Mechanisms of hypoxemia

Robert Rodriguez-Roisin
Josep Roca
This research was supported by the Red Respira-ISCIII-RTIC-03/ 11 and the Comissionat per a Universitats i Recerca de la Generalitat de Catalunya (2001 SGR00386). R.R.-R. holds a career scientist award from the Generalitat de Catalunya.
Introduction
A fundamental aspect of cardiopulmonary homeostasis is the adequate delivery of oxygen to meet the metabolic demands of the body. Cardiac output, O2-carrying capacity
(i.e., hemoglobin concentration and quality), and arterial PO2 (PaO2) determine O2 transport. Relevant to this discussion, arterial hypoxemia commonly occurs in patients with acute respiratory failure (ARF). If arterial hypoxemia is severe enough, it is not compatible with life. The two primary causes of ARF are acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and chronic obstructive lung disease (COPD). Although the treatment for arterial hypoxemia always includes increases in the fractional inspired O2 concentration (FIO2), the degree to which patients’ PaO2 improves and the need for adjuvant therapies differ markedly between these two groups of disease processes. The mechanisms by which arterial hypoxemia occurs in ALI/ARDS and COPD have been characterized using the multiple inert gas elimination technique (MIGET) approach [1]. MIGET provides precise estimates of the distributions of alveolar ventilation and pulmonary perfusion (VA/Q) and their relationships,
there is no need to change the FIO2 during measurements, hence avoiding variations in the pulmonary vascular tone, and it facilitates the unraveling of the active interplay between intrapulmonary, namely VA/Q imbalance, intrapulmonary shunt and limitation of alveolar to end-capillary O2 diffusion, and extrapulmonary (i.e., FIO2, total ventilation, cardiac output and oxygen consumption) factors governing hypoxemia [2]. The cardinal gas exchange features under which the lung operates that uniquely determine the PO2 and PCO2 in each gas exchange unit of the lung are the VA/Q ratio, the composition of the inspired gas, and the mixed venous blood gas composition [3]. Each of these three factors may play key role influencing oxygenation. For example, the major mechanism of arterial hypoxemia in ALI/ARDS is intrapulmonary shunt (zero VA/Q ratios) induced by the presence of collapsed or flooded alveolar units, whereas in COPD the primary mechanism of hypoxemia is VA/Q mismatching. Effect of breathing oxygen on oxygenation In ALI/ARDS, as FIO2 increases, PaO2 increases as long as the amount of shunt is limited. The greater the degree of shunt, the less PaO2 increases. In contrast, in COPD, in which the prime mechanism of hypoxemia is VA/Q mismatching, the response to high FIO2 levels is broadly similar irrespective of disease severity. With moderate VA/Q imbalance PaO2 increases almost linearly as FIO2 is increased. In severely acute COPD the degree of very low VA/Q ratios resembles shunt; the increase in PaO2 in response to increasing FIO2 is only slightly limited, becoming less responsive to increases FIO2. Importantly, FIO2 can also alter VA/Q balance through two additional mechanisms: hypoxic pulmonary vasoconstriction (HPV) and reabsorption atelectasis (RA).One of the main means by which the normal lung adjusts to low regional VA is to induce vasoconstriction of the associated pulmonary vasculature to redirect perfusion away from nonventilated or under ventilated alveolar units. Thus HPV minimizes VA/Q inequality, limiting the decrease in PaO2 that would have occurred if such redistribution of blood flow had not occurred. One of the best VA/Q indicators of the presence of HPV, as measured by MIGET, is the behavior of the area with normal and low VA/Q ratios, reflected in the dispersion of pulmonary blood flow. In sequential measures one sees a significant increase in the latter VA/Q descriptor while breathing 100% O2. By contrast, shunt and the dispersion of alveolar ventilation that incorporates areas with normal and high VA/Q ratios remain unchanged during HPV release. Breathing 100% O2 (FIO2=1.0) can induce intrapulmonary shunt because lung units with low inspired VA/Q ratios, termed “critical” VA/Q ratios, can result in absent expired ventilation because all the inflated gas is absorbed. This results in alveolar denitrogenation, allowing complete gas resorption with atelectasis (RA) to developspontaneously [4]. These critical VA/Q units are dependent on the FIO2, increasing both their potential area of collapse and rate of collapse considerably as FIO2 approaches 1.0. Alternatively, these critical units may remain
open despite increasing FIO2 levels if functional residual capacity and tidal volume are increased, owing to alveolar interdependence. This is the rationale for using
positive end-expiratory pressure (PEEP) and larger tidal volumes in patients with ALI/ARDS to prevent RA. Both RA and HPV and can be observed, respectively, in the responses of patients with ALI/ARDS and COPD needing mechanical support who are given an FIO2 of 1.0 [5] (Fig. 1). Intrapulmonary shunt increases moderately
then remains stable for at least 30 min in ALI/ARDS patients given an FIO2 of 1.0. In contrast, in COPD patients the dispersion of pulmonary blood flow, one of the
most common VA/Q indicators in COPD, further increases to an FIO2 of 1.0 while the modest levels of intrapulmonary shunt remain unchanged, a response that strongly suggests HPV release. Both responses to pure O2 breathing are accompanied with increases in PaO2, which are much more prominent inpatients with COPD. The increase in intrapulmonary shunt in ALI/ARDS is likely due to RA. If cardiac output increases as part of the sympathetic response to arterial hypoxemia, one may also
see a parallel increase in mixed venous PO2 owing to increased O2 delivery. This can offset the increased shunt fraction minimizing the decrease in PaO2. The deleterious
effects of RA on pulmonary gas exchange may be enhanced
by the mechanical trigger imposed on peripheral airways by ventilator support. Indeed, the repeated opening and closing of distal airways and/or the overexpansion
of closed alveolar units with abnormally high shear stresses may result in moreinflammatory lung changes, aggravating the initial mechanical stress injury.
On the other hand, the changes observed in COPD during hyperoxia suggest that inhibition of HPV is the primary process. Interestingly, gas exchange abnormalities in both entities take place in the absence of measurable changes
in pulmonary hemodynamics, suggesting that regional blood flow redistribution can have relevant effects on gas exchange despite minimal changes in pulmonary arterial
pressure and blood flow. If VA were to decrease or dead space to increase, arterial
PCO2 (PaCO2) would increase. Hyperoxia-induced increases in PaCO2 in response to FIO2 1.0 breathing are more notable in ALI/ARDS than in COPD and can be
attributed almost completely to the parallel increases in dead space, with a marginal role of the Haldane effect (i.e., decreasing PaO2 increases PaCO2 off-loading from
Fig. 1 Index of oxygenation (PaO2/FIO2), intrapulmonary shunt (expressed as percentage of cardiac output), and dispersion of
pulmonary blood flow (log SDQ, dimensionless) while breathing 100% O2. In ALI/ARDS (open circles) both PaO2/FIO2 and log SDQ remain essentially unchanged while shunt increases significantly, indicating RA; note that after reinstatement of maintenance FIO2 shunt still remains increased. In COPD exacerbation (closed
squares) PaO2/FIO2 and log SDQ substantially increase while the very modest shunt unvaried, indicating HPV release (by permission from [5])
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