Mismatching of ventilation and blood flow (ventilation perfusion inequality [Va/Q]) within diseased lungs is the most common cause of hypoxemia. Although it is not clear from our data which of pentoxifyllines numerous attributes is responsible for the observed improvement, they are consistent with several of the reported effects on the circulation, described below.
(1) Pentoxifylline has been shown repeatedly to increase cardiac output. In addition, West and Wagner demonstrated that increasing cardiac output alone would result in improved arterial Po2 in individuals with large Va/Q abnormalities, but it would have little effect in people with normal Va/Q. Since patients with COPD have abnormal Va/Q, this mechanism might help account for some of their improvement. It would not, however, explain the improvement in healthy subjects, since the Va/Q in healthy exercising subjects is already maximized.
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(2) Dantzker and Bower demonstrated that hypoxemia in patients with chronic obliterative pulmonary vascular disease occurred only when Va/Q inequality was combined with a low mixed venous oxygen content, and Kawakami et al observed that patients with COPD with the worse prognosis have the lowest mixed venous Po2. West observed that an increase in mixed venous Po2 is reflected in a higher end- pulmonary capillary Po2. For a given shunt, this would result in higher arterial Po2 values. Pentoxifylline increases both peripheral perfusion and tissue oxygenation. This perfusion increase, which is amplified in exercise, would translate to an increased mixed venous Po2. Thus, another, albeit speculative, mechanism that may explain the improvement of the treated patients with COPD is the increase in mixed venous Po2 due to increased peripheral blood flow. This effect would probably not be manifested in exercising healthy subjects where, presumably, the peripheral vascular beds would already be maximally dilated because of local regulation.
(3) As reviewed by Muller, pentoxyphyllines primary effect is to lower blood viscosity and decrease red blood cell and platelet aggregation. As stated in Hagen-Poiseuilles law, resistance is proportional to viscosity:
where R = resistance, r = radius, 1 = length of the vessel, and T| = viscosity. Any decrease in viscosity would be expected to improve blood flow, which should then improve gas exchange if it is also associated with perfusion of high Va/Q alveoli.
Under normal circumstances, recruitment of new capillaries involves increasing pulmonary artery pressure. In the patients with COPD, pulmonary artery pressure is already elevated due to hypoxic vasoconstriction. Healthy people increase their pressure during exercise to recruit previously unrecruited capillaries in the highest levels of the lung. Thus, it is unlikely that there would be any additional capillary recruitment.
The diameter of the alveolar capillary sheath varies inversely with alveolar volume and hypoxia-induced contraction of interstitial cells. Seven of our 12 patients with COPD had some degree of hypoxemia, and eight had hyperinflated lungs (Table 1). During strenuous exercise, healthy subjects increase their tidal volume to nearly 80 percent of their inspiratory capacity, during which time pulmonary blood flow is impeded because of reduced capillary diameter. We speculate, therefore, that in hypoxemic patients with COPD, the combination of hyperinflation and active contraction of interstitial cells narrows the alveolar capillaries. Similarly, in healthy subjects during exercise the increased tidal volume compresses the alveolar capillaries. Pentoxifylline, by increasing erythrocyte flexibility, could promote perfusion of these units and thereby improve Va/Q in both groups of subjects.
(4) Shear stress at the vessel wall is a major factor in the development of thrombi. As shear stress increases, more platelets come into direct contact with the vessel wall and react with its component, thereby, promoting thrombotic processes. The shear stress of blood is proportional to blood flow velocity and inversely proportional to the vessels diameter.
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Hypothetically, patients with COPD may be at significantly greater risk of microembolization. Support for this possibility is found in the following: (1) Although controversial, the weight of the evidence, as reviewed by Light et al, indicates that cardiac output is normal in patients with COPD. Consequently, since the pulmonary vascular bed is reduced, blood velocity through the lung must be increased if cardiac output is to remain the same. This was demonstrated by Wagner et al who observed a significant reduction in capillary transit time as pulmonary artery pressure increased during hypoxia. (2) Chronic hypoxia increases the relative proportion of muscular pulmonary arteries with a caliber smaller than 70 um, thus reducing the cross-sectional area of the pulmonary bed.
Microembolization, in turn, would aggravate any existing Va/Q inequality. The possibility exists, therefore, that by decreasing platelet aggregation and fibrinogen levels, pentoxifylline may reduce microembolization in patients with COPD and thereby improve Va/Q.
In conclusion, although further study on a larger population is needed, these preliminary data demonstrate that pentoxifylline improves treadmill walk time, arterial saturation, and pulmonary gas exchange in patients with moderate to severe COPD. It also increases exercising pulmonary diffusing capacity in healthy people. Possible mechanisms for these effects are (1) increasing cardiac output, and/or (2) raising mixed venous Po2, and/or (3) perfusing previously unperfused or underperfused alveoli.