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J Appl Physiol 89: 2263-2267, 2000;
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Vol. 89, Issue 6, 2263-2267, December 2000

Vasomotor tone does not affect perfusion heterogeneity and gas exchange in normal primate lungs during normoxia

Robb W. Glenny, H. Thomas Robertson, and Michael P. Hlastala

Departments of Medicine and Physiology and Biophysics, University of Washington 98195


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

To determine whether vasoregulation is an important cause of pulmonary perfusion heterogeneity, we measured regional blood flow and gas exchange before and after giving prostacyclin (PGI2) to baboons. Four animals were anesthetized with ketamine and mechanically ventilated. Fluorescent microspheres were used to mark regional perfusion before and after PGI2 infusion. The lungs were subsequently excised, dried inflated, and diced into ~2-cm3 pieces (n = 1,208-1,629 per animal) with the spatial coordinates recorded for each piece. Blood flow to each piece was determined for each condition from the fluorescent signals. Blood flow heterogeneity did not change with PGI2 infusion. Two other measures of spatial blood flow distribution, the fractal dimension and the spatial correlation, did not change with PGI2 infusion. Alveolar-arterial O2 differences did not change with PGI2 infusion. We conclude that, in normal primate lungs during normoxia, vasomotor tone is not a significant cause of perfusion heterogeneity. Despite the heterogeneous distribution of blood flow, active regulation of regional perfusion is not required for efficient gas exchange.

regional perfusion; spatial heterogeneity; fluorescent microspheres; baboons; hypoxic pulmonary vasoconstriction


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

AS THE SPATIAL RESOLUTION of regional blood flow and ventilation measurements have improved, it has become apparent that both are quite heterogeneous (21, 31). Although vertical gradients in blood flow and ventilation exist because of the influences of gravity (37), a remarkable degree of perfusion and ventilation variability exists within isogravitational planes. Despite this large degree of variability, regional perfusion and ventilation are well matched (21, 31). This raises the question: How are perfusion and ventilation matched within isogravitational planes? One possible explanation is that the majority of perfusion heterogeneity is due to local hypoxic pulmonary vasoconstriction (HPV) attempting to match regional perfusion to ventilation.

To determine the contribution of vasoregulation to pulmonary perfusion heterogeneity, we explored the effects of prostacyclin (PGI2) on the distribution of pulmonary blood flow and gas exchange in baboons. The hypotheses we studied were that there is an intrinsic tone to the pulmonary vascular bed producing heterogeneous perfusion and that this vasomotor tone is needed to actively match heterogeneous perfusion and ventilation. We chose baboons because their anatomy, distribution of vascular resistances, and hemodynamic responses to hypoxia are similar to those of humans (16, 17).


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Experimental protocol. The University of Washington Animal Care Committee approved the study. Five male baboons (Papio anuba), weighing 23.5-33.0 kg, were studied. These animals were also used to study the effects of varying posture on pulmonary blood flow distribution, and data from four of them have been previously published (11). The data reported here include only the two measurements obtained in the upright postures before and during prostacyclin infusion. Hemodynamic and blood gas data were also obtained for 2 h before the initiation of this study.

The animals were chemically restrained with intramuscular ketamine injections, intubated, and mechanically ventilated with air. Tidal volumes (8-10 ml/kg) and rates were adjusted to produce an initial arterial partial pressure of O2 of 35-40 mmHg. Once set, tidal volumes and ventilatory rates were not altered. Anesthesia was maintained with intravenous and intramuscular ketamine. A right internal jugular cordis and a carotid catheter were placed with the use of local anesthesia. A flow-directed pulmonary arterial catheter was introduced through the right internal jugular cordis. Two forearm peripheral veins were cannulated. One animal was observed to aspirate food from its cheek pouch during intubation and on postmortem examination was found to have near complete obstruction of the left lower lobe bronchus. Data from this animal were not previously reported but are included here to demonstrate the influence of vasomotion regulation in the abnormal lung.

Fluorescent 15-µm-diameter microspheres (FluoSpheres, Molecular Probes, Eugene, OR) were injected intravenously through a forearm vein over 30 s in 5 ml of saline and followed by a 10-ml saline flush. The microspheres were sonicated and vortexed before injection. Two million microspheres of each color were injected. Before each microsphere injection, two sets of stacked breaths were administered to recruit atelectatic lung regions; arterial blood gases were obtained; cardiac outputs were determined by thermal dilution; and systemic, pulmonary, and airway pressures recorded.

The anesthetized animals were studied in a seated upright posture. One microsphere color was injected 20 min after the animals were seated. An infusion of prostacyclin was begun at 5 ng · kg-1 · min-1 after the first microsphere injection. The rate was increased by 5 ng · kg-1 · min-1 every 5 min up to a final rate of 25 ng · kg-1 · min-1. This infusion rate was held constant for 20 min, and a final microsphere injection was performed. Arterial blood gas samples were obtained before each microsphere injection. Alveolar-arterial O2 differences were calculated by using an R value of 1.0, as appropriate for a fasting, mechanically ventilated animal anesthetized with ketamine (7).

After the final microsphere injection, each animal was deeply anesthetized, given 10,000 units of heparin, and exsanguinated. A sternotomy was performed, large bore catheters were placed in the pulmonary artery and left atrium, and the thoracic aorta was tied off. The lungs were perfused with 2% dextran (molecular weight 74,000) in normal saline until clear of blood, removed from the chest, and allowed to dry inflated at an airway pressure of 25 cmH20.

When dry, the lungs were coated with Kwik Foam (DAP, Dayton, OH), suspended vertically in a plastic-lined, squared box, and embedded in rapidly setting urethane foam (2 lb Polyol and Isocyanate, International Sales, Seattle, WA) to create a rigid form to which a three-dimensional coordinate system was applied. The foam block was sliced and cut into uniformly sized, 1.9-cm3 cubes. Foam adhering to lung pieces was removed, and each lung piece was weighed and assigned a three-dimensional coordinate and lobe designation.

The fluorescent signals for each color were determined by extracting the fluorescent dyes from each piece with an organic solvent and then measuring the concentration of fluorescence in each sample (10). Spillover from adjacent colors was corrected by using a matrix-inversion method (32). Relative blood flow to each lung piece was calculated by dividing the measured fluorescence of each piece by the mean fluorescence of all pieces for that color. The data set for each baboon consisted of an x, y, and z coordinate, lobe designation, weight, and relative flow for each lung piece before and during prostacyclin infusion. The relative flow to each lung piece in each condition was determined by dividing the fluorescent signal by the weight of each lung piece and normalizing it to the mean.

To minimize observed flow heterogeneity caused by artifact or measurement noise, pieces weighing <50 mg were excluded. Between 16 and 22 pieces containing >25% airway were also excluded before analyses in each of the five animals.

Statistical analysis. Weight-normalized flows are used for all analyses and are hereafter referred to as flow or perfusion. The coefficient of variation (= SD/mean) is used to characterize perfusion heterogeneity within each animal over space. Paired t-tests are used to compare perfusion heterogeneity between baseline and during prostacyclin infusion. Pearson's correlation coefficient (r) calculated between perfusion to lung pieces within a baboon is used to quantify the relationship between regional perfusion before and during prostacyclin infusion.

The coefficient of variation is only a general descriptor of perfusion distribution and contains no spatial information. Significant changes can occur within a distribution that may not be reflected in the coefficient of variation. For example, if the spatial location of lung pieces and their flows are shuffled in space, the coefficient of variation remains unchanged. Other measures that include spatial information are therefore used to explore changes in perfusion induced by ablating vasoregulation. The fractal dimension provides a scale-independent measure of perfusion heterogeneity (3). Fractal dimensions are 1.5 for a spatially random perfusion distribution and approach 1.0 as perfusion becomes more uniform. The spatial correlation rho (d) measures the correlation in flow between all pairs of lung pieces separated by a distance d (9) and ranges from 1.0 for perfect correlation to -1.0 for perfectly negatively correlated flows. The algorithms for determining the fractal dimensions and spatial correlations have been published previously (1, 9).


    RESULTS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Hemodynamic data. During prostacyclin infusion, heart rate increased in all animals. Among the four normal animals, there were no statistically significant changes in cardiac output, pulmonary artery pressures, or systemic pressures from baseline after prostacyclin infusion (Table 1).

                              
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  		Table 1.   Hemodynamic and gas exchange data

Spatial heterogeneity. Only data from the four normal animals were used to characterize the changes in spatial heterogeneity. The number of lung pieces from each animal, the coefficient of variation before and during prostacyclin infusion, and the correlation coefficient between flows before and during prostacyclin infusion are presented in Table 2. Pulmonary perfusion heterogeneity did not change significantly after ablation of vasoregulation. Correlation between regional flow before and during prostacyclin infusion was high (Table 2).

                              
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  		Table 2.   Measure of perfusion heterogeneity and regional perfusion correlation between baseline and during prostacyclin infusion

The spatial distributions as measured by the fractal dimensions and spatial correlations did not change appreciably with ablation of vasoregulation (Table 3).

                              
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  		Table 3.   Measures of perfusion distribution at baseline and during prostacyclin in fusion

Gas exchange. In the four normal animals, the alveolar to arterial alveolar-arterial O2 difference did not change significantly from baseline during prostacyclin infusion (Fig. 1). In the one animal subsequently found to have a lobar obstruction, the alveolar-arterial O2 difference was normal at baseline and increased significantly during prostacyclin infusion. This incidental finding documents both the effectiveness of HPV in matching regional perfusion to ventilation in pathological conditions and that this response is ablated with prostacyclin infusion.


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  		Fig. 1.   Changes in gas exchange before and after prostacyclin (PGI2) infusion. open circle , 4 Normal animals; , the 1 animal known to have a lobar obstruction. Note that the normal alveolar-arterial O2 (A-aO2) difference in all animals was stable before and at baseline. The prior observations were obtained between 60 and 90 min before the baseline measurements. With prostacyclin infusion, only the pathological lung shows worsening gas exchange.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

An important finding of this study is that pulmonary vasomotor tone does not contribute to pulmonary perfusion heterogeneity at the scale of resolution used in this study. The remarkable finding of this study is that, despite heterogeneous perfusion, active regulation of regional blood flow is not required for efficient gas exchange in the normal lungs when breathing air. The pulmonary vascular bed appears to have little intrinsic vascular tone in the normal primate lung.

An important concern in this study is the lack of any measurable effect of the prostacyclin infusion. How do we know that we did not observe any changes in perfusion distribution or gas exchange for the simple reason that we did not give enough prostacyclin? The literature from human studies suggests that our infusion rate of 25 ng · kg-1 · min-1 should be adequate to ablate vasomotor tone. In patients with primary pulmonary hypertension (25), acute administration of prostacyclin at a rate of 8 ± 4 ng · kg-1 · min-1 produced a significant fall in pulmonary vascular resistance. An equivalent response was obtained in the same population with adenosine at a rate of 200 ± 53 ng · kg-1 · min-1. Patients with ventilatory failure secondary to emphysema who were given intravenous prostacyclin had a significant decrease in pulmonary vascular resistance with an infusion rate of 8 ± 4 ng · kg-1 · min-1 (2). In a group of patients with acute respiratory distress syndrome, a prostacyclin infusion at 12.5-35 ng · kg-1 · min-1 caused a significant reduction in pulmonary vascular resistance (29). In these last two populations, gas exchange worsened with prostacyclin infusion. We also think that the marked decrease in pulmonary vascular resistance in one abnormal animal (animal 5 in Table 1) supports our contention that the dose of prostacyclin used in this study was adequate to ablate HPV. Human studies and an observation in a single baboon cannot fully substitute for formal studies determining the dose-response curve of the pulmonary circulation to prostacyclin in normal baboons. The results of our study must therefore be viewed as exploratory, and this caveat should be kept in mind when assessing our results.

The small differences in perfusion heterogeneity and the high correlations between regional flows before and during prostacyclin infusion suggest that perfusion distribution changes little when vasoregulation is ablated. This conclusion must be softened by the spatial and temporal resolutions of our methods. We are unable to detect changes in perfusion below the level of our piece sizes (~2 cm3), a volume well above the level of gas exchange. We have only two measurements in time. Observed changes in perfusion over these two time points may be due to methodological noise or "twinkling" unrelated to vasomotor regulation. Prior studies (13, 14) using similar methods have shown the methodological noise to be quite small. The temporal variation in regional perfusion has been documented in anesthetized and awake dogs without physiological interventions. The magnitudes of the temporal changes seen in the present study are similar to prior observations.

An additional concern is that anesthetic agents may alter normal vasoregulation in the lung. Most studies have concluded that inhaled anesthetics inhibit HPV (4), whereas intravenous anesthetics, such as ketamine, preserve HPV (23). We therefore used only ketamine anesthesia in this study.

Recent studies using microspheres in laboratory animals have demonstrated that regional perfusion and ventilation heterogeneity are substantially greater than suggested by prior radionuclide imaging (12, 21, 24, 31). Perfusion heterogeneity, independent of gravity, has been confirmed by studies performed with humans on the space shuttle (28). Human studies have also demonstrated that a large component of regional ventilation heterogeneity is gravity independent (34) and that ventilation-perfusion inequalities persist under conditions of microgravity (27). These new observations suggest that, although gravity plays a role in ventilation and perfusion matching (18), it cannot be the primary mechanism responsible for efficient gas exchange.

Although HPV is an important mechanism for maintaining gas exchange in the pathological lung, its role in the normal lung during normoxia has not been well studied (19). Naeije and coworkers (22) studied the effects of intravascular vasodilating agents on pulmonary artery pressure and gas exchange in normal volunteers breathing air. They found that pulmonary artery pressures and gas exchange did not change with nitroprusside or nifedipine administration. They were unable to explain a slight worsening of gas exchange during nitroglycerin infusion. Frostrell and co-workers (8) administered inhaled nitric oxide (NO) to normal subjects breathing air. There were no changes in pulmonary arterial pressures or oxygenation when the subjects inhaled 40 ppm of NO and air compared with air alone. In a similar study with normal sheep, Pison and co-workers (26) used conventional blood gas analysis and the multiple inert gas elimination technique to estimate ventilation-perfusion heterogeneity. They found no change in pulmonary hemodynamics or gas exchange when NO was administered at 20 ppm during normoxia. Using new methods with high spatial resolution, Melsom and colleagues (20) have recently shown that NO has no apparent effect on the local matching of ventilation and perfusion in the normal sheep lung.

Because inhaled NO reaches only those lung regions that receive ventilation, some lung regions may have active vasoconstriction but will not be vasodilated with inhaled NO. We chose to use prostacyclin because 1) it has a potent vasodilatory effect on the pulmonary circulation (5), 2) it has been shown to cause degradation in gas exchange when ventilation and perfusion are mismatched (2), and 3) it is delivered to the entire pulmonary circulation in proportion to regional flow. The results of this and prior studies (8, 22) suggest that regulation of pulmonary vascular tone is not responsible for perfusion heterogeneity or efficient gas exchange in the normal lung during normoxia.

In the past, variability in perfusion and ventilation was interpreted within the gravitational model as noise. However, it is now generally accepted that perfusion and ventilation heterogeneity is a fundamental characteristic of the lung, and new models have been introduced that characterize perfusion and ventilation as fractal processes (1, 15). The fractal vascular and airway trees are responsible for the large variability in regional ventilation and perfusion. These fractal structures have also been shown to provide strong evolutionary advantages across a wide range of species and phyla (36). Weibel (35) has suggested that airway and vascular geometries are closely matched, providing a mechanism for matching of regional ventilation and perfusion. This model contrasts with the generally accepted concept that regional ventilation is determined primarily by local parenchyma compliance. Others have suggested that local blood volume (6) or CO2 concentration (33) may alter regional compliance, matching ventilation to perfusion.

Although ventilation and blood flow are heterogeneously distributed within isogravitational planes, they remain tightly matched. HPV is an attractive explanation for both isogravitational heterogeneity (30) and the regional matching of perfusion and ventilation. However, this study demonstrates that vasoregulation is not responsible for the heterogeneity or close coupling of ventilation and perfusion in the normal lung. It appears that structural components such as vascular and airway geometry or local parenchymal compliance are important in matching regional ventilation and perfusion. This design departs from the usual way we conceptualize physiological systems with feedback loops needed to regulate an imperfectly matched system. A more perfectly designed system does not require active regulation because matching is adequate without it. Apparently, feedback loops and vasoregulation are necessary only during pathological conditions in the pulmonary vascular bed. These new observations underscore the realization that the mechanisms matching regional perfusion and ventilation in the normal lung have not yet been elucidated (19).


    ACKNOWLEDGEMENTS

We thank Heather McCown and John Wehrich in the University of Washington Primate Center for technical assistance with the animal experiments and Dowon An for assistance with lung sample processing.


    FOOTNOTES

Address for reprint requests and other correspondence: R. W. Glenny, Karolinska Hospital and Institute, Dept. of Anesthesia and Intensive Care, Bldg. F2, 00, SE-171 76 Stockholm, Sweden (glenny{at}u.washington.edu).

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.

Received 18 May 2000; accepted in final form 18 July 2000.


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J APPL PHYSIOL 89(6):2263-2267
8750-7587/00 $5.00 Copyright © 2000 the American Physiological Society


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