas due to regional bronchoconstriction, leading to a lesser decrease in effective alveolar ventilation than predicted and a more homogeneous distribution of ventilation throughout the lung. The purpose of the present investigation is to examine how the distribution of ventilation per se is affected in a carefully controlled animal model with microemboli of specific size and to quantify these changes by the MBHW technique.

Ventilation is primarily determined by convection and diffusion (15, 29). Despite the asymmetrical narrowing and branching of airways (12), as well as the asynchronous ventilation between different gas exchange units (16), ventilation in a healthy lung is remarkably homogeneous (31). By analyzing the expired marker gas concentration recorded during the multiple-breath washout, previous investigators examined the normalized phase III slope (SnIII) of the alveolar plateau (30, 32) and were able to separate the conductive from the acinar component (8, 38). The conductive component is due to the nonuniform ventilation between larger parallel airways where gases are transported by convection and are not affected by diffusion. On the other hand, the acinar component occurs between small airway regions where gases are mixed by the interaction of diffusion and convection in the vicinity of the diffusion-convection front. We have recently demonstrated that, after oleic acid-induced pulmonary edema, the total ventilation heterogeneity (VH) is increased as lung water accumulates progressively (35). Furthermore, this increase can be mostly accounted for by the acinar component as a result of the decrease in peripheral tissue compliance and distal airway closure throughout the injured lung.

We hypothesize that, after pulmonary microembolism, the total VH will be increased, regardless of the changes in the pattern of pulmonary blood flow (36). However, because the microemboli will likely exert injurious effects in the periphery, we expect that the conductive component of VH will be unchanged, whereas the acinar component of VH will be increased.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Animals and Surgical Preparation

Ten mongrel dogs, weighing 20 ± 5 kg, were anesthetized with an intravenous injection of pentobarbital sodium (30 mg/kg), placed in a supine position, and intubated with a cuffed endotracheal tube. In each animal, a 7-Fr Swan-Ganz catheter (Edwards Laboratory) was placed in the pulmonary artery to measure the mean pulmonary arterial pressure (Ppa), mean pulmonary wedge pressure (Ppaw), and cardiac output (QT) by the thermodilution technique. For infusion of fluid and microembolic materials, a large-bore intravenous catheter was placed near the right atrium via the right femoral vein. A carotid arterial catheter was used to monitor the systemic blood pressure (BP). All pressures were referred to the midchest position. Warming blankets were used to maintain the animal's body temperature between 36° and 38°C.

Physiological Measurements

The baseline measurements of Ppa, Ppaw, BP, QT, and Hb, as well as the arterial and venous blood gases, were obtained at time = 0 min, which was ~1 h after the induction of anesthesia. The animals were randomly divided into three groups. Group 1 (n = 3) served as controls and received only normal saline at 50 ml/h as the maintenance fluid. These control animals were studied and monitored with the same experimental protocol as groups 2 and 3 for the next 2 h but without further intervention. Group 2 animals (n = 4) were induced with acute pulmonary microembolism by receiving repeated infusions of 0.5 g of polystyrene beads that were 250 µm in diameter (Bio-Rad Laboratories, Richmond, CA) via the right femoral venous catheter. These polystyrene beads were suspended in 0.9% saline and were injected at 10, 40, 80, and 120 min so that the Ppa would be raised to about two to four times the baseline value. Group 3 animals (n = 3) were induced with similar embolic injury by receiving 0.5 g of larger beads at the same time intervals; the diameter of these beads was 1,000 µm (Duke Scientific, Palo Alto, CA). All the physiological measurements were repeated at 10, 40, 80, and 120 min in all three groups.

Ventilation Parameters

All the animals were anesthetized and ventilated with room air under paralysis (pancuronium bromide, 1-3 mg/h iv). A linear motor ventilator was used so that exhalation could be controlled at a constant flow rate. The inspiratory-to-expiratory ratio was maintained at 1:1, and positive end- expiratory pressure (PEEP) was set at zero. The tidal volume was kept between 12 and 15 ml/kg and the respiratory rate at 18-20 breaths/min to maintain a PCO2 between 36 and 42 Torr before embolic injury. These ventilation parameters were kept constant throughout the whole experiment, and no further adjustment was made regardless of the changes in the arterial blood gases. Because a constant ventilatory setting was maintained, the end-expiratory lung volume was not expected to change abruptly during the experiment (6, 7); thus the observations would reflect the pathological changes in the embolized lung over time.

MBHW Technique

Before each washout run, 3% helium was added to the inspired gas until its concentration was established evenly during all phases of respiration. Just before any measurement was made, helium was discontinued and its concentration was monitored for the subsequent 18 breaths by an on-line mass spectrometer. All MBHW measurements were done in duplicate under the same experimental conditions, i.e., at 0, 10, 40, 80, and 120 min, immediately after the physiological measurements designated at that time. The SnIII was measured for each breath by methods described below.

Wet-to-dry ratios. At the end of the experiments, the animals received a large dose of intravenous pentobarbital sodium and were killed by an injection of saturated KCl. The chests of these animals were then opened, and 10 tissue samples were obtained randomly from the lung. The samples were placed in preweighed empty vials, so that the wet weight of each sample could be measured immediately. All the lung samples were dried in an oven for a period of 3 wk until a constant weight could be obtained. After the dry weights were measured, the wet-to-dry ratio (W/D) of each of these samples was calculated.

SnIII analysis. Through use of the MBHW technique, the VH was quantified by measuring the changes in the phase III alveolar plateau slopes of the 18 breaths during the washout. This method was adopted as the one described by Verbanck et al. (38), which used a linear regression method instead of the exponential approximation. This allows the separation of VH into two components: the large airway conductive component [SnIII(cond)] and VH in the small airway or acinar regions [SnIII(acinar)]. Briefly, the data were analyzed by the following steps.

NORMALIZATION OF SNIII. After a least-squares linear regression was performed for the best fit of raw data in the phase III alveolar plateau of each breath, the difference in the helium concentration ([He]) at 75% and 95% of expiration was obtained. This value was then divided by the differences in the gas volume between 75% and 95% of expiration for the calculation of the phase III alveolar plateau of that breath. To obtain the "normalized" phase III slope of alveolar plateau, SnIII, this ratio was further divided by [He] at 85% of the expired volume of the same breath. Doing so would minimize the influence of helium dilution during the successive washout breaths so that SnIII of all breaths in the same washout could be compared (32) (Fig. 1).


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  		Fig. 1.   Normalization process of phase III alveolar plateau (SnIII) during multiple-breath helium washout technique. [He], helium concentration; V, volume of gas expired. Normally present cardiogenic oscillations have been excluded for clarity. Subscripts 75, 85, and 95 on V and [He] represent the values of the volume and helium concentrations at 75%, 85%, and 95% of expiration, respectively, in a given breath.

CALCULATION OF LUNG TURNOVER NUMBER. The number of lung turnover (TO) was defined as the accumulated expired volume divided by the functional residual capacity (FRC), or n × tidal volume/FRC, where n = breath number. In our experiments, FRC was not directly measured but taken to be 850 ml, after the animals' size, posture, anesthetic state, and paralysis were taken into consideration (28).

PLOTTING OF THE SNIII VS. LUNG TO NUMBER. For each MBHW run, the raw data were plotted in an x-y graph. For the points located between TO 1.5 and 5.5, a linear regression was made so that the slope (m) of the line could be estimated (Fig. 2).


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  		Fig. 2.   Schematic representation of normalized phase III alveolar plateau slope [SnIII(total)] vs. lung turnover (TO). Linear regression was obtained for TO between 1.5 and 5.5. m, Slope of linear regression. With the use of the value for m, tidal volume, estimated functional residual capacity (FRC), SnIII(total), and its two conductive and acinar components are calculated for breath number 1 where the lung TO = 1 × tidal volume/FRC (see text for details). a and b: Abscissa and ordinate in breath 1, obtained from the raw data during multiple-breath helium washout.

PARTITION OF SNIII AT FIRST BREATH. The total SnIII, or SnIII(total), was assumed to be due to only two processes, i.e., SnIII(cond) and SnIII(acinar). Previous reports have shown that the influence of SnIII(acinar) beyond breath number 5 became minimal (8), i.e., when TO was larger than 1.5. Thus the SnIII(cond) of the first breath could be calculated as follows: At breath number 1, SnIII(total) = b; TO = 1 × tidal volume/FRC = a. SnIII(cond) = m × a and SnIII(acinar) = b - m × a.

PLOTTING OF SNIII(TOTAL) OF THE FIRST BREATH WITH THE CONDUCTIVE AND ACINAR COMPONENTS AT DIFFERENT TIMES DURING THE EXPERIMENT. All the SnIII values of the first breath were plotted at 0, 10, 40, 80, and 120 min for each group so that the influence of time and progressive embolic loads on SnIII and its two components could be presented graphically.

Statistics

The hemodynamic and blood gas data before and after the infusion of polystyrene beads were compared by multiple ANOVA with Bonferroni corrections where applicable. Similarly, the values of SnIII(total) and its two components at the first breath were compared within groups at different times and between groups at the same time during the experiments. The level of significance was considered to be P < 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Figures 3A and 4A show that there was no significant change in hemodynamics or arterial blood gases in the control animals during the course of the experiments. Figure 3, B and C, shows that, after the induction of acute pulmonary microembolism at 10 min, Ppa in groups 2 and 3 progressively increased and remained elevated, whereas systemic BPs did not change significantly. QT stayed comparable before and after acute embolic injury.




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  		Fig. 3.   Hemodynamics of animals in control (group 1; A), 250-µm-bead-infused (group 2; B), and 1,000-µm-bead-infused (group 3; C) groups over time course of experiment. * Statistically significant difference from same parameter within same group at time = 0 min.





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  		Fig. 4.   Blood gas data of animals in groups 1 (A), 2 (B), and 3 (C). * Statistically significant difference from same parameter within same group at time = 0 min.

Figure 4, B and C, shows the blood gas data in groups 2 and 3. After the infusion of polystyrene beads, PO2 steadily decreased, whereas PCO2 became higher with increasing embolic loads. These results are compatible with the development of ventilation and perfusion mismatch and increase in physiological dead space as the perfusion to the embolized region was decreased while the minute ventilation was kept constant.

Figure 5 shows the changes in SnIII(total) in groups 1, 2, and 3, respectively, at breath number 1 over the time course of the experiment. Its components, SnIII(cond) and SnIII(acinar), are also presented. The data show that, in all three groups, SnIII(total) remains relatively unchanged despite significant pulmonary hypertension and hypoxemia after repeated administration of embolic load every 40 min. Among the two partitioned components, the vast majority of the VH can be accounted for by SnIII(acinar), whereas SnIII(cond) remains a minor component.




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  		Fig. 5.   SnIII(total) at breath number 1 in groups 1 (A), 2 (B), and 3 (C) during experiments. Its conductive and acinar components are also presented. There was no statistical difference in all 3 parameters after embolic injury induced after time = 0 min.

Tables 1 and 2 show the percent change of SnIII(total) and SnIII(acinar) vs. time, where the baseline value at time = 0 of each animal was taken to be 100%. A decrease in SnIII(total) or SnIII(acinar) represents a decrease in VH or an improvement of ventilation homogeneity. After acute embolic injury, we have actually observed a brief trend toward more homogeneous ventilation in group 2. However, there was no statistical difference in SnIII(total) and SnIII(acinar) before and after embolic injury in all three groups over time.

                              
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  		Table 1.   Change in SnIII(total) over time


                              
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  		Table 2.   Change in SnIII(acinar) over time

W/D of the lung samples obtained from the control and embolized lung samples was 4.48 ± 0.59 in group 1, 5.58 ± 0.40 in group 2 (P < 0.05), and 5.47 ± 0.52 (P < 0.05) in group 3.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The present study was designed to investigate the changes in the distribution of ventilation after acute microembolic injury in the lung. Our data show that the distribution of ventilation does not change significantly despite repeated episodes of embolic injury induced by polystyrene beads (Tables 1 and 2).

The MBHW technique is a well-established method for the quantification of VH (8, 38). By using this technique, we have recently demonstrated that, in oleic acid-induced pulmonary edema, the distribution of ventilation in the distal airways becomes progressively less homogeneous as the lung water accumulates over time (35). If there is a detectable difference in the present investigation, it is expected to be within the limit of resolution.

Our investigation is a basic physiological study rather than a clinical one. We aim to study a complex pathophysiological condition by partitioning it into various components so that each part can be examined with a specific hypothesis. Many previous investigators have used the method of inducing acute pulmonary microembolism by infusing inert beads into the lung because of the beads' reproducible nature, uniform size, and resistance to fibrinolysis. Thus far they have provided us with many important observations: the identification of functional lung unit (41), the time course of pulmonary vascular response to microembolism (24), the effects of different size microemboli on lung fluid and protein exchange (19), and regional neutrophil retention in the lung after acute microembolization (34).

In our experiments, the ventilatory parameters were kept constant in order that the FRC would be least affected (6, 7). Although FRC was estimated by approximation, the overall pattern of our data should remain valid. Admittedly, the exact value of lung TO might not be numerically exact. The data from group 1 indicate that there is minimal influence on SnIII over time under the control condition. Finally, the gas exchange during the respiratory cycle might also account for some errors in estimating SnIII (5). We did not correct for this factor because the correction was likely to be below 10% and it would not affect SnIII disproportionately over time.

We have chosen to analyze the data points between lung TO of 1.5 and 5.5 by linear regression according to methods by Verbanck et al. (38). Our data points beyond TO = 5.5 show significantly more scatter because [He] decreases along with its accuracy in the later breaths. We have also analyzed the TO data points between 1.5 and 4.5 and reached the same conclusions.

The value of SnIII is dependent on the molecular weight of the indicator gas (12) because the diffusivity of that gas affects the position of the diffusion front. In humans, this front for nitrogen is estimated to be near the terminal bronchioles or the 16th generation of the bronchus. The same position for helium is located more mouthward at approximately the 12th generation or at airways measuring 800 µm in diameter (12, 39). The sizes of distal airways and pulmonary arterioles closely approximate each other in the lung periphery (39). Because the sizes of the functional lung units are affected according to bead size (41), we used different sizes of beads in order that VH in airways between 250 and 1,000 µm could be examined for change after embolic injury. Our data did not show any significant changes in SnIII(cond) despite the use of different beads. We conclude that uniformity of conductive ventilation is maintained after microembolic injury where the airway diameter is between 250 and 1,000 µm.

Our data also did not show significant changes in SnIII(acinar) after microembolic injury. Levy and Simmons (21) have proposed earlier that there were shifts in ventilation 30 min after similar lung injury, which resulted in a less-than-expected decrease in alveolar ventilation and a more uniform overall distribution of ventilation. Although our results support their observation that uniformity of ventilation is generally maintained after embolic injury, their proposed explanation remains questionable. They speculated that regional bronchoconstriction occurred in the embolized and hypocapnic zones and that ventilation became diverted to the nonembolized regions where ventilation was homogeneous.

Electron microscopic studies have demonstrated the existence of the pores of Kohn (23), the bronchoalveolar channels of Lambert (20), and the interbronchiole channels of Martin (25). These collateral channels of ventilation at the periphery will contribute to the rapid equilibration of CO2 at the alveolar level, thus diminishing the possibility of induced regional bronchoconstriction. Our data in Fig. 4, B and C, show that the PCO2 became progressively higher with increasing embolic load because of the increase in dead space and fixed minute ventilation, thus further decreasing the likelihood of regional hypocapnea. Recently, several investigators have used fluorescent microspheres (0.5 µm) to study the distribution of ventilation by delivering them to the airways of mechanically ventilated dogs and found no significant changes in the distribution of ventilation after pulmonary microembolism (1).

We should point out that these data must be interpreted in the context of our experimental model, which is different from the clinical situation where the location and size of the embolic load are quite variable and may change over time. Our model is one of diffuse microembolic lung injury in which embolic beads were repeatedly infused into the lung over a 2-h period. Toward the end of the experiment, the embolic injury in the lung would be quite diffuse even though it might be patchy at the beginning (36). Besides the anatomic differences and the applied positive pressure ventilation, which may well eliminate most atelectasis, these animals cannot compensate for hypoxemia by hyperventilating to a lower PCO2.

Our data show that the acinar component accounts for the vast majority of total VH. This pattern of data is different from that seen in spontaneously breathing subjects (38). However, several recent reports involving mechanically ventilated dogs and pigs under paralysis (13, 35) or postmortem rat lungs (37) also show a data pattern similar to ours, in terms of the relative contributions of the conductive and acinar components.

Having observed the unremarkable changes in ventilation after acute pulmonary microembolic injury, we suggest that the resultant hypoxemia is less likely to be related to the changes in bronchomotor tone and is more likely related to perfusion abnormalities (17). Supporting evidence includes recent studies in which the endothelin-1 level is found to be increased in the blood among patients with pulmonary embolism (33) and its release from the embolized lung is found to cause coronary vasoconstriction in an isolated perfusion model (14). The release of this potent vasoconstrictive mediator is triggered in the endothelial cells after most forms of injury (2, 3), which presumably include the embolic kinds. Several clinical reports have shown that patients undergoing pulmonary thromboembolectomy benefited postoperatively from the hemodynamic and oxygenation standpoints (4, 18) after the inhalation of nitric oxide, a vasodilator and an endothelin-1 antagonist (26).

The change in W/D of the lung tissue in groups 2 and 3 was modest. There was no edema fluid ever seen in the endotracheal tube among these animals. W/D is in the range where mild interstitial edema is expected but well below the range of diffuse alveolar flooding (27). The severe degree of hypoxemia cannot be readily explained by W/D alone. In the absence of any compensatory shift in ventilation after acute embolic injury, the overall ventilation-perfusion mismatch may be aggravated (1, 13). We suggest that the deterioration in gas exchange occurs partly as a result of this lack of ventilatory compensation to perfusion abnormalities.

In summary, our study described the distribution of ventilation before and after microembolic injury in the dog's lung using a sensitive technique of the MBHW. We conclude that the ventilation does not change significantly after microembolic injury by beads of uniform size and that the majority of the observed VH can be accounted for by the acinar component in our model. The conductive component, which represents heterogeneity subtended by larger airways, remains unchanged and less important. Our observations suggest that the unremarkable changes in ventilation after pulmonary microembolism may result partly in sustaining the hypoxemia, as they do not redistribute to compensate for the perfusion abnormalities due to vascular embolization. Whether the failure to redistribute ventilation after bead embolization seen in this study also occurs in human thromboembolism remains to be determined.


    ACKNOWLEDGEMENTS

We thank Mical Middaugh for technical assistance and Brad Brush for organization of graphics and manuscript.


    FOOTNOTES

This project was supported by a research grant from the British Columbia Lung Association and a grant (HL-12174) from the National Heart, Lung, and Blood Institute.

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. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: J. Y. C. Tsang, UBC Pulmonary Research Lab., St. Paul's Hospital, 1081 Burrard St., Vancouver, BC, Canada V6Z 1Y6 (E-mail: jtsang{at}interchange.ubc.ca).

Received 17 July 1998; accepted in final form 25 October 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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