Mechanisms of hypoxaemia in severe pulmonary hypertension associated with COPD

To the Editor:

Pulmonary hypertension (PH) is a frequent complication of COPD, with a poor prognosis, especially in its severe form [1]. Accordingly, current guidelines distinguish patients with severe PH from those with moderate PH [2]. Patients with COPD and severe PH often present with worse hypoxaemia than those with moderate PH, despite having milder airflow obstruction [3–5]. The mechanisms underlying severe hypoxaemia in these patients have not been elucidated. This study aimed to analyse the determinants of hypoxaemia in severe PH associated with COPD by assessing ventilation/perfusion (V_A/Q) relationships with the multiple inert gas elimination technique (MIGET).

We retrospectively analysed 88 COPD patients who underwent simultaneous assessments of pulmonary haemodynamics and V_A/Q distributions with MIGET in our laboratory. Patients were grouped as: without PH (mean pulmonary artery pressure (mPAP) ≤20 mmHg or pulmonary vascular resistance (PVR) ≤2 Wood units (WU)); moderate PH (mPAP >20 mmHg, PVR 2.5–5.0 WU and pulmonary artery wedge pressure (PAWP) ≤15 mmHg); and severe PH (mPAP >20 mmHg, PVR >5 WU and PAWP ≤15 mmHg). Studies were performed as previously described [6]. In a subgroup of 51 patients, measurements were repeated while breathing 100% oxygen to assess the effects of inhibiting hypoxic pulmonary vasoconstriction (HPV).

The dispersion of perfusion (logSD Q) and ventilation (logSD V) distributions were used as indices of V_A/Q mismatch (normal: logSD Q <0.60, logSD V <0.65). The difference between retention and excretion (R−E*) for each inert gas was computed and the whole R−E* of all gases (DISP R−E*, normal <3) was used as an overall descriptor of V_A/Q inequality. The amount of blood flow in units with low V_A/Q ratio (0.005–0.1) or non-ventilated areas (shunt), and the amount of ventilation in units with high V_A/Q ratio (10–100) or non-perfused areas (dead space) were computed. The difference between measured arterial oxygen partial pressure (P_aO2) and that predicted by the MIGET (Pr-Ms P_aO2) was used to assess alveolar-to-capillary diffusion limitation to oxygen.

Groups were compared with an independent samples Kruskal–Wallis one-way analysis of variance for continuous variables, post hoc Dunn's test for pairwise comparisons, and chi-square test for categorical variables. Comparisons between room air and oxygen breathing were performed with a paired-samples t-test. A p-value <0.05 was considered significant. The study was approved by the hospital ethics committee.

The groups had similar age and sex distribution. Patients with severe PH had less airflow obstruction than those with moderate or without PH (figure 1a), and lower carbon monoxide diffusing capacity (median (interquartile range) 29 (23–37), 44 (28–58) and 46 (28–61) % predicted for severe, moderate and without PH, respectively; p<0.05). Pulmonary haemodynamic profiles are shown in figure 1a.

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FIGURE 1

a) Airflow obstruction, pulmonary haemodynamics and gas exchange measurements breathing room air in patients with COPD without pulmonary hypertension (PH), with moderate PH and with severe PH. b) Representative plots of the distribution of blood flow and ventilation as a function of the ventilation/perfusion (V_A/Q) ratio on a logarithmic scale in COPD patients without PH, with moderate PH and with severe PH. Closed symbols indicate blood flow and open symbols ventilation. The amount of shunt and dead space are expressed as percentage of cardiac output and minute ventilation, respectively. c) Changes in pulmonary haemodynamics and gas exchange measurements breathing 100% oxygen in COPD patients without PH, with moderate PH and with severe PH. d) Quantitative contribution of determinants of hypoxemia in COPD patients with severe PH. Green bar shows the average arterial oxygen partial pressure (P_aO2) predicted by the multiple inert gas elimination technique (MIGET) algorithm in patients without PH and the dark blue bar that of patients with severe PH. Light blue bars show the P_aO2 predicted by the MIGET in patients with severe PH if their ventilation, cardiac output, mixed-venous partial pressure of oxygen (P_vO2) and V_A/Q distribution data had been those of patients without PH. The last light blue bar reflects the effect of the concurrence of higher P_vO2 with more homogenous V_A/Q distributions, as seen in patients without PH. e) Schematic representation of the relative contribution of different factors on the difference in P_aO2 between patients with severe PH and those without PH. Boxplots (a, c) show the median and the interquartile range, whiskers mark the 5th and 95th percentiles. *: p<0.05 compared with the other group; ^#: p<0.05 compared with the value breathing room air in the same group. FEV₁: forced expiratory volume in the first second; mPAP: mean pulmonary artery pressure; PVR: pulmonary vascular resistance; CI: cardiac index; logSD Q: dispersion of the distribution of blood flow (normal <0.6) that reflects the severity of V_A/Q mismatch; shunt: perfusion of unventilated lung units. Δ denotes the change between measurements at room air and those breathing 100% oxygen (c).

Patients with severe PH had significantly lower P_aO2 and numerically lower mixed-venous partial pressure of oxygen (P_vO2) than the other groups (figure 1a). They also had greater impairment of V_A/Q relationships, with the highest DISP R−E* (17.3 (13.7–24.4)) and logSD Q values, and an increased proportion of shunt (figure 1a and b). No differences in logSD V, high V_A/Q units or dead space were observed. The P_aO2 was fully explained by the severity of V_A/Q mismatching, without differences in Pr-Ms P_aO2.

Breathing 100% O₂, mPAP and PVR decreased to a greater extent in the severe PH group (figure 1c). The increase in P_aO2 was significantly less in patients with severe PH (348 (228–485) mmHg) than in patients with moderate or without PH (498 (443–512) and 505 (474–532) mmHg, respectively; p<0.05). V_A/Q relationships worsened (increased logSD Q) in patients without PH and with moderate PH, but not in those with severe PH (figure 1c). The amount of shunt remained unchanged in all groups.

Our study shows that, in COPD patients with severe PH, the marked impairment of gas exchange is explained by the concurrence of severe V_A/Q mismatch, with a prominent amount of blood diverted to areas with low V_A/Q ratio and shunt, lower P_vO2 and a poor contribution of HPV to V_A/Q matching. This profile differs from that usually seen in COPD [7, 8], which we corroborated in patients without PH, and with moderate PH. Since the severe PH group had less airflow limitation, further worsening of V_A/Q relationships is likely due to changes in pulmonary vasculature. In fact, pulmonary vascular remodelling is associated with the severity of V_A/Q mismatching in COPD [9] and some features observed in the severe PH group (areas of very low V_A/Q and shunt) concur with those shown in idiopathic pulmonary arterial hypertension [10]. We hypothesise that in COPD patients with severe PH, pulmonary vascular abnormalities add to changes in small airways and lung parenchyma, further increasing the V_A/Q imbalance due to airflow obstruction. Of note, patients with severe PH had a significant amount of shunt, the origin of which is not apparent since they did not have obvious areas of alveolar occupation or collapse. Potential explanations include: a patent foramen ovale, although this was ruled out with contrast echocardiography in the majority of patients with severe PH; loss of peripheral vascular bed [11] that could divert blood to poorly ventilated units, further decreasing their V_A/Q ratio; or the hypothetical presence of anastomoses between pulmonary and bronchial vessels bypassing the pulmonary capillaries, similar to those described in pulmonary arterial hypertension [12].

We explored the quantitative contribution of factors determining P_aO2, using the MIGET algorithm, in patients with severe PH, as compared to those without PH [13] (figure 1d). The principal factor, accounting for 54% of the difference in P_aO2, was reduced P_vO2; the remaining 46% was explained by greater V_A/Q mismatch and shunt, which also determine lower capacity to counterbalance the effect of a diminished P_vO2 (figure 1e). This analysis highlights the important role of P_vO2, determined by cardiac output, in modulating P_aO2 in PH [14].

V_A/Q relationships (logSD Q) significantly worsened on 100% oxygen in patients without PH or with moderate PH, but not in those with severe PH, who instead presented a significant decrease in mPAP and PVR. This suggests that HPV did not contribute substantially to maintaining V_A/Q balance in COPD with severe PH. Presumably, greater endothelial dysfunction in severe PH may reduce the ability to finetune the matching of perfusion to alveolar ventilation [9]. The lack of deterioration of V_A/Q relationships when releasing HPV with oxygen in COPD patients with severe PH may suggest that pulmonary vasodilators might not adversely affect gas exchange in this group. Indeed, controlled trials of pulmonary vasodilators in COPD patients with severe PH have not reported oxygenation worsening [15].

This study is limited by the relatively small sample size of the severe PH group, which is a rare condition, although it was sufficiently robust to detect significant differences in gas exchange determinants, which was its main goal. Another limitation is the absence of imaging in many patients, which could have informed on the parenchymal derangement, due to the retrospective nature of the study.

In conclusion, our study shows that patients with severe PH associated with COPD present distinctive features in pulmonary gas exchange that may contribute to characterising this clinical phenotype. In these patients, severe hypoxaemia is caused by the combination of greater V_A/Q mismatch, increased intrapulmonary shunt and reduced P_vO2, along with a negligible role of HPV in preserving V_A/Q matching. From a practical point of view, these results suggest that pulmonary vasodilators might not be detrimental to gas exchange in this population; theoretically, they could even improve it by increasing cardiac output.

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