In Reply:
We thank Dr Champion for his particular interest in our study and his thorough comments. However, we would like to share our concerns related to his comments.
In our point of view, we should use the microvascular oxygen extraction rate with caution, as it is not yet a valid accurate index to use. This index does not take into account all of the factors that influence oxygen delivery, such as cardiac output, serum hemoglobin levels, and hemoglobin dissociation curve, and to the best of our knowledge, it has not been investigated previously in patients with chronic hypoxemia.
Resting tissue oxygen saturation (StO2) values depend mainly on the ratio of tissue oxygen delivery to tissue oxygen extraction. In our study,1 pulmonary arterial hypertension (PAH) patients presented with a relatively normal cardiac index (median value of 2.5 L/min/m2) and normal serum hemoglobin levels (median value of 16 g/dL) with mild hypoxemia (SpO2 median value of 94%), the latter being a possible factor that might slightly decrease tissue oxygen supply. However, tissue oxygen delivery depends also on regional tissue perfusion, which seems to be altered in these patients.
Supporting evidence provided using the near-infrared spectroscopy (NIRS) 3-min vascular occlusion technique in our study showed that there was a reduction in oxygen consumption rate in PAH patients compared with healthy subjects (median values of 33% and 44%/min, respectively), making the mechanism of increased oxygen extraction an unlikely explanation of the decrease in resting StO2 in these PAH patients. For these reasons, we strongly believe that the main mechanism explaining the decrease in resting StO2 is rather a regional impaired tissue perfusion. The presence of an imbalance of autonomic nervous system activity2 and the pronounced increased sympathetic overactivity3 of local and systemic neurohumoral factors, such as the increased endothelin-1/nitric oxide activity ratio4 and the anatomical and functional skeletal muscle alterations (muscle atrophy and mitochondrial dysfunction),5 in PAH patients are possibly the main mediators of a skeletal muscle mismatch of regional tissue perfusion and oxidative metabolism. These local and systemic alterations may explain the peripheral microcirculatory abnormalities observed using NIRS methodology in PAH patients. Interestingly, an impaired oxygen extraction ratio has been demonstrated previously in PAH patients during maximal exercise6 further supporting the above-proposed explanatory mechanism.
Thus, the decreased resting StO2 reflects mainly the peripheral microcirculatory alterations in PAH rather than an increased oxygen extraction. However, the innovative findings of our study are demonstrated not only by resting StO2 values but also by the increased hyperemia time after 3 min of vascular occlusion, indicating important endothelial dysfunction. Moreover, the deleterious hyperoxic breathing effects on endothelial function in PAH patients that emerged in our study are of particular importance and merit further investigation. These data might have important clinical implications in the use of oxygen therapy in these patients. The mechanisms underlying hyperoxia-induced vasoconstriction effects are nicely described in a recent review from Sjöberg and Singer.7
The possible role of right-sided “outflow obstruction” that might affect peripheral microcirculation and NIRS results in PAH patients is of interest. However, more data are needed to clarify better its possible effects in PAH microcirculation prior to any definite conclusion.
We strongly believe that the novel findings of this pilot study will stimulate further investigation that will provide evidence to confirm the present data and more accurate explanatory mechanisms. NIRS with the vascular occlusion technique is a simple valid method that can easily estimate microcirculatory and tissue oxygenation changes useful to daily clinical practice. Its combination with novel, more sophisticated imaging techniques, such as sidestream dark field imaging, may also be helpful to confirm and possibly extend the results of our pilot study.
Footnotes
The authors have disclosed no conflicts of interest.
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