Among the important functional consequences of pulmo-xjL nary hypertension are disordered pulmonary gas exchange and impaired exercise tolerance. Both result, to a major degree, from the elevated pulmonary vascular resistance (PVR) and thus may be significantly influenced by alterations in pulmonary vascular tone. In this discussion, we will consider both beneficial and detrimental effects on gas exchange and exercise tolerance which may occur subsequent to a reduction of pulmonary vascular resistance by pharmacologic agents.
In patients with chronic obliteration of the pulmonary vascular bed without significant parenchymal lung disease, as seen with primary and embolic pulmonary hypertension, a widened alveolar-arterial gradient for oxygen P(A-a)02 is inevitable. The mechanism for this widened P(A-a)02 was investigated utilizing the technique of multiple inert gas elimination to measure the distributions of ventilation-perfusion (Va/Q) ratios. Despite the marked and sometimes assymetric loss of pulmonary vascular bed cross-sectional area, the Va/Q relationships were relatively well perserved (Fig l). Patients had a bimodal Va/Q distribution, with the majority of the cardiac output (66 to 99 percent) distributed to normal lung units and the remainder perfusing lung units with very low Va/Q ratios (less than 0.1) or shunt. There was no evidence for a failure of arterial-end capillary 02 equilibration. Despite this minor degree of abnormality in the matching of ventilation and blood flow and the absence of a diffusion impairment, most of these patients were significantly hypoxemic (Pa02 = 67 ± 16 mmHg, range 46 to 90 mm Hg). This seemingly excessive hypoxemia resulted from the presence of an abnormally low mixed venous Po2 (TOJ and its impact on the end capillary Po2 of the shunt and low Va/Q units. For example, the patient in Figure 1 had а PO2 of 24 mm Hg. Had it been 40 mm Hg instead, the Pa02 would have been 88 mm Hg rather than 58 mm Hg. The low PO2 was due to the low cardiac output characteristic of these patients. Latest responses on Canadian Neighbor Pharmacy are interesting for reading and make you think over about it.
In a subsequent study, it was found that the preservation of Va/Q matching could be explained in part by the presence of active vascular tone. In patients in whom pulmonary vascular resistance was reduced pharmacologically, there was a significant increase in the perfusion of lung units with low Va/Q ratios and/or shunt (Fig 1). The pattern of increased Va/Q inequality was independent of the agent used. The impact of the worsening Va/Q inequality on the Pa02 was variable, and the development of increased hypoxemia was frequently attenuated or eliminated by increases in cardiac output with concomitant increases in the Fv02. It was concluded that a portion of the reversible component of the vascular tone in patients with pulmonary hypertension contributes to the appropriate matching of ventilation and blood flow in the lungs. The stimulus for this vasoconstriction is unclear, as hypoxic vasoconstriction could be identified in only two of seven patients who responded to vasodilators. Thus, the propensity for inducing significant Va/Q mismatch and arterial hypoxemia is present whenever a significant reduction in vascular tone is achieved.
As a result of the high pulmonary vascular resistance and thus limited cardiac reserve in patients with pulmonary hypertension, there is an abnormal response to exercise. Janicki et al demonstrated that the maximal achievable exercise capacity (Vo2max) was closely related to the degree of pulmonary hypertension. They postulated that the determination of Vo2max may be a practical, noninvasive screening test for the presence and severity of pulmonary vascular disease. If so, then alterations in pulmonary vascular resistance should be characterized by improvements in exercise tolerance.
To test this hypothesis, patients with obliterative pulmonary hypertension and no parenchymal lung disease were studied before and eight weeks after the initiation of vasodilator therapy with a calcium channel blocker. During both studies the patients underwent a routine three-minute progressive treadmill exercise study and then cardiac catheterization, during which a period of moderate, steady state, supine bicycle exercise was monitored. There was a heterogeneous response of the pulmonary vascular tone to therapy, with seven of eight patients showing some fall in pulmonary vascular resistance at rest (range = + 36 percent to — 30 percent) and six of eight showing a fall during exercise (range = +3 percent to —62 percent). However, the changes in rest and exercise PVR correlated with the changes in both Vo2max (rest PVR, p =.005; exercise PVR, p =.016) and the 02 pulse at maximum exercise (VOj/heart rate), (rest PVR, p =.015; exercise PVR, p =.007). The 02 pulse is an index of the ability to increase stroke volume. In addition, a delay in the development of the anaerobic threshold also correlated with a fall in pulmonary vascular resistance during exercise. An increase in anerobic threshold (the oxygen consumption at which, during increasing work, the ventilation begins to increase more steeply) presumably reflected improvement in cardiovascular function. From this study of a small number of patients with pulmonary hypertension, we are encouraged that exercise capacity may, in addition to estimating the degree of pulmonary vascular disease, be useful as a way of monitoring the success of therapy.
If we are to utilize exercise effectively and safely to diagnose and monitor patients with pulmonary hypertension, it is important to understand its physiologic consequences on cardiovascular function and pulmonary gas exchange. While the amount of data is limited, it appears that patients with pulmonary vascular resistances of greater than 4.4 mm Hg • L • min have a diminished stroke volume response to exercise, while patients with PVR greater than 12.5 mm Hg • L • min depend entirely on an increase in heart rate to increase oxygen delivery. The inefficiency of this strategy as a means of meeting increasing 02 demands is demonstrated by the increased blood lactate levels found in these patients at very low intensity exercise, despite an increased 02 extraction. It may also account for the syncope and chest pain that accompanies unrestricted exercise and which mandates careful monitoring of such studies in patients with severe pulmonary hypertension.
The abnormal gas exchange found with pulmonary hypertension at rest is often accentuated during even minimal exertion. In seven patients with pulmonary hypertension (mean PA pressure = 46 ±16), we found a significant fall in Pa02 from 64 ±6.1 to 54±5.4 mm Hg during low-level exercise, averaging only 2.4 times baseline oxygen consumption (Fig 2). Measurements of the distribution of Va/Q showed that there was no increase in the ventilation-perfu-sion mismatch or shunt during exercise and no evidence that diffusion impairment contributed to the worsening gas exchange at this low level of work. The increased hypoxemia was due to a further fall in the PO2 as oxygen extraction increased in response to increasing metabolic demands. For example, had the exercising subjects maintained the PO2 observed at rest, the Pa02 would have risen instead of falling (Fig 2). Thus the lower PaOa resulted from an exaggeration of the mechanism causing hypoxemia at rest.
The ventilatory response to exercise was greater than that seen in normal subjects for the same workload. This tendency toward apparently excessive ventilation has been previously described in patients with pulmonary hypertension and resulted in a shift in the main body of the Va/Q distribution to the right, so that the Va/Q ratios for most of the lung increased. This increase in the Va/Q ratio was able to ameliorate but not abolish what would have been an even greater impact of the falling PO2 on arterial oxygenation (Fig 2).
Effective pulmonary vasodilation improves the cardiovascular response to exercise, but the effects on gas exchange are likely to be complex and not easily predictable. On one hand, a reduction of PVR should improve the cardiac output at any level of exercise, reducing the dependency on increased 02extraction as a major way of increasing the oxygen supplied to the tissues. This should improve the arterial Po2 at any given level of work, since the PO2 will be higher. On the other hand, vasodilation may increase the degree of Va/Q inequality, worsening the efficiency of pulmonary gas exchange. Further studies will be necessary before any definitive statements can be made, although preliminary results suggest that successful vasodilation does not often lead to marked worsening of exercise hypoxemia.
Figure 1. Distribution of ventilation-perfusion ratios in a patient with chronic obliterative pulmonary hypertension before and during the administration of nitroprusside which resulted in a fell in vascular resistance from 36 to 19 mm Hg*L1_*min. The baseline distribution shows the typical bimodal blood flow distribution. During nitroprusside infusion, there is an increase in intrapulmonary shunting without significant change in the remainder of the distribution. The fall in Pa02 was buffered by the increase in cardiac output (Qt). (Reprinted from reference 5 with permission.)
Figure 2. The effect of exercise of the arterial Po2 (PaOJ in eight patients with chronic obliterative pulmonary hypertension. The fall in PaOa was due to the fall in mixed venous Po2 (PvOJ due to the increased 02 extraction expected with exercise. Had the Pv02 remained at the resting value, the Pa02 would have increased due to a slight improvement in Va/Q matching during exercise, while a lesser ventilatory response to exercise would have resulted in an even greater fall in the Pa02. (Reprinted from reference 8 with permission.)