We previously found that, following surgical resection of ∼58% of lung units by right pneumonectomy (PNX) in adult canines, oxygen-diffusing capacity (DlO2) fell sufficiently to become a major factor limiting exercise capacity, although the decline was mitigated by recruitment, remodeling, and growth of the remaining lung units. To determine whether an upper limit of compensation is reached following the loss of even more lung units, we measured pulmonary gas exchange, hemodynamics, and ventilatory power requirements in adult canines during treadmill exercise following two-stage resection of ∼70% of lung units in the presence or absence of mediastinal distortion. Results were compared with that in control animals following right PNX or thoracotomy without resection (Sham). Following 70% lung resection, peak O2 uptake was 45% below normal. Ventilation-perfusion mismatch developed, and pulmonary arterial pressure and ventilatory power requirements became markedly elevated. In contrast, the relationship of DlO2 to cardiac output remained normal, indicating preservation of DlO2-to-cardiac output ratio and alveolar-capillary recruitment up to peak exercise. The impairment in airway and vascular function exceeded the impairment in gas exchange and imposed the major limitation to exercise following 70% resection. Mediastinal distortion further reduced air and blood flow conductance, resulting in CO2 retention. Results suggest that adaptation of extra-acinar airways and blood vessels lagged behind that of acinar tissue. As more lung units were lost, functional compensation became limited by the disproportionately reduced convective conductance rather than by alveolar diffusion disequilibrium.
- lung diffusing capacity
- ventilation-perfusion distribution
- pulmonary arterial hypertension
- dysanaptic lung growth
- work of breathing
in previous studies of adult canines after removing 42–45% of total lung units by left pneumonectomy (PNX), functional compensation arose by 1) recruitment of existing alveolar-capillary reserves via expansion of, and increased perfusion to, the remaining lung, and 2) remodeling of the remaining lung structure (10, 12, 14, 15), which led to a normal exercise capacity. In adult canines after removing 55–58% of total lung units by right PNX, the average reduction in maximal O2 uptake was only ∼15% (17). In addition to recruitment and remodeling, compensatory growth of new acinar tissue also occurred in the remaining lung (16, 24), which minimized the expected decrement in post-PNX lung function (16, 19, 20) and partially returned exercise capacity, maximal cardiac output, lung-diffusing capacity for oxygen (DlO2) or carbon monoxide (DlCO), as well as lung elastic recoil to normal. Because of the vigorous compensatory response following 55–58% resection, we could not ascertain whether an upper limit of compensation in alveolar function had been reached. In earlier reports, Schilling et al. (36) studied canines during exercise following multiple-stage surgical resection of up to 80% of total lung units. DeGraff et al. (6) also performed exercise studies in patients who had undergone resection of up to 67% of total lung mass. We reasoned that, following more extensive lung resection, the potential for adaptation might be exhausted and an upper limit of functional compensation reached. We hypothesized that more extensive loss of lung units (70%) would exhaust alveolar-capillary reserves in the remaining lung units and exceed the capacity for new alveolar-capillary tissue growth. If so, maximal O2 uptake would be primarily limited by arterial hypoxemia caused by a pronounced reduction of the diffusion-to-perfusion (DlO2/Q̇) ratio following 70% resection compared with 58% resection. To define the extent and sources of exercise limitation, we performed two-stage resection of 70% of lung units in adult canines. Between 1 and 2 years following surgery, we measured exercise capacity, gas exchange, ventilation-perfusion (V̇a/Q̇) distribution, DlO2, hemodynamic function, and ventilatory power requirements and compared these results with that in control animals following 58% lung resection (right PNX) or thoracotomy without lung resection (Sham).
The Institutional Animal Care and Use Committee approved all procedures. In separate studies (33, 34) we have determined the in vivo volume fractions of normal canine lobes by high-resolution computed tomography at 20 cmH2O of transpulmonary pressure (Fig. 1). Fourteen litter-matched male mixed breed hounds (∼9 mo old) were obtained from the Louisiana State University School of Veterinary Medicine (Baton Rouge, LA); 12 animals completed the study. Eight animals underwent two-stage bilateral resection of 70% of total lung units. In four animals, bilateral lung resection was roughly balanced with the right cranial (12%), left cranial (12%), and left middle (7%) lobes remaining. Since 12–19% of the original lung units remained in each hemithorax, the mediastinum maintained its normal midline position (Fig. 1). These animals tolerated balanced resection without complications. In four animals, bilateral resection was unbalanced (left cranial lobe was removed followed 1 mo later by right PNX), leaving 30% of lung in the left hemithorax only and causing marked mediastinal shift (Fig. 1). In the unbalanced group, two animals died immediately after the second operation due to acute pulmonary edema; the remaining two animals recovered uneventfully and completed the study. As simultaneous controls, three other animals underwent right PNX only (58% resection), and three animals underwent right thoracotomy without lung resection (Sham).
PNX and lobectomy.
Animals were fasted overnight and premedicated with buprenorphine, acepromazine, glycopyrrolate, and a prophylactic antibiotic. Anesthesia was induced with propofol and maintained with isoflurane. The animal was intubated with a cuffed endotracheal tube and ventilated (tidal volume of <10 ml/kg). Rectal temperature, heart rate, and transmucosal O2 saturation were monitored continuously. In a sterile manner, either the right or left lung was exposed via a lateral thoracotomy through the fifth intercostal space. The lobar blood vessels were dissected, tied with silk ligature, and cut. The appropriate main stem or lobar bronchi were stapled and cut. Loose mediastinal tissue was sewn over the bronchial stump for added protection, and the stump was immersed under saline to check for leaks. After ensuring hemostasis, the chest wall was closed in layers. Topical lidocaine was applied to the intercostal nerve and muscle during closure. Following PNX, residual air in the hemithorax was evacuated to underwater seal. Following lobectomy, a Heimlich valve was left in the pleural cavity for 24 h to prevent atelectasis of the remaining lobe(s). Buprenorphine was administered regularly for 2 days. Wound dressings were changed daily, and skin stitches were removed after 7–10 days.
For 70% resection, a left lateral thoracotomy was performed followed by a right lateral thoracotomy 3–4 wk later; the two-stage surgical procedure was employed to minimize peri-operative mortality. In the balanced group, the left caudal lobe was removed in the first operation followed by removal of the right middle, caudal, and infra-cardiac lobes in the second operation. In the unbalanced group, the left cranial lobe was removed in the first operation followed by removal of the entire right lung in the second operation. Since a modest volume increase of the left middle and caudal lobes easily made up for the loss of the small left cranial lobe, there was no mediastinal shift after the first operation, but marked mediastinum shift developed following the second operation. Control animals (Sham) for right PNX underwent right thoracotomy once with exposure of the right lung without resection.
External carotid loops.
To permit hemodynamic measurements and avoid the complications of chronic indwelling vascular catheters, both carotid arteries were exteriorized into dermal loops using established techniques (29) in a separate operation; loops were ready for use after ∼4 wk of recovery.
A customized, leak-free respiratory mask was constructed for each animal and sealed around the muzzle using a modified latex glove and duct tape (1). The mask connected to a large two-way non-rebreathing valve (Hans Rudolph, model 2700). Inspired and expired ventilation were measured by separate screen pneumotachographs (Hans Rudolph model 3813). Expired gas concentrations were sampled continuously by a mass spectrometer (Perkin-Elmer MGA-1100) distal to a mixing chamber. Minute ventilation, O2 uptake, CO2 production, and respiratory rate were followed breath by breath and averaged every 10 breaths. Electrocardiogram and rectal temperature were continuously recorded.
The physical training program has been described previously (17). Each animal was familiarized with the motor-driven treadmill over 1–2 wk. Training consists of running for 30 min/day, 5 days/wk at a workload equivalent to 60–80% of predicted or measured maximal O2 uptake. Animals were rewarded with praise and treats. They were considered “trained” when reproducible levels of O2 uptake could be obtained at each speed and incline, and when a maximum speed and incline was established beyond which exercise could not be sustained for 5 min. Training began before surgery, resumed 3 wk after surgery, and continued throughout the study. The present studies were performed 1–2 yr after completion of the surgical procedures.
Maximal O2 uptake.
The external jugular vein was cannulated under local anesthesia on the day of study for blood sampling. Maximal O2 uptake was determined by an incremental exercise protocol. After 5 min of warm-up at 6 miles/h and 0% grade, the treadmill speed was increased to 8 miles/h for 3 min. Then the treadmill grade was incremented by 5% every 3 min until a plateau in O2 uptake was reached or until volitional termination. A blood sample (3 ml) was drawn each minute for measurement of lactate and hemoglobin concentrations and hematocrit before and during exercise and every 2 min for 6 min after the cessation of exercise.
On a separate day, both jugular veins and the carotid artery were cannulated under local anesthesia. Through a 22-gauge needle, a wire guide was passed into the carotid artery. A 5-Fr 10-cm catheter was inserted into the carotid artery and advanced to the aorta for blood sampling and pressure monitoring. A 7.5-Fr balloon-tipped triple-lumen thermal dilution catheter was threaded via one jugular cannula into the pulmonary artery for pressure and temperature monitoring and mixed venous blood sampling. The contralateral jugular catheter was used for infusion of inert gas solutions (see Multiple inert gas elimination technique below). Catheters were flushed with heparinized saline, sutured to the skin, and connected to pressure transducers (Statham Instruments, P23 ID) that had been calibrated on the same study day using a manometer. Arterial pressures were referenced to an open fluid-filled catheter sutured to the skin at the midpoint along the antero-posterior diameter of the chest. Ventilation, O2 uptake, CO2 output, respiratory rate, heart rate, and pulmonary and systemic arterial pressures, as well as heart rate and rectal and pulmonary arterial blood temperature were monitored continuously.
Multiple inert gas elimination technique.
We have used this technique extensively (9, 11, 14, 20, 21). Briefly, six inert gases with different solubility (SF6, ethane, cyclopropane, enflurane, acetone, and ether) were dissolved in saline and infused at a constant rate via one jugular venous catheter at an infusion rate ∼1/4,000 of the animal's minute ventilation to ensure an adequate signal-to-noise ratio. At rest, the infusion began 20 min before sampling. Upon exercise, inert gas exchange at the blood-gas interface equilibrates rapidly; therefore, sampling was performed after 3 min of infusion. Blood-gas partition coefficients of the inert gases were measured in duplicate for each animal and corrected for temperature differences between the animal's blood during exercise and the water bath at which samples were equilibrated. Inert gas concentrations of mixed venous blood were calculated by mass conservation from arterial and expired values, ventilation, and cardiac output.
At each workload, arterial and mixed venous blood was sampled for analysis of conventional blood gases (ABL-500, Radiometer, Copenhagen, Denmark), O2 content, hemoglobin (OSM3, Radiometer), and lactate (YSI, Yellow Springs, OH) concentrations. Hematocrit was measured by microcapillary centrifuge. The Po2, Pco2, and pH were adjusted to blood temperature (25). Cardiac output was determined by the Direct Fick method from measured O2 uptake and arterial and mixed venous O2 content. Oxygen delivery was calculated as the product of arterial O2 content and cardiac output.
Each animal was studied at rest and during exercise while breathing 21 and 14% O2 in balanced order. Baseline measurements were obtained while standing at rest on the treadmill. After 5 min of warm-up at 6 miles/h and 0% grade, the speed and incline were increased quickly to a predetermined level equivalent to 50% of the animal's previously measured peak O2 uptake and sustained for 4–5 min. Relative exercise intensities were used to ensure that each animal achieved the highest work output for the duration necessary to obtain all the measurements. By the end of minute 3 when O2 uptake and ventilation reached a near-plateau, duplicate arterial blood samples (7 ml each) and quadruplicate mixed expired gas samples (30 ml each) were collected in glass syringes for analysis of inert gas concentrations by a gas chromatograph (model 5890A, Hewlett Packard, Palo Alto, CA). Expired gas samples were collected after blood samples by a time delay equal to the time of gas transit through the mixing chamber. Additional duplicate arterial and mixed venous blood samples (2 ml each) were drawn for blood gas measurements. After sample collection, the treadmill was adjusted in speed and grade to achieve 80% of peak O2 uptake and the above sample and measurement sequence repeated. After this, the animal cooled down by walking on the treadmill at 4 miles/h, 0% grade for 10 min followed by a rest period until heart rate, respiratory rate, and ventilation returned to baseline.
Ventilatory power requirements.
The animal swallowed a latex balloon-tipped polyethylene catheter with 8–10 side holes at the tip into the distal one-third of the esophagus. Through a side hole in the respiratory mask, the catheter was connected to a differential pressure transducer and a carrier amplifier to continuously measure changes in esophageal pressure (Pes). The balloon was inflated with 1.0 ml of air. Mouth pressure (Pm) was monitored using identical apparatus. Pressure transducers were calibrated with a mercury manometer on the day of study. Transpulmonary pressure was defined as the difference between Pes and Pm. Ventilatory power output against the combined resistances of the lung and the apparatus was measured breath-by-breath from the end-tidal difference in Pes (ΔPes), tidal volume (btps), and the area of the ΔPes-tidal volume loop not recovered from the stored lung elastic recoil, as described previously (18, 23).
Individual data were normalized by body weight. Group averages (means ± SD) were compared by factorial ANOVA. Ventilatory, gas exchange, hemodynamics, V̇a/Q̇ indexes and DlO2 were plotted with respect to minute ventilation, O2 uptake, or cardiac output, and these relationships were compared among groups by analysis of covariance. Ventilatory power requirement was averaged over successive intervals (10 l/min) of minute ventilation and compared among groups by repeated-measures ANOVA. Post hoc testing was performed using Fisher's protected least significant difference. Differences were considered significant at P ≤ 0.05.
The dispersion of V̇a/Q̇ distributions about the mean was quantified by the log-scale second moments with respect to ventilation (log SDV̇) and perfusion (log SDQ̇). From the combined data (inert gas concentrations, cardiac output, ventilation, hemoglobin concentration, blood temperature, base excess, barometric pressure, inspired Po2 and Pco2, and mixed venous Po2 and Pco2), we determined the arterial Po2 (PaO2), the arterial Pco2 (PaCO2), and the alveolar-arterial O2 tension difference (A-aDO2) attributable to V̇a/Q̇ inhomogeneity assuming complete alveolar-capillary diffusion equilibrium (i.e., predicted A-aDO2) (40). The measured A-aDO2 was calculated from PaO2 and the ideal alveolar Po2 using the standard alveolar gas equation. When the measured A-aDO2 exceeded that predicted from V̇a/Q̇ inhomogeneity alone, the difference was attributed to a combination of alveolar-end capillary diffusion impairment and postpulmonary shunting.
To assess the relative magnitude of V̇a/Q̇ mismatch and diffusion impairment, V̇a/Q̇ distributions were measured at two inspired O2 tensions. Breathing 21% O2 accentuates the A-aDO2 caused by V̇a/Q̇ mismatch and shunts while minimizing the A-aDO2 caused by diffusion impairment. Breathing 14% O2 has the opposite effect (27). Differences in response arise because both O2 and inert gases are perturbed by V̇a/Q̇ mismatch and intrapulmonary shunt, but only O2 is diffusion limited and affected by extrapulmonary shunt. Assuming negligible diffusion-perfusion (DlO2/Q̇) heterogeneity and extrapulmonary shunt, an estimate of the whole lung DlO2 that accounts for the difference between measured and predicted A-aDO2 during hypoxic exercise was obtained using established algorithms (7). To the extent that diffusion-perfusion heterogeneity and extrapulmonary shunts exist and contribute to arterial hypoxemia, this estimate of DlO2 is the minimal value.
The in vivo volume fractions of canine lobes estimated by CT scan (33, 34) are consistent with earlier reports based on postmortem lobar volumes and weights (31, 32, 35). All animals lost weight initially following lung resection but regained their normal weight within 1–2 mo and maintained a normal body weight throughout the remainder of the study. Even following 70% resection, the animals regularly exercised up to a moderate workload (at least 6 miles/h and 15% grade). Hematological indexes were normal. As more lung tissue was removed and as resection became asymmetrical, peak O2 uptake progressively fell (Table 1). Exercise measurements obtained at the highest sustained workload (80% of maximal) while breathing 21 and 14% O2 are shown in Tables 2 and 3. Cardiac output at a given O2 uptake and peak cardiac output progressively declined with more severe resection (Fig. 2), associated with an elevated mean pulmonary arterial pressure (Fig. 3, left). Pulmonary arterial pressure increased in proportion to the expected increase in blood flow to the remaining lung following 58 and 70% balanced resection but was disproportionately higher following 70% unbalanced resection while breathing 21 or 14% O2 (Fig. 3, middle). Pulmonary vascular resistance also progressively increased following 58 and 70% balanced resection but was disproportionately higher following 70% unbalanced resection (Fig. 3, right). Compared with breathing 21% O2, breathing 14% O2 further exaggerated pulmonary vascular resistance in all groups as well as the inter-groups differences. Mean systemic arterial pressure did not differ significantly among groups (data not shown). Arterial O2 saturation during exercise declined earlier with progressive lung resection, particularly while breathing 14% O2 (Fig. 4, left). Unexpectedly, arterial Pco2 was significantly elevated following unbalanced 70% resection during exercise breathing 21% O2 but not 14% O2, resulting in a corresponding decline in arterial Po2 (Fig. 4, middle and right).
At rest, log SDV̇ fluctuated due to variable respiratory rates, but on exercise log SDV̇ was similar among groups while breathing 21 or 14% O2 (Fig. 5, left). Following 58% resection, log SDQ̇ was modestly elevated with respect to cardiac output only while breathing 14% O2 and not while breathing 21% O2 (Fig. 5, middle). Following 70% resection, log SDQ̇ was elevated with respect to cardiac output while breathing either 21 or 14% O2 (Fig. 5, middle). In all groups, there was a linear relationship between log SDQ̇ and pulmonary arterial pressure, evident while breathing 14% O2 (Fig. 5, right).
While 21% O2 was breathed at rest or exercise, measured A-aDO2 did not exceed that predicted from V̇a/Q̇ distributions in normal animals or following 58 and 70% lung resection (data not shown). While 14% O2 was breathed during exercise, measured A-aDO2 was elevated with respect to O2 uptake following 58 and 70% balanced resection compared with Sham animals (Fig. 6, left). Based on simultaneous inert gas, CO2 and O2 exchange, the portion of the measured A-aDO2 that could be explained by V̇a/Q̇ heterogeneity increased following 70% lung resection compared with 58% resection or Sham groups (Fig. 6, middle). The portion of measured A-aDO2 that could not be explained by V̇a/Q̇ heterogeneity and was attributed to diffusion disequilibrium did not increase further following 70% resection compared with that in Sham and 58% resection groups (Fig. 6, right).
Following 70% resection, the slope of the relationship between DlO2 and cardiac output measured during exercise breathing 14% O2 remained normal (Fig. 7, top). When expressed per fraction of remaining lung, DlO2 continued to increase following resection in a linear relationship with respect to blood flow (Fig. 7, bottom), indicating preserved alveolar microvascular recruitment.
Ventilatory power requirement at a given ventilation increased progressively with the extent of lung resection and with unbalanced resection (Fig. 8, top). Following 58 and 70% balanced resection, the increase in ventilatory power requirement extended the expected exponential relationship with respect to airflow through the remaining lung (Fig. 8, bottom). Following 70% unbalanced resection, the increase was greater than expected at any given airflow, suggesting that mediastinal distortion per se further exaggerated ventilatory power requirements.
Summary of results.
In our previous studies involving adult canines following 42 or 58% lung resection by left or right PNX, respectively, disequilibrium of alveolar diffusion assessed from a reduced DlCO and DlO2 with respect to perfusion contributed to a modest reduction in maximal O2 uptake, whereas V̇a/Q̇ distributions remained normal (13, 14, 19, 20). We hypothesized that diffusion disequilibrium would be further accentuated as more lung units are lost. We observed that peak O2 uptake, cardiac output, and arterial O2 saturation declined further as lung resection increased from 58 to 70%. Unexpectedly, V̇a/Q̇ mismatch developed during exercise following 70% resection, indexed by an elevated log SDQ̇ in direct proportion to pulmonary arterial hypertension. Since log SDQ̇ is sensitive to low V̇a/Q̇ regions, which in turn is commonly caused by local reduction in ventilation, a higher log SDQ̇ most likely reflects non-uniform regional ventilation that caused low V̇a/Q̇ regions. In contrast, the relation between DlO2 and cardiac output and hence the DlO2-to-Q̇ ratio remained within the normal range, implying preserved recruitment of remaining alveolar microvascular reserves even as perfusion per unit of remaining lung at a given cardiac output increased as much as 3.3-fold compared with the normal lung.
Compared with breathing 21% O2, breathing 14% O2 exaggerated pulmonary vascular resistance and the A-aDO2 attributed to diffusion limitation at a given O2 uptake in all groups. Breathing 14% O2 also worsened progressive pulmonary arterial hypertension and the development of low V̇a/Q̇ regions but not the A-aDO2 attributed to diffusion limitation following 70% balanced and unbalanced resection. Unbalanced 70% resection was associated with selective arterial CO2 retention during exercise breathing 21% O2 but not 14% O2, which may have been due to the Haldane Effect. Compared with balanced 70% resection, unbalanced 70% resection resulted in a much higher pulmonary vascular resistance under any condition, indicating the effect of mediastinal distortion.
Taken together, these results indicate that diffusion resistance to O2 uptake per se did not contribute to progressive exercise impairment following 70% resection compared with 58% resection. Instead, resistance to convective gas and blood flows, particularly airways resistance, increased precipitously, resulting in greater V̇a/Q̇ mismatch, right ventricular afterload and an exponential increase in ventilatory power requirements. Although the relationship of DlO2 to perfusion is linear, the increase in ventilatory power requirement with respect to airflow to the remaining lung is exponential. Exaggerated convective abnormalities following 70% resection probably contributed to the progressive restriction of peak cardiac output and alveolar ventilation. At the same level of resection, mediastinal distortion further increased convective flow resistance but not diffusive resistance. The combination of reduced alveolar ventilation, V̇a/Q̇ mismatch, and restricted cardiac output severely diminished total body O2 supply following 70% lung resection. Simultaneously, a higher O2 cost of breathing mandates a higher O2 delivery to respiratory muscles, leaving little O2 to sustain locomotive muscles. The intensified competition between ventilatory and nonventilatory muscle groups for a limited total O2 supply ultimately led to early cessation of exercise (8, 22). Exaggerated respiratory effort may also impede venous return from locomotor muscles (30), whereas fatiguing diaphragm contractions reflexively decreases blood flow to locomotor muscles (38), further contributing to exercise limitation.
Critique of the methods.
Sham-operated animals underwent right thoracotomy intended as controls for 58% resection. We did not study separate control animals following bilateral thoracotomy without lung resection. In previous cohorts, there was little difference in exercise cardiopulmonary function between postthoracotomy and unoperated control foxhounds (9, 11) so that long-term differences between unilateral and bilateral thoracotomy procedures are likely small. Pulmonary capillary wedge pressure was not measured. In our experience, post-PNX animals would falter or collapse on wedging the pulmonary arterial catheter during heavy exercise; therefore, this maneuver was not attempted.
Limitation after 42% resection.
In adult dogs after 42% resection by left PNX, we found minimal to no impairment in exercise capacity. Modest but significant diffusion limitation developed on exercise without significant V̇a/Q̇ mismatch (13, 14). Lung diffusing capacity at a given exercise cardiac output was reduced 20–30% but continued to increase in a linear relationship without reaching a plateau (4). Pulmonary arterial blood pressure rose as expected from the increase in perfusion through the remaining lung but neither the pressure-flow relationship nor peak cardiac output was altered (12). Similarly, work of breathing rose after left PNX as ventilation through the remaining lung increased, but the relationship of ventilatory work with respect to air flow through the remaining lung was unchanged, and respiratory muscle O2 requirement during exercise constituted only a small fraction of total body O2 uptake (23). Postmortem examination of the remaining lung showed increased capillary blood volume and alveolar-capillary surface area without a net increase in gas exchange tissue volume (10, 15). Compensation occurred through the expansion of and increased perfusion through the remaining lung, which recruited the remaining alveolar microvascular reserves to augment gas exchange and mitigate the expected functional decrement.
Limitation after 58% lung resection.
In adult dogs after right PNX, we previously found that average peak O2 uptake (123 ml·mn−1·kg−1) was ∼15% below control level (143 ml·mn−1·kg−1) (17). In the present study, peak O2 uptake after right PNX was ∼30% below control level (113 vs. 164 ml·mn−1·kg−1, respectively) owing to a 14% higher peak O2 uptake in the Sham group and a 8% lower peak O2 uptake in the PNX group compared with corresponding groups in the previous study (17). Alveolar diffusion disequilibrium was more pronounced after 58% than 42% resection but V̇a/Q̇ distributions remained normal (20). Pulmonary arterial hypertension was more pronounced after 58% than after 42% resection and was associated with a lower maximal cardiac output (17, 20). Work of breathing was also more elevated after 58% than 42% resection, but the abnormality was less than anticipated from the anatomical loss of lung units (5, 18). When adjusted for the expected fraction of lung remaining, DlCO was higher whereas A-aDO2 and pulmonary arterial pressure were lower after 58% than 42% resection, implying a more vigorous compensatory response following more extensive resection (19, 20). Postmortem, there was evidence for growth of additional alveolar tissue as well as respiratory bronchioles (16, 24). These results suggest that progressive lung resection elicited both greater intensity as well as additional mechanisms of compensation within acini.
Although diffusion disequilibrium was the major limiting factor to exercise, abnormalities in pulmonary hemodynamics and ventilatory mechanics also became evident following 58% resection. Unlike acinar structure, including alveolar tissue and respiratory bronchioles, that retain the potential for re-initiating growth (24, 39), the stiffer remaining conducting structures respond only by elongation and dilatation. As the remaining lung units expanded, extra-acinar airways became elongated initially (5, 26), which would accentuate the increase in airflow resistance at any given ventilation. With time, the remaining airways gradually dilated and partially mitigated the increase in airflow resistance (5). The discrepancy between the strong rapid response of acinar structure and the weak slow response of extra-acinar structure is termed “dysanaptic” or “unequal” growth. This term had been used in reference to postnatal lung development where relative rates of alveolar growth exceed that of airway growth (3). Accordingly, processes that alter alveolar growth and adaptation such as high-altitude residence (2, 37) and lung resection (5, 28) also influence relative expiratory airflow resistance. A similar slow adaptive pattern in the remaining conducting blood vessels could also explain the progressive pulmonary arterial hypertension following increasing lung resection.
Limitation after 70% resection.
We hypothesized that, as more lung units are removed, the remaining alveolar microvascular reserves would be exhausted, causing DlO2 to decline further at any given pulmonary blood flow. This was not the case. The relationship between DlO2 and cardiac output remained normal and linear up to peak measured values, providing evidence that microvascular recruitment continued with increasing perfusion to the remaining lung. How was it possible to maintain normal DlO2 recruitment when only 30% of the original lung units remained? There are two potential explanations. One explanation is that compensatory alveolar-capillary growth or remodeling was accentuated following 70% resection compared with 58%, resulting in enlargement of microvascular reserves. Structural analysis of the remaining lung is currently underway and will be able to address this issue. Another explanation is that discrepant adaptive rates between the remaining acini and conducting structures became more evident following 70% resection. As the compensatory response in airway and vascular structures lagged further behind that of alveolar tissue, the decline in convective flow conductance exceeded that in alveolar diffusive conductance, and hemodynamic and airway dysfunction became the major limiting factors that disproportionately reduced maximal cardiac output as well as alveolar ventilation, leading to early cessation of exercise. From the present data, we cannot ascertain whether DlO2 after 70% resection would have been even higher had global convective flow conductance remained normal.
In addition to a shift in the main source of exercise limitation from diffusive to convective resistance, we observed that mediastinal distortion following unbalanced 70% resection further accentuated the impairment in gas and blood flow conductance but not DlO2 at a given cardiac output compared with balanced 70% resection. Since the same amount of lung remained following balanced and unbalanced resection, these findings most likely reflect the anisotropic nature of airway and vascular trees, which renders convective flows sensitive to asymmetric anatomical distortion, whereas the isotropic acinar diffusion paths are less sensitive to asymmetric distortion.
We conclude that, following increasingly severe lung resection, the primary source of functional limitation progressively shifted from alveolar dysfunction (diffusion disequilibrium) to airway and vascular dysfunction (convective flow resistance). This shift most likely reflects disparate rates as well as mechanisms of adaptation between intra- and extra-acinar structures. The slower or dysanaptic adaptation of conducting airways and vessels can potentially restrict the magnitude of functional augmentation achievable through re-initiation of alveolar growth.
This research was supported by National Heart, Lung, and Blood Institute Grants R01 HL-045716, HL-040070, HL-054060, and HL-062873. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute or of the National Institutes of Health.
The authors thank Deborah C. Hogg and Richard T. Hogg for assistance with exercise training and testing, and the staff of the Animal Resources Center at the University of Texas Southwestern Medical Center for veterinary care and assistance.
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.
- Copyright © 2008 the American Physiological Society