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Am J Physiol Heart Circ Physiol 292: H1777-H1781, 2007. First published December 1, 2006; doi:10.1152/ajpheart.01024.2006
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Direct demonstration of 25- and 50-µm arteriovenous pathways in healthy human and baboon lungs

Andrew T. Lovering,1,2 Michael K. Stickland,1 Amy J. Kelso,2 and Marlowe W. Eldridge1,2,3

1John Rankin Laboratory of Pulmonary Medicine; and 2Departments of Pediatrics, and 3Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Submitted 19 September 2006 ; accepted in final form 27 November 2006


   ABSTRACT
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Postmortem microsphere studies in adult human lungs have demonstrated the existence of intrapulmonary arteriovenous pathways using nonphysiological conditions. The aim of the current study was to determine whether large diameter (>25 and 50 µm) intrapulmonary arteriovenous pathways are functional in human and baboon lungs under physiological perfusion and ventilation pressures. We used fresh healthy human donor lungs obtained for transplantion and fresh lungs from baboons (Papio c. anubis). Lungs were ventilated with room air by using a peak inflation pressure of 15 cmH2O and a positive end-expiratory pressure of 5 cmH2O. Lungs were perfused between 10 and 20 cmH2O by using a phosphate-buffered saline solution with 5% albumin. We infused a mixture of 25- and 50-µm microspheres (0.5 and 1 million total for baboons and human studies, respectively) into the pulmonary artery and collected the entire pulmonary venous outflow. Under these conditions, evidence of intrapulmonary arteriovenous anastomoses was found in baboon (n = 3/4) and human (n = 4/6) lungs. In those lungs showing evidence of arteriovenous pathways, 50-µm microspheres were always able to traverse the pulmonary circulation, and the fraction of transpulmonary passage ranged from 0.0003 to 0.42%. These data show that intrapulmonary arteriovenous pathways >50 µm in diameter are functional under physiological ventilation and perfusion pressures in the isolated lung. These pathways provide an alternative conduit for pulmonary blood flow that likely bypasses the areas of gas exchange at the capillary-alveolar interface that could compromise both gas exchange and the ability of the lung to filter out microemboli.

intrapulmonary arteriovenous anastomoses; shunt; baboon; pulmonary circulation

RECENT WORK has demonstrated the transpulmonary passage of saline contrast microbubbles during exercise, but not at rest, in healthy adult human subjects without cardiac anomalies, suggesting that intrapulmonary arteriovenous pathways are recruited during hyperdynamic conditions (5, 14, 22). Although the actual size of the saline contrast microbubbles is not known, theoretical and experimental data have estimated that the size distribution of microbubbles that survive to enter the pulmonary microcirculation to be 60 to 90 µm in diameter (8, 10, 16, 31, 32). These estimates prompted Eldridge et al. (5) to suggest that these inducible intrapulmonary arteriovenous pathways must be at least 60 µm in diameter. Postmortem studies in adult human lungs have documented the existence of intrapulmonary arteriovenous pathways for more than 100 years (20). More recent studies using microspheres have demonstrated that these vessels are functional under various conditions. For example, Tobin and Zariquiey (25) demonstrated that arteriovenous anastomoses were functional in atelectatic, fresh human lungs with perfusion pressures ranging from 50 to 300 mmHg. The authors poured "several hundred" glass microspheres ranging from 10 to 750 µm in diameter into the perfusate and found that an average of 38 glass microspheres with diameters up to 500 µm traversed the pulmonary circulation in 45% (9/20) of the lungs (25). In a subsequent study, Tobin (24) studied 10 human lungs that were previously frozen. These atelectatic lungs were perfused with 2,000–5,000 glass microspheres 200 ± 25 µm in diameter at an unreported perfusion pressure. The microsphere injection was followed by a perfusion of a radiopaque formalin with visualization of microspheres in the pulmonary veins (24). Although these studies demonstrate the existence of intrapulmonary arteriovenous pathways, the experimental perfusion and inflation pressures were either not reported or nonphysiological. Thus it is not known if these anastomoses are functional under physiological conditions. Furthermore, because the authors did not report the amount of microspheres able to traverse the pulmonary circulation relative to the total number of each size infused, the relative number of the intrapulmonary arteriovenous pathways cannot be determined. Accordingly, the aim of the current study was to determine whether or not large-diameter (>50 µm) intrapulmonary arteriovenous pathways are functional in isolated human and non-human primate lungs under physiological ventilation and perfusion pressures and to determine the percentage of microspheres able to traverse the pulmonary circulation under these conditions.


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All procedures involving animals were approved by the University of Wisconsin Animal Care and Use Committee. The human lungs were originally procured for organ donation and key identifiers were not obtained; therefore, the human lung studies received an exemption from the University of Wisconsin Health Sciences Institutional Review Board.

Animal lung preparation. Non-human primate lungs were harvested from baboons (Papio c. anubis) (n = 4, 12.6–15.6 kg body wt, all male). All animals were anesthetized and subsequently heparinized and euthanized by exsanguination. Lungs were gravity flushed in situ via a peripheral vein with 2 liters of lactated Ringer. The trachea was cannulated with a cuffed endotracheal tube, the trachea was clamped to maintain the lungs at functional residual capacity, and the lungs and heart were removed intact from the animal and immediately prepared for ventilation and perfusion studies.

The lungs were placed on a Styrofoam platform, and the pulmonary artery and the left atrium were cannulated in two baboons (baboons 3 and 4). The left atrium was cannulated, and the right and left branches of the pulmonary artery were cannulated in two baboons (baboons 1 and 2) such that the left and right lobes could be perfused independently. After vascular cannulations, the lungs were ventilated via the endotracheal tube to a peak inflation pressure of 15 cmH2O, with 5 cmH2O positive end-expiratory pressure at 20–25 breaths/min with an inspiratory duration-to-total breath duration ratio of 0.5. Airflow pressures were measured using a Grass PT5 pressure transducer.

Lungs were perfused using a nonpulsatile, reservoir system similar to that detailed by Conhaim et al. (2, 3). The reservoir had an overflow outlet so that the perfusion pressure could be held constant using a pump to deliver the perfusate to the reservoir. The pressure was measured using a Gould-Statham P23 D6 pressure transducer, which was set to level with the pulmonary artery. Pulmonary artery perfusion pressure was manipulated by adjusting the height of the reservoir above the heart. The venous outflow from the left atrial cannula was level with the heart (or pulmonary veins) so that left atrial pressure was atmospheric, or 0 cmH2O. Flow rate was determined using a graduated cylinder. Before microsphere infusion began, the lungs were perfused at 10–15 cmH2O for 5–10 min until flows were stable. All lungs were kept at room temperature to minimize edema formation.

Human lung procurement and preparation. Healthy human lungs (n = 6, one female) were procured by the University of Wisconsin Organ Procurement Team. Lungs were procured from donors who died from either a cerebrovascular accident, cerebral anoxia, or head trauma. All of the human lungs used in this study were appropriate for transplantation. Most often the recipient patient condition dictated whether a bilateral or single lobe transplant could be done safely. If a single lobe transplant was necessary, then the surgeon would choose the lobe in the best condition. If both lobes were in optimal condition, then the surgeon would typically prefer to transplant the larger (right) lung. Alternately, the lungs were split at procurement and the patient condition did not allow for transplant. Because of our IRB waiver, we were only provided with the donor's age, weight, and cause of death and were not provided with the exact reasons for nontransplantation. The average donor age was 29 ± 12 y (range 13–42 y). Lungs were gravity flushed in situ with 4 liters of University of Wisconsin (UW) solution (ViaSpanTM, DuPont Pharmaceuticals) with 10 mg of phentolamine injected into the pulmonary artery before aortic cross clamp. Lungs were inflated and removed, and the trachea was stapled closed. This was followed by a 2-liter gravity flush using UW solution (5 mg phentolamine/l). The lungs were then stored in UW solution refrigerated on ice, and all lungs were studied within 24 h of procurement. We received either the right or left lung (see GoTable 2). As detailed above, the lungs were placed on a Styrofoam platform, the airway, pulmonary artery, and pulmonary veins were cannulated, and the lungs were ventilated and perfused. Edema formation during experimentation was determined by visual inspection, and lungs 4 and 5 appeared to become edematous during the experimentation.


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  		Table 1. Pressure-flow relationships before and after microsphere injection and percent microsphere passage in baboon lungs

 

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  		Table 2. Pressure-flow relationships before and after microsphere injection and percent microsphere passage in human lungs

 
Microsphere studies. The perfusate for all studies was phosphate-buffered saline (PBS) with 5% albumin to prevent alveolar edema. All lungs were ventilated with a peak inflation pressure of 15 cmH2O and perfused at 20 cmH2O except for the left lungs of baboons 1 and 2, which were perfused at 10 cmH2O. We used 25 ± 2.5 and 50 ± 4 µm (means ± SD) fluorescent-labeled (red and green, respectively) microspheres (Duke Scientific), which were combined in solution and injected together. The number of dry microspheres per gram for a given vial of microspheres was provided by Duke scientific. A stock solution of 1 million microspheres/ml (10 ml of PBS total volume, 1% albumin) was prepared so that the required amount of microspheres could then be withdrawn from the stock solution. Five hundred thousand total microspheres were used for baboon studies (250 K of each size), and one million microspheres (500 K of each size) were used for human studies. The solution of microspheres (5 ml total volume of PBS, 1% albumin to prevent microspheres from adhering to each other) was infused at 1 ml/min into the pulmonary artery cannula using a constant infusion pump via an infusion plug. The microsphere solution was continuously agitated during the infusion to maintain an even distribution within the solution. Venous outflow was collected beginning at infusion and continuing for 1 min following the termination of the infusion for 6 min total. Venous outflow rates (i.e., pulmonary blood flow) at a given perfusion pressure were obtained pre- and postmicrosphere injection to estimate the degree of embolization (i.e., percent change on venous outflow) caused by the microspheres. Paired t-test was used to determine whether changes in flow rates were significant and significance was set at P < 0.05.

Microspheres analysis. The vials containing the venous outflow samples were gently agitated to ensure a uniform distribution of microspheres and then were immediately vacuum filtered using a 42-mm total diameter, 36-mm functional diameter, 0.45-µm pore filter (Millipore). Filters were imaged using fluorescent microscopy (Nikon Eclipse 50i, EXFO X-Cite 120 fluorescent illumination system; Spot Camera v7.4 slider, Spot Advanced software v4.1) to determine the number and sizes of microspheres not trapped in the lung. Microspheres were counted manually on a given filter. If >500 microspheres of a given size were found on a filter, then microspheres from those filters were resuspended in PBS (1% albumin), and refiltered in aliquots so that there would be <500 microspheres on a given filter. Resuspension was necessary for human lung 1.


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Pressure-flow relationships pre- and postmicrosphere injection and the percentages of microspheres that traversed the lungs are listed in Tables 1 (baboon) and 2 (human).

Baboon lungs. The left and right lung from baboons 1 and 2 were perfused individually. The percentages of 25- and 50-µm microspheres that traversed these lungs ranged from 0.003% to 0.2% (Table 1). Lungs from baboons 3 and 4 were perfused as a pair. The percentages of 25- and 50-µm microspheres that traversed these lungs ranged from 0 to 0.01% (Table 1). Pre- and postmicrosphere injection venous outflow rates revealed variable changes in individual and paired lobe perfusions, but the changes in flow were not significant.

Human lungs. Left lung shunt fractions ranged from 0 to 0.29% for 25-µm microspheres and 0 to 0.42% for 50-µm microspheres (Table 2). Right lung shunt fractions ranged from 0.0005 to 0.01% for 25-µm microspheres and 0.0003 to 0.02% for 50-µm microspheres (Table 2). Venous outflow rates revealed that flow was reduced on average after microsphere injection (Table 2), but these reductions were not significant. Lungs 4 and 5 became slightly edematous during the experiment, despite the use of identical conditions for previous lungs, which did not become edematous.

Across species, there was no significant relationship between the percent change in venous outflow and the percentage of microspheres that were able to traverse the pulmonary circulation (r = –0.18 and –0.16 for 25- and 50-µm microspheres, respectively). Thus lungs with greater reductions in venous outflow (i.e., a greater degree of embolization) did not consistently demonstrate more transpulmonary passage of microspheres.


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Our findings directly demonstrated that intrapulmonary arteriovenous pathways >25 and 50 µm are functional under physiological perfusion and ventilation pressures in human and baboon lungs.

Transpulmonary passage via arteriovenous anastomoses or distended capillaries? Under physiological perfusion pressures, microspheres >7–10 µm should be filtered by the capillaries and other vessels and are therefore unable to traverse the pulmonary circulation in the absence of arteriovenous anastomoses. However, overembolization due to extensive microsphere occlusion of the pulmonary vasculature may cause excessive regional pulmonary pressures resulting in either the opening of an arteriovenous anastomoses or microspheres being forced through a grossly distended capillary. In the current study we attempted to minimize the degree of overembolization. Nevertheless, there were instances where pulmonary venous outflow was reduced as much as 30% following microspheres infusion. Importantly, our perfusion system maintained a constant pressure so that when embolization occurred, flow was reduced and an excessively elevated perfusion pressure was prevented. The extent of capillary distention is unknown in humans. Estimates from animal studies have demonstrated in horses, dogs, and rabbits that averages of pulmonary capillary radii at high pressures are between 3.2 and 3.6 µm (1, 29), and therefore it is extremely unlikely that capillaries would distend to 25–50 µm. Furthermore, we found that there was no correlation between the degree of embolization, measured by change in pulmonary venous outflow, and the percentage of microspheres able to traverse the pulmonary circulation. Thus it seems highly unlikely that microspheres were either traveling through arteriovenous anastomoses opened by nonphysiological pressures or through abnormally distended capillaries.

Intrapulmonary arteriovenous pathways in primates. We chose to examine lungs from humans and baboons because of the difficulty in obtaining fresh healthy human lungs. Both humans and baboons have a common evolutionary ancestry with the hominoid lineage (humans, gorillas, chimpanzees, etc.) and the Old World monkeys (macaques, baboons, etc.) diverging ~25 to 30 million years ago (7, 17, 21). Because of this common ancestry, we hypothesized that lungs from both species would have intrapulmonary arteriovenous anastomoses >50 µm. Our data clearly support the idea that other hominids as well as other Old World monkeys could potentially have intrapulmonary arteriovenous conduits.

Why is there a disparity between reports of intrapulmonary arteriovenous anastomoses in humans? Despite our current findings and the findings of others (24–26, 28), there are reports that suggest these vessels do not exist in humans (12, 27). Based on our findings in exercising humans, these pathways appear to be recruitable since they are not open at rest but become functional during exercise (5, 14, 22). Furthermore, these pathways are likely small in number, as suggested by our findings of small shunt fractions. Indeed, these inducible pathways may be very difficult to identify with histological methods, particularly when the conditions required to open them are essentially unknown. Our findings provide strong, compelling evidence that pulmonary arteriovenous pathways (at least 50 µm in diameter) are functional in healthy human lungs under physiological ventilation and perfusion pressures.

Significance of intrapulmonary arteriovenous pathways in human and baboon lungs. We have previously shown that microbubbles do not traverse the pulmonary circulation at rest but are able to traverse the pulmonary circulation during exercise in the majority of healthy humans (5, 22). Eldridge and colleagues (5) hypothesized that these bubbles were traveling through exercise-inducible arteriovenous anastomoses that were between 60 and 90 µm in diameter. Their estimate of the diameter of these vessels was based on the size of microbubble that would have a survival time sufficient to traverse the pulmonary circulation under high pressure and high flow conditions (15, 30–32). The current study supports our previous hypothesis by directly demonstrating that there are intrapulmonary arteriovenous vessels with functional diameters >50 µm in both healthy human lungs and baboons. Most likely, our estimate of the percentage of microspheres able to traverse the pulmonary circulation represents a minimum shunt fraction. Indeed, with the increased pulmonary pressures and flows associated with exercise, it is likely that more, and potentially larger, intrapulmonary arteriovenous pathways would be recruited.

We have previously hypothesized that blood traveling through intrapulmonary arteriovenous anastomoses during exercise would add to the venous admixture and negatively impact gas exchange inefficiency (5, 13, 22). Stickland et al. (22) demonstrated a good correlation between the alveolar-to-arterial oxygen difference and the onset of intrapulmonary shunt as detected by saline contrast echocardiography. Indeed, during heavy exercise, a shunt percentage as small as 1–2% of cardiac output would have a significant effect on gas exchange (5, 6, 13). In the current study, the amount of microspheres passing through the isolated lung was <1%. Importantly, the experimental conditions we used for our isolated ventilated and perfused lung studies are significantly different from the conditions the lung endures during exercise. Our data demonstrate that pressures and flows obtained in the isolated, ventilated, and perfused lung, which mimic zone I and II conditions at peak inspiration, are sufficient to open some of these pathways. It is likely that the greater pulmonary pressures and flows achieved during whole body exercise would create conditions that would recruit more of these pathways, because their patency is likely flow and/or pressure dependent (22).

Non-gas exchange consequences of arteriovenous anastomoses. In addition to contributing negatively to pulmonary gas exchange, these pathways would impact the lung's role as a biological filter. The importance of the lung's role as a biological filter becomes apparent when this filter is bypassed, as in the case of an intracardiac shunt (patent foramen ovale, PFO), or when the filter becomes compromised, as in the case of intrapulmonary shunting caused by a disease process such as hereditary hemorrhagic telangiectasia (HHT). For example, it is well known that patients with either a PFO or HHT are more susceptible to embolic stroke and neurological symptoms (4, 9, 11, 18). Furthermore, recent work has linked intrapulmonary shunting and migraine headaches (23). Although the vessels described in this report can only be estimated at slightly >50 µm in functional diameter and therefore may not be able to pass millimeter-sized emboli, recent studies in the rat demonstrate neurological impairment from microemboli less than 100 µm (19).

To summarize, we have demonstrated here that intrapulmonary arteriovenous pathways exist in healthy human and baboon lungs under physiological conditions. These pathways were found to have a functional diameter >50 µm in diameter, indicating that these vessels are not capillaries. If blood flowing through these conduits did not participate in gas exchange and was 1–3% of cardiac output, the efficiency of pulmonary gas exchange would be reduced, particularly under conditions such as exercise. These vessels were functional under physiological perfusion and ventilation pressures, but clearly, the conditions required to open these pathways have yet to be fully elucidated.


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Support for this project was provided by National Heart, Lung, and Blood Institute (NHLBI) Grant HL-15469, a Grant-in-Aid from the American Heart Association 0550176Z, and the Department of Pediatrics, University of Wisconsin Medical School. A. T. Lovering was supported by a NHLBI Training Grant T32 HL-07654.


   ACKNOWLEDGMENTS
 
We thank Dr. Rob Conhaim and Kal Watson for help setting up the perfusion system in our lab. We also thank Dr. Rudolf Braun, Dr. Robert Love, and Dr. Takushi Kohmoto for invaluable assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. T. Lovering, John Rankin Laboratory of Pulmonary Medicine, Dept. of Pediatrics and Population Health Sciences, Univ. of Wisconsin School of Medicine and Public Health, Rm. 4245 MSC, 1300 Univ. Ave., Madison, WI 53706-1532 (E-mail: atlovering{at}wisc.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.


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