# Gas exchange principles in the critically ill

- DOI:
- 10.1093/med/9780199600830.003.0075

Key points

◆ Gas exchange is a process of molecular movement governed by the unifying principle of mass conservation applied equally to both gas uptake and elimination.

◆ Pulmonary gas exchange in the critically-ill patient is almost always impaired with multiple causes both internal and external to the lung.

◆ In a normal subject breathing sea level air at rest, the $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio of the lung as a whole is around 1 because total alveolar ventilation and pulmonary blood flow are about the same. In the critically ill, inequality can be very severe.

◆ The $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio uniquely determines PaO

_{2}and PaCO_{2}in a given lung region, since all lung regions are subject to the same boundary conditions and O_{2}-Hb and CO_{2}dissociation curves.◆ Hypoxaemia and hypercapnia are caused by $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality, inspiratory hypoxia, hypoventilation, diffusion limitation, shunt, or extrapulmonary factors.

Introduction

This chapter discusses the several reasons for, and mechanisms of, abnormal gas exchange in critically-ill patients in intensive care units (ICUs). The principles underlying gas exchange have been well known since the 1950s when Rahn and Fenn [1], and Riley [2,3,4] and colleagues developed quantitative approaches to its understanding. While these principles apply equally to normal subjects and patients with lung disease, nowhere is their application and understanding both more difficult and also more important than in the ICU. It is well known that patients in the ICU usually endure severe lung disease, no matter what the cause of their illness, and that supportive interventions to improve gas exchange carry their own, sometimes severe, risks of further lung damage.

What follows applies only under steady-state conditions—that is, conditions in which concentrations of gases (such as O_{2} and CO_{2}) are constant in time for at least several minutes. Rapid changes in cardiopulmonary structure or function frequently occur in the ICU, and then the steady state is disturbed, with O_{2} and CO_{2} concentrations rapidly changing, and the use of steady-state concepts will be in error.

Basic principle: mass conservation

Gas exchange is a process of molecular movement governed by the unifying principle of mass conservation, both when movement is by convection (ventilation and blood flow) and by diffusion (gas transfer across the alveolar-capillary blood gas barrier). It applies equally to gas uptake (e.g. O_{2}) and elimination (e.g. CO_{2}).

To best understand this, one applies conservation of mass equations, similar for O_{2} and CO_{2}, so that illustrating the case using O_{2} is here sufficient. Conservation of mass decrees that all the inhaled O_{2} not exhaled on the next breath (eqn 1) is transferred into the pulmonary capillary blood (eqn 2). This transfer rate is the O_{2} uptake, $\dot{\text{V}}{\text{O}}_{2}$:

Taking eqns 1 and 2, and rearranging gives:

$\dot{\text{V}}\text{A}$ is alveolar ventilation and $\dot{\text{Q}}$ total pulmonary blood flow; CaO_{2} and CvO_{2} are systemic and pulmonary arterial O_{2} concentrations, respectively; FiO2 and FaO_{2} are inspired and alveolar O_{2} concentrations respectively. A minor approximation appears above—inspired and expired gas volumes are taken to be the same, which is true to within about 1%.

This equation is written for the whole lung, so that CaO_{2} is mixed arterial blood [O_{2}], while FaO2 is mixed alveolar gas O_{2} fractional concentration. It applies equally to small homogeneous regions in the lung (i.e. approximately, the acinus [5], but the terminology differs:

where ‘c'’, or ‘end-capillary’, represents [O_{2}] in the pulmonary venule draining the homogeneous region, and FaO_{2} is now the alveolar [O_{2}] in the same region.

Eqn (4) shows that three factors determine gas exchange:

◆ The region’s $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio.

◆ The ‘boundary conditions’, i.e. O

_{2}composition of inspired gas (FiO_{2}) and pulmonary arterial blood (CvO2).◆ The characteristics of the O

_{2}-Hb dissociation curve.

The latter is involved because Cc’O_{2} and FaO_{2} are directly linked through that curve. Since by Dalton’s law of partial pressures PO_{2} = FO_{2} * [Pb–PH_{2}O], the alveolar PO_{2} (PaO_{2}) is also defined. Thus, there is only a single value of PaO_{2} that satisfies eqn 4 for
any set of the three groups of variables listed immediately previously. This is shown in Fig. 75.1, where the boundary conditions and O_{2}Hb dissociation curve are held constant (using normal values), while the $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio is systematically varied from zero to infinity. Fig. 75.1 also shows the results for CO_{2}, based on identical considerations and normal values. Eqn 4 is called the ventilation/perfusion ($\dot{\text{V}}\text{A}/\dot{\text{Q}}$) eqn for O_{2}. For CO_{2}, it is in essence identical, but because CO_{2} is eliminated while O_{2} is taken up, the quantities appear in reverse order to avoid negative signs:

It is also useful to write the analog of eqn 1 for CO_{2}, giving:

This is useful, because, disregarding inspired [CO_{2}] as negligible, the ratio of eqn 6 to eqn 1, gives:

or,

because F (fractional alveolar gas concentration) and P (alveolar partial pressure) are proportional. $\dot{\text{V}}\text{A}$ cancels out of the equation; R is the respiratory exchange ratio (the ratio of CO_{2} produced to O_{2} consumed). Re-arranging gives:

This is the simple form of the alveolar gas equation. It suffices for clinical use, but if one wishes to account for $\dot{\text{V}}\text{I}$ and $\dot{\text{V}}\text{A}$ being slightly different, it becomes:

The alveolar gas equation defines the PaO_{2} if we know PaCO_{2}, PiO_{2}, and R. It applies to the lung as a whole or to a small homogenous region, just like the ventilation/perfusion equation.

The most important outcome is understanding that the $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio uniquely determines PaO_{2} and PaCO_{2} in a given lung region (since all lung regions are subject to the same boundary conditions and O_{2}-Hb and CO_{2} dissociation curves); see Fig. 75.1.

Ventilation/perfusion matching and gas exchange

If all lung regions had the same $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio, they would all have the same PaO_{2} and PaCO_{2}. In a normal subject breathing sea level air at rest, the $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio of the lung as a whole is around 1 because total alveolar ventilation and pulmonary blood flow are about the same at 5–6 L/min. PaO_{2} is ~100 mmHg, while PaCO_{2} is ~40 mmHg (Fig. 75.1). Because all regions reach diffusion equilibrium of O_{2} exchange across the blood–gas barrier at rest in health [6], end capillary PO_{2} and PCO_{2} would equal their alveolar counterparts in each region, and thus the systemic arterial blood would also have a PO_{2} of 100 mmHg and PCO_{2} of 40 mmHg. However, if regional $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio was lower than average. Fig. 75.1 shows PaO_{2} is reduced and PaCO_{2} increased in that region. Symmetrically, in a high $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ region, PaO_{2} will rise, and PACO_{2} fall.

Using Fig. 75.1, we may consider what we call $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality, when not all regions have the same values of $\dot{\text{V}}\text{A}/\dot{\text{Q}}$. In the critically ill, inequality can be very severe. A simple ‘two-compartment’ model suffices to illustrate the principles, lung is usually far more complex. The top panel (Fig. 75.2A) shows the two-compartment model in the homogeneous state, with both ventilation ($\dot{\text{V}}\text{A}$) and blood flow ($\dot{\text{Q}}$) equally distributed. With total ventilation and perfusion each set to 6 L/min, the $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio is 1.0 in each compartment. From Fig. 75.1, PaO_{2} is 104 mmHg and PaCO_{2} 39 mmHg in each compartment. Mixed exhaled gas will also have these partial pressures, as will the mixed pulmonary venous blood returning to the left heart, and then systemic arterial PO_{2}.

If the left airway is now largely partially obstructed (by mucus, bronchoconstriction, airway wall thickening, aspirated foreign object, tumour, etc.) as in the lower panel, Fig. 75.2B, $\dot{\text{V}}\text{A}$ of the obstructed compartment will be reduced (here by 90%) to 0.3 L/min. Because we wish to model only the effects of $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality, total ventilation, and blood flow are unchanged. Thus, the right-hand compartment now receives more ventilation than normal, here 5.7 L/min. There is, thus, one compartment with low $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio (0.1) and one with high $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio (1.9), but the total ventilation and blood flow remain normal. From Fig. 75.1, the alveolar (and end capillary) PO_{2} are 45 (low $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ unit) and 122 mmHg (high $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ unit). PO_{2} in mixed exhaled gas (Pe) is the ventilation-weighted average of the two PaO_{2} values. Ventilation weighting is required to ensure conservation of mass.

This calculation should strictly use concentration, rather than partial pressure. However, partial pressure can be used because Dalton's Law states that partial pressure and concentration are proportional.

This is 14 mmHg higher than in the homogeneous lung (Fig. 75.2A). Inspired PO_{2} is about 150 mmHg and thus the inspired-exhaled PO_{2} difference in the homogeneous state is 150 – 104 = 46 mmHg and after airway obstruction is 150 – 118 = 32 mmHg. If mixed exhaled gas has a higher PO_{2}, more O_{2} is
exhaled and therefore less is transferred into the blood: $\dot{\text{V}}{\text{o}}_{\text{2}}$ has fallen to 32/46 (i.e. ~70%) of that in the homogeneous lung.

PO_{2} in the mixed pulmonary venous blood is calculated from the perfusion-weighted average of the two O_{2} concentration values, using the O_{2}-Hb dissociation curve to compute the corresponding PO_{2}. This PO_{2} is only 58 mmHg.

For CO_{2}, the numbers are quite different, but the outcome is qualitatively identical, but opposite: CO_{2} elimination is reduced, but only by ~13%, and arterial PCO_{2} rises, but by less than 1 mmHg. Indeed, the exchange of all gases is impaired by $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality and is manifest by a fall in arterial blood values for all gases taken up (e.g. O_{2}) and a rise in arterial blood values for all gases being eliminated (e.g. CO_{2}).

In this example, the effects are greater for O_{2} than for CO_{2}. The same analysis obstructing the pulmonary artery of the left compartment (and restoring equal ventilation distribution) is shown in Fig. 75.3. Here, everything else is identical to that in Fig. 75.2B. The resulting compartmental ratios of $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ are 10.0 and 0.53. As in the airway obstruction model, the two compartments have a below-average (right) and above-average (left) $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio. Reading off Fig. 75.1, PaO_{2} are 142 and 77 mmHg, respectively. Mixed exhaled PO_{2} is 110 mmHg (weighted mean of 142 and 77), while arterial PO_{2} is 78 mmHg. $\dot{\text{V}}{\text{o}}_{2}$ is reduced, to (150–110)/(150–104), or 87% of control, while $\dot{\text{V}}{\text{co}}_{2}$ falls to 75% of control and arterial PCO_{2} increases by 2 mmHg.

Thus, the two models—airway and vascular obstruction—both show impaired overall gas transfer, hypoxaemia, and hypercapnia, but airway obstruction affects O_{2} transfer more than it affects CO_{2}, while with vascular obstruction, CO_{2} transfer is more affected.

The causes of hypoxaemia and hypercapnia

There are six possible physiological causes of hypoxaemia and hypercapnia:

◆ $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality.

◆ Inspiratory hypoxia.

◆ Hypoventilation.

◆ Diffusion limitation.

◆ Shunt.

◆ Extra-pulmonary factors related to metabolic rate and cardiac output.

${\dot{\text{V}}}_{}/\dot{\text{Q}}$ inequality

Very important in critically-ill patients, inequality is defined as a range of $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratios throughout the lung. In some regions, the $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio is low, in others normal, and in others high. This impairs overall O_{2} uptake and CO_{2} elimination (until compensated by increased O_{2} extraction, ventilation, or cardiac output), and causes hypoxaemia and hypercapnia.

There are many reasons for $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality in ICU patients. They result from the pathological processes in the lung—infection, inflammation, fluid accumulation, vascular obstruction, tissue breakdown, and effects of ventilator management and other therapies. Importantly, these processes are never uniformly distributed throughout the lung. They are conveniently discussed by site of origin—airways, alveoli, blood vessels, and pleura. What follows is not exhaustive, but addresses the majority of mechanisms of inequality.

In the airways, bronchial wall thickening, mucus secretions, alveolar debris (cells, bacteria, inhaled particles, fluid) moved up the airways by ciliary function, bronchial smooth muscle contraction, and diminished parenchymal radial traction on the airway wall (the latter especially with pre-existing COPD) will each act to reduce airway lumen size, (partially) obstructing the airway, and increasing airflow resistance. Because some regions will be more obstructed than others, more affected regions become underventilated, and a low regional $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio will usually develop. With overall lung ventilation maintained, less affected regions (taking the air originally designated for the obstructed regions) are over-ventilated, raising the $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio above normal, and causing hyperinflation and risk of barotrauma.

In affected alveoli, cellular debris, oedema fluid, and bacterial fragments will (partly) displace the air, diminishing their ventilation (even if the airways are normal). Alveoli completely filled with such material will not be ventilated at all, resulting in shunt. Collapsed alveoli will not receive ventilation, also resulting in shunt. Impaired surfactant activity often occurs, reducing compliance and promoting atelectasis. Interstitial oedema will also reduce compliance, and, with airways factors mentioned in the preceding paragraph, reduce regional ventilation.

Thus, a large number of specific processes all acting to impair regional ventilation may be present in the lungs of critically-ill patients, creating regions of low $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio, $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality and hypoxaemia. At the same time, over-ventilation of less affected regions occurs. As pathological processes continue, partial airway obstruction may become complete, converting what was $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality into shunt.

Pulmonary vascular pathology may also cause $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality and hypoxaemia. In the ICU, one cause is pulmonary thromboembolism. It may be classical emboli from thrombosed veins in extra-pulmonary regions of the body or local thrombosis in damaged pulmonary vessels. The resulting (partial) vascular obstruction diverts blood flow to less affected lung regions. In this manner, the affected regions develop high $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratios due to loss of perfusion, while the unaffected regions become over-perfused, so their $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio falls.

High $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ regions may develop from mechanical ventilation with high airway pressures. This may overventilate and hyperinflate the most normal, compliant alveoli, stretching alveolar walls, compressing alveolar capillaries [7], increasing vascular resistance, reducing their perfusion and increasing the $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio. At first sight, this may not seem problematic (a high $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio corresponds to a high PO_{2} and low PCO_{2}, Fig. 75.1). However, there are three major concerns:

◆ Risk of barotrauma from the hyperinflation.

◆ Poorly perfused alveoli are not effective for gas exchange, because little O

_{2}can be added to the blood or CO_{2}removed.◆ The ventilation delivered to these alveoli causes the perfused alveoli that undertake most of the gas exchange to become under-ventilated and CO

_{2}retention may develop.

Pleural processes that may affect gas exchange include pneumothorax and effusion, both of which promote atelectasis (and thus shunt), or pleural thickening that restricts lung inflation.

To summarize, many mechanisms may co-exist in ICU patients to produce $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality. Those that primarily affect the airways, alveoli, and pleura lead mostly to regions of reduced $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio, while those that primarily affect the vasculature result in regions of high $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio. These different locations of effect may then result in different arterial PO_{2}/PCO_{2} pictures, as expressed in Figs 75.2 and 75.3, gas exchange is always impaired.

Inspiratory hypoxia

Reduced inspired PO_{2} (e.g. ascent to altitude, plane flight) causes arterial hypoxaemia, but in the ICU, this should not occur and will not be discussed.

Hypoventilation

Insufficient ventilation to the lungs as a whole will cause arterial PO_{2} to fall and PCO_{2} to rise. Fig. 75.4 (representing eqns 1 and 6) shows how sensitive PO_{2} and PCO_{2} are to changes in ventilation, especially when reduced. Unless by therapeutic design, overall hypoventilation is not commonly seen in ICU patients.

Diffusion limitation

An assumption of the preceding analysis has been that diffusion of O_{2} and CO_{2} between alveolar gas and capillary blood is complete within the transit time of a red cell through the lung capillaries, such that alveolar and end-capillary PO_{2} are equal (and similarly for PCO_{2}). In critically-ill patients in the ICU, this assumption is known to be reasonable.

Shunt

Shunt is defined as blood flowing from the right side to the left side of the heart without any alveolar gas contact, thus affording no O_{2} uptake or CO_{2} elimination. Shunt pathways include direct communications between the ventricles or atria of the heart, and blood passing through completely unventilated lung regions. Common causes include atelectasis, alveolar filling with fluid or exudate, and pneumothorax. Shunting is common and often substantial in the ICU. Uncommonly, dilated pulmonary vessels may carry blood that fails to (fully) oxygenate, even when adjacent alveoli are ventilated. This may happen in chronic liver disease [8], and in infants/children suffering bronchopulmonary dysplasia.

Extrapulmonary factors

For a given metabolic rate ($\dot{\text{V}}{\text{o}}_{2}$), reduction in cardiac output will necessitate greater tissue O_{2} extraction to maintain adequate O_{2} supply. If cardiac output falls (in relation to $\dot{\text{V}}{\text{o}}_{2}$), PO_{2} of the venous blood returning to the lungs also falls. Similarly, high cardiac output (in relation to $\dot{\text{V}}{\text{o}}_{2}$) will result in an elevated venous PO_{2}. As
the ventilation/perfusion equation shows (eqn. 4), the boundary conditions (composition of pulmonary arterial blood and inspired gas) affect the values of PO_{2} and PCO_{2} independently of the $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio. As venous PO_{2} falls, alveolar, and end-capillary PO_{2} will fall at a given $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio, and vice versa. In this way, extrapulmonary factors (cardiac output and $\dot{\text{V}}{\text{o}}_{2}$
especially) will affect arterial PO_{2}, in addition to all the preceding potential causes of hypoxaemia. Reduction in blood [Hb] has the same effect as reduction in cardiac output—greater fractional extraction of O_{2} and lower venous PO_{2}.

The message is that when changes in metabolism, cardiac function, and/or [Hb] occur, changes in arterial oxygenation are expected that have nothing to do with lung health. Recognizing this is paramount in providing the best therapeutic response. For example, thinking a sudden fall in arterial PO_{2} is due to new alveolar oedema or collapse when it is due to cardiac dysfunction may lead to poor clinical decisions.

In closing, two special cases of the role of extrapulmonary factors deserve mention—the first is dependence of shunt on total pulmonary blood flow. In patients with shunt, a change in cardiac output changes not just venous PO_{2} as discussed, but also the volumetric flow distribution between the shunt channels and the rest of the lung. The reason remains unclear, but may have to do with differing degrees of hypoxic pulmonary vasoconstriction in the shunt vessels compared to the rest of the lungs. Fig. 75.5 shows an extraordinary example of this effect [9]. The implication is clear—increasing blood flow through a damaged lung has the potential of worsening the shunt, which will oppose any beneficial effect of higher blood flow on the venous PO_{2}.

The second example occurs when high positive airway pressure are used. This impedes venous return to the heart and cardiac output falls. As a result, even if higher airway pressure successfully re-inflates collapsed alveoli and reduces shunt, the expected benefit in arterial PO_{2} may not occur, or may be lessened, because the reduced cardiac output lowers venous PO_{2}.

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