Mechanisms of hypoxemia

Robert Rodr
guez-Roisin

Josep Roca Mechanisms of hypoxemia

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, O

-carrying ca- pacity (i.e., hemoglobin concentration and quality), and arterial PO

(PaO

) determine O

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 in- creases in the fractional inspired O

concentration (FIO

), the degree to which patients’ PaO

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 elimina- tion technique (MIGET) approach [1]. MIGET provides

precise estimates of the distributions of alveolar ventila- tion and pulmonary perfusion (V

/Q) and their relation- ships, there is no need to change the FIO

during mea- surements, hence avoiding variations in the pulmonary vascular tone, and it facilitates the unraveling of the ac- tive interplay between intrapulmonary, namely V

/Q imbalance, intrapulmonary shunt and limitation of alve- olar to end-capillary O

diffusion, and extrapulmonary (i.e., FIO

, 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 PO

and PCO

in each gas exchange unit of the lung are the V

/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 V

/Q ratios) induced by the presence of collapsed or flooded alveolar units, whereas in COPD the primary mechanism of hypoxemia is V

/Q mismatching.

Effect of breathing oxygen on oxygenation

In ALI/ARDS, as FIO

increases, PaO

increases as long as the amount of shunt is limited. The greater the degree of shunt, the less PaO

increases. In contrast, in COPD, in which the prime mechanism of hypoxemia is V

/Q mis- matching, the response to high FIO

levels is broadly similar irrespective of disease severity. With moderate V

/Q imbalance PaO

increases almost linearly as FIO

is increased. In severely acute COPD the degree of very low V

/Q ratios resembles shunt; the increase in PaO

in re- sponse to increasing FIO

is only slightly limited, be- coming less responsive to increases FIO

.

Importantly, FIO

can also alter V

/Q balance through

two additional mechanisms: hypoxic pulmonary vaso-

constriction (HPV) and reabsorption atelectasis (RA).

1018

One of the main means by which the normal lung adjusts to low regional V

is to induce vasoconstriction of the associated pulmonary vasculature to redirect perfusion away from nonventilated or under ventilated alveolar units. Thus HPV minimizes V

/Q inequality, limiting the decrease in PaO

that would have occurred if such re- distribution of blood flow had not occurred. One of the best V

/Q indicators of the presence of HPV, as measured by MIGET, is the behavior of the area with normal and low V

/Q ratios, reflected in the dispersion of pulmonary blood flow. In sequential measures one sees a significant increase in the latter V

/Q descriptor while breathing 100% O

. By contrast, shunt and the dispersion of alve- olar ventilation that incorporates areas with normal and high V

/Q ratios remain unchanged during HPV release.

Breathing 100% O

(FIO

=1.0) can induce intrapul- monary shunt because lung units with low inspired V

/Q ratios, termed “critical” V

/Q ratios, can result in absent expired ventilation because all the inflated gas is ab- sorbed. This results in alveolar denitrogenation, allowing complete gas resorption with atelectasis (RA) to develop spontaneously [4]. These critical V

/Q units are depen- dent on the FIO

, increasing both their potential area of collapse and rate of collapse considerably as FIO

ap- proaches 1.0. Alternatively, these critical units may re- main open despite increasing FIO

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 FIO

of 1.0 [5] (Fig. 1). Intrapulmonary shunt increases moderately then remains stable for at least 30 min in ALI/ARDS patients given an FIO

of 1.0. In contrast, in COPD pa- tients the dispersion of pulmonary blood flow, one of the most common V

/Q indicators in COPD, further in- creases to an FIO

of 1.0 while the modest levels of in- trapulmonary shunt remain unchanged, a response that strongly suggests HPV release. Both responses to pure O

breathing are accompanied with increases in PaO

, which are much more prominent in patients 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 PO

owing to increased O

delivery. This can offset the increased shunt fraction minimizing the decrease in PaO

. The deleterious effects of RA on pulmonary gas exchange may be en- hanced by the mechanical trigger imposed on peripheral airways by ventilator support. Indeed, the repeated opening and closing of distal airways and/or the overex- pansion of closed alveolar units with abnormally high shear stresses may result in more inflammatory 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 V

were to decrease or dead space to increase, ar- terial PCO

(PaCO

) would increase. Hyperoxia-induced increases in PaCO

in response to FIO

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 PaO

increases PaCO

off-loading from Fig. 1 Index of oxygenation (PaO

/FIO

), intrapulmonary shunt (expressed as percentage of cardiac output), and dispersion of pulmonary blood flow (log SDQ, dimensionless) while breathing 100% O

. In ALI/ARDS (open circles) both PaO

/FIO

and log SDQ remain essentially unchanged while shunt increases signifi- cantly, indicating RA; note that after reinstatement of maintenance FIO

shunt still remains increased. In COPD exacerbation (closed squares) PaO

/FIO

and log SDQ substantially increase while the very modest shunt unvaried, indicating HPV release (by permission from [5])

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References

1. Glenny R, Wagner PD, Roca J, Rodriguez-Roisin R (2000) Gas ex- change in health: rest, exercise, and aging. In: Roca J, Rodriguez-Roisin R, Wagner PD (eds) Pulmonary and pe- ripheral gas exchange in health and disease. Dekker, New York, pp 121–

148

2. Rodriguez-Roisin R, Wagner PD (1990) Clinical relevance of ventilation-perfu- sion inequality determined by inert gas elimination. Eur Respir J 3:469–482

3. West JB (1977) State of the art:

Ventilation-perfusion relationships.

Am Rev Respir Dis 116:919–943 4. Dantzker DR, Wagner PD, West JB

(1975) Instability of lung units with low V

/Q ratios during O

breathing. J Appl Physiol 38:886–895

5. Santos C, Ferrer M, Roca J, Torres A, Hernandez C, Rodriguez-Roisin R (2000) Pulmonary gas exchange re- sponse to oxygen breathing in acute lung injury. Am J Respir Crit Care Med 161:26–31

6. Mancini M, Zavala E, Mancebo J, Fernandez C, Barbera JA, Rossi A, Roca J, Rodriguez-Roisin R (2001) Mechanisms of pulmonary gas ex- change improvement during a protective ventilatory strategy in acute respiratory distress syndrome.

Am J Respir Crit Care Med 164:

1448–1453 hemoglobin). Conceivably, the increased dead space in-

dicates redistribution of pulmonary blood flow from high V

/Q areas either to regions with no ventilated (shunt) alveolar units in ALI/ARDS or to those poorly ventilated with low V

/Q areas in COPD. This process, however, has not been definitely characterized. An alternative and/

or complementary mechanism in ALI/ARDS for the ob- served increase in PaCO

could be overexpansion of re- maining normal lung zones provoked by RA, but in COPD by bronchodilation secondary to the hypercapnia.

Protective ventilator support

Protective ventilator support with low tidal volume and high PEEP levels has become the preferred approach to decrease the impact of ventilator-associated lung injury [6]. This protective support causes a substantial im- provement in gas exchange by increasing PaO

and de- creasing intrapulmonary shunt. However, this strategy of increased PEEP and small tidal volumes is often accom- panied by hypercapnia. Hypercapnia induces both vaso- dilatation and increased cardiac output, both of which increase intrapulmonary shunt and potentially impair ar- terial oxygenation. The principal factor to explain the observed reduction in shunt in protective lung ventilation is the recruitment of previously collapsed alveoli, as shown by the close correlation between the decreased intrapulmonary shunt and the amount of PEEP-induced lung volume recruitment. Furthermore, the parallel in- crease in cardiac output caused by the hypercapnia-in- duced vasodilatation does not induce any proportional

injurious increases in intrapulmonary shunt. Conceivably, the alveolar recruitment induced by recruitment effi- ciently redistributes pulmonary blood flow to regions with alveolar units with normal V

/Q balance. A parallel finding in protective lung ventilation is the significant increase in physiological dead space, possibly related to the combined effects of a decreased alveolar ventilation and increased functional residual capacity. Thus the ap- plication of a protective ventilator support combining low tidal volumes and high PEEP levels represent a beneficial ventilator strategy in ALI/ARDS both in terms of mini- mizing lung stress and augmenting gas exchange.

Summary

The primary mechanisms leading to arterial hypoxemia in ARF secondary to COPD exacerbations and ALI/ARDS are V

/Q imbalance and intrapulmonary shunt while the conditions that uniquely determine the PO

and PCO

in gas exchange units of the lung are the V

/Q ratio and the composition of inspired gas and mixed venous blood. This is why the extrapulmonary factors governing hypoxemia, i.e., FIO

, total ventilation, cardiac output, and O

con- sumption, always need to be considered. The increase in intrapulmonary shunt characteristically shown in ALI/

ARDS patients breathing high FIO

levels is secondary to the development of RA, whereas in COPD patients it is usually due to withdrawal of HPV, reflected by further V

/Q worsening only without parallel increases in intra- pulmonary shunt.

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