# Gas exchange assessment in the critically ill

- DOI:
- 10.1093/med/9780199600830.003.0076

Key points

◆ The cornerstone of insightful monitoring is directly sampled systemic arterial blood, but there are both more and less complex and invasive methods.

◆ Pulse oximetry is the least invasive measure, but limitations include poor signal and inability to track substantial change in PO

_{2}at higher SaO_{2}(flat O_{2}-Hb curve).◆ The PaO

_{2}/FiO_{2}ratio is used in the ICU so measurements at different FiO_{2}can be compared, although it is not completely independent of FiO_{2}in the critically ill.◆ The alveolar-arterial PO

_{2}difference corrects the alveolar PO_{2}for values of PaCO_{2}different than 40 mmHg. It becomes less useful as FiO_{2}is increased if $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality is the main problem.◆ Using oximeter-tipped catheters placed in the pulmonary artery, mixed venous saturation is continuously available. A high arteriovenous difference implies high O

_{2}demand in relation to supply, and vice versa but correct interpretation depends on $\dot{\text{V}}{\text{o}}_{2}$ and cardiac output.

Introduction

Since most patients admitted to the intensive care unit (ICU) have damaged lungs, monitoring of gas exchange is critical to informed management. Monitoring can be descriptive (how abnormal is gas exchange?) and mechanistic (how may gas exchange reveal pathophysiological insights?)

The cornerstone of insightful monitoring is directly sampled systemic arterial blood, but there are both more and less complex and invasive methods. Usually, the more complex and invasive, the greater will be the insights gained, and vice versa. The key is to balance the complexities against the information content to select an approach that is sufficiently useful yet not overly complex.

Pulse oximetry

The simplest, least invasive approach is pulse oximetry, which measures arterial O_{2} saturation (SaO_{2}). With immediate, continuous, low cost, non-invasive response requiring no specialty training, it is widely used to good advantage. The clinical range of use is mostly 85–100%. If SaO_{2} is <85–90%, direct arterial blood sampling and urgent therapeutic responses are usually required.

Oximetry does not measure arterial PCO_{2}/pH and usually does not reveal mechanistic information. Moreover, as the O_{2}-Hb dissociation curve shifts when pH, temperature, and PCO_{2} change, a given saturation may correspond to different PO_{2} values.

Two major limits to pulse oximetry are:

Inadequate signal: most oximeters are lightly clamped on a finger. They are easily dislodged and require adequate digital perfusion.

The shape of the O_{2}-Hb dissociation curve: when arterial PO_{2} lies on the flat part of the O_{2}-Hb curve (SaO_{2}> ~95%), large changes in PO_{2} may occur from significant changes in lung function without measureable differences in SaO_{2}.

Since the standard deviation of SaO_{2} is ~2%, a true SaO_{2} of 97% (normal) may read 95%, while a true value of 93% (abnormal) may also read 95%. It is thus problematic to know whether such a value represents poor lung function or random variation from normal.

Additionally, when saturation falls below ~70%, many oximeters will indicate an even lower (i.e. erroneous) value. This should not happen in the ICU, because saturations this low imply life-threateningly poor lung function, requiring placement of an arterial catheter to directly sample arterial blood.

Arterial blood gas sampling

Arterial blood sampling, via in-dwelling catheter or needle puncture, is the current backbone of ICU gas exchange assessment. Unlike oximetry, sampling is discrete, not continuous (continuously recording in-dwelling electrodes are under development). Sample volume can be less than 200 µL, enabling paediatric use. Analysis (blood gas analyser) takes only 1–2 minutes, and yields PO_{2}, pH, PCO_{2}, SaO2 [Hb], lactate, bicarbonate, and base excess, thus evaluating acid–base state and gas exchange.

Precautions in arterial blood sampling

Several important precautions are necessary to avoid errors:

◆ The sample must be taken and kept without exposure to air until measured.

◆ The sample syringe must be free of air (bubbles). These distort the results and should be immediately expelled from the syringe.

◆ The syringe must be pre-heparinized to prevent clotting, which obstructs analysers and causes malfunction. Use just enough heparin to prevent coagulation without diluting the sample.

◆ The sample should be analysed immediately. If delay is unavoidable, keep it iced to reduce white blood cell metabolism, which will reduce PO

_{2}and raise PCO_{2}. This is especially important when PO_{2}is high, since PO_{2}may otherwise fall 10–20 mmHg/min.◆ Aggressively rotate the sample until the moment of analysis to avoid red cell settling causing errors in [Hb] and haematocrit.

◆ Document patient temperature, to understand temperature-induced shifts in the O

_{2}-Hb dissociation curve, and to correct of PO_{2}, PCO_{2}and pH back to body temperature (clinical analysers usually run at 37°C). Suppose a patient’s temperature is 39°C. As the sample cools to 37°C in the analyser, the number of O_{2}molecules per unit volume cannot change (no air contact). Thus, SaO_{2}is not affected by cooling. However, the O_{2}-Hb curve shifts leftward, and so PO_{2}falls. We usually need PO_{2}at body temperature, and so temperature-correct the value accordingly, about 6% per degree Centigrade. Thus, a PO_{2}of 80 mmHg would become ~90 mmHg expressed when the patient’s temperature was 39°C. Directional changes are similar for PCO_{2}and blood [H^{+}], yielding a higher PCO_{2}and lower pH than indicated by the analyser. The opposite is true when the patient is below 37°C. Most analysers temperature-correct automatically.◆ Document inspired [O

_{2}] at sampling. A PO_{2}of 90 mmHg, breathing room air, is interpreted very differently from the same PO_{2}measured during 100% O_{2}breathing.

Interpretation of blood gas variables

First, ask only how different PO_{2}, PCO_{2}, pH, SaO_{2}, and [Hb]/haematocrit are from normal. Two things are required—expected normal values, and analyser measurement error, to establish the 95% confidence limits (roughly, mean ± 2 SD). If the values lie outside those limits, there is at least a 95% chance that the data are abnormal. When FiO_{2} is elevated, (common in the ICU), normal alveolar PO_{2} expected at any FiO_{2} can be estimated from the alveolar gas equation:

FiO_{2} is inspired O_{2} fraction, Pb is barometric pressure; Ph_{2}o is saturated water vapour pressure (47 mmHg at 37°C); PaCO_{2} is arterial PCO_{2} and R is respiratory exchange ratio, usually assumed to be 0.8.

In sea level room air, normal alveolar PO_{2} is about 100 mmHg. On 100% O_{2}, it rises to ~660 mmHg. The relationship is essentially linear in between. Normal arterial PO_{2} should be a few mmHg lower than alveolar.

Clinical analysers commonly have a coefficient of variation for PO_{2} of ~5% (thus if PO_{2} = 100 mmHg, 95% confidence limits are 90–110 mmHg). If PO_{2} is 500 mmHg, 95% confidence range is ~450–550 mmHg.

PCO_{2} usually shows less variance; if PCO_{2} = 40 mmHg, 95% confidence limits should be 38–42 mmHg, while when pH = 7.40, 95% confidence limits should be 7.38–7.42. However, ignoring the above sampling precautions will increase uncertainty.

Arterial blood gas variables can answer more than whether the results are normal or not. Well-established equations and relationships exist for quantifying gas exchange disturbances to estimate the extent of lung damage, and responses to interventions and therapies.

Pao_{2}/Fio_{2} ratio

This simple and popular ratio [1] is used in the ICU so measurements at different FiO_{2} can be compared. Since arterial PO_{2} in health rises linearly with FiO_{2}, PaO_{2}/ FiO_{2} is somewhat constant as FiO_{2} changes. This attractive concept has limitations: Fig. 76.1 shows the PaO_{2} (upper panel) and PaO_{2}/ FiO_{2} ratio (lower panel) over the FiO_{2} range from room air to 100% O_{2} in several computational models [2] of varying gas exchange abnormality, labelled A through G.

Curve A (open squares) represents the normal lung. PaO_{2} rises linearly (upper panel) and PaO_{2}/FiO_{2} is very high and is essentially constant. However, even here, PaO_{2}/FiO_{2} is not totally independent of FiO_{2}—small changes must not be over-interpreted.

Curves B, C, and D represent lungs with increasing heterogeneity of ventilation with respect to blood flow ($\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality), quantified by the term SDQ (in effect, the standard deviation of the $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ distribution). The normal range is 0.3–0.6 [3]. SDQ = 1.0 represents moderate inequality as in stable chronic lung disease; SDQ = 2.0 corresponds to a very ill ICU patient. In B, C, and D, there is zero shunt. PaO_{2}/FiO_{2} increases considerably and non-linearly with increasing Fio_{2} despite a constant amount of $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality. Both PaO_{2}/FiO_{2} itself and its change with FiO_{2} depend on the amount of $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality and the FiO_{2}, making PaO_{2}/FiO_{2} somewhat difficult to interpret.

Curves E, F, and G represent lungs without $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality, but with shunting of 10, 20, and 30%, respectively. The behaviour
of PaO_{2}/FiO_{2} as FiO_{2} is different again—the ratio first falls as FiO_{2} increases, before modestly rising as FiO_{2} approaches 1. Especially important is the region encompassed by the dashed-line box: over a wide FiO_{2} range (room air to 0.6), PaO_{2}/FiO_{2} is largely independent of FiO_{2}, but lungs with moderate to severe $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality and lungs with 20–30% shunt are, in practice, unable to be distinguished.

When FiO_{2} = 1, no matter the severity of $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality, PaO_{2}/ FiO_{2} is very high while with shunt, the ratio falls progressively as shunt increases. Fig. 76.1 also suggests that it may be useful to assess PaO_{2}/FiO_{2} at two different values of FiO_{2}. Its behaviour as FiO_{2} changes allows more insight into the gas exchange defect.

The alveolar-arterial Po_{2} difference: A-apo_{2}

The alveolar gas equation allows calculation of alveolar PO_{2}, and subtracting arterial PO_{2} from this yields the A-aPO_{2}. The advantage of A-aPO_{2} is that it corrects the alveolar PO_{2} for values of PaCO_{2} different than 40 mmHg. Thus, if a patient with normal lungs, breathing room air, hypoventilates and PaCO_{2} rises to 80 mmHg, alveolar PO_{2} is 50 mmHg (PaO_{2} = 150 – 80/0.8 = 50). If arterial PO_{2} were 48 mmHg, A-aPO_{2} = 50 – 48 = 2 (normal). This shows that the hypoxaemia is fully explained by hypoventilation, which is not evident from looking at PaO_{2} alone. Had arterial PO_{2} been 40 mmHg, A-aPO_{2} would have been 10 mmHg, and this would have suggested the presence of significant additional gas exchange defect from shunt or $\dot{\text{V}}\text{A}\text{/}\dot{\text{Q}}$ inequality (or both).

While very useful in patients breathing room air, A-aPO_{2} becomes less useful as FiO_{2} is increased if $\dot{\text{V}}\text{A}\text{/}\dot{\text{Q}}$ inequality is the main problem. This is because at high FiO_{2}, A-aPO_{2} falls, approaching zero on 100% O_{2}, no matter how severe the $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ mismatch is. However, if A-aPO_{2} on 100% O_{2} is elevated, the reason has to be a shunt, and A-aPO_{2} is very useful.

In between room air and 100% O_{2}, A-aPO_{2} will change with FiO_{2} in a manner specific to the nature and extent of the gas exchange disturbance, as shown in Fig. 76.2, which uses the same data as Fig. 76.1. With $\dot{\text{V}}\text{A}\text{/}\dot{\text{Q}}$ inequality (open symbols), A-aPO_{2} first rises as FiO_{2} is increased, and then falls, to nearly zero when 100% O_{2} is breathed. The maximal A-aPO_{2} and the FiO_{2} at which it occurs depends on the severity of the inequality as shown. This behaviour is explained by the shape of the O_{2}-Hb dissociation curve. However, when the problem is shunt, A-aPO_{2} rises steadily with FiO_{2} as shown.

There is an important cautionary note—Figs 76.1 and 76.2 reflect constancy of the main determining variables as FiO_{2} is altered. Thus, the extent of $\dot{\text{V}}\text{A}\text{/}\dot{\text{Q}}$ heterogeneity and/or shunt, together with tidal volume and respiratory frequency, cardiac output, metabolic rate, [Hb], acid–base state, and temperature are all presumed to remain fixed. If any of these change over time, or from changing FiO_{2}, the data shown in these figures must change. Absorption atelectasis, release of hypoxic pulmonary vasoconstriction, and changes in cardiac output may all occur as FiO_{2} is raised. Any of these may change shunt and $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality.

Physiological shunt: $\dot{\text{Q}}\text{S}\text{/}\dot{\text{Q}}\text{T}$

Since the 1950s [4,5,6], a further, simple, analysis of blood gas data has proven useful. The calculation of physiological shunt, or ‘$\dot{\text{Q}}\text{S}\text{/}\dot{\text{Q}}\text{T}$’. $\dot{\text{Q}}$ denotes blood flow, s denotes shunt and T denotes total. It reflects the shunt equation, based on mass conservation, applied to a lung imagined as two compartments, one having zero ventilation. The second compartment performs all gas exchange. The shunt equation is:

$\dot{\text{Q}}\text{T}$
is total pulmonary blood flow and $\dot{\text{Q}}\text{S}$ is blood flow through the shunt compartment, which transmits blood unchanged (with mixed venous O_{2} concentration) to the pulmonary veins. CaO_{2} is systemic arterial O_{2} concentration, CvO_{2} is O_{2} concentration in mixed venous (pulmonary arterial) blood, and Cc’O_{2} is end-capillary O_{2} concentration of the second, ventilated compartment. Cc'O_{2} is computed from the O_{2}-Hb dissociation curve based on the alveolar PO_{2} from the alveolar gas equation. The equation states that arterial O_{2} concentration is the perfusion-weighted average of O_{2} concentrations in the two compartments. After rearrangement:

The equation can be used at any FiO_{2}. However at FiO_{2} < 1.0, $\text{Q}\text{s}/\dot{\text{Q}}\text{T}$ is termed ‘venous admixture’ or ‘physiological shunt’, while when FiO_{2} = 1.0, it is regarded as ‘true shunt’. This is because at FiO_{2} < 1.0, $\dot{\text{V}}\text{A}\text{/}\dot{\text{Q}}$ inequality will contribute to $\text{Q}\text{s}/\dot{\text{Q}}\text{T}$, while at FiO_{2} = 1.0, $\dot{\text{V}}\text{A}\text{/}\dot{\text{Q}}$ inequality ceases to contribute and $\text{Q}\text{s}/\dot{\text{Q}}\text{T}$ does, in fact, represent only shunt (see Figs 76.1 and 76.2).

Fig. 76.3 shows $\dot{\text{Q}}\text{s}/\dot{\text{Q}}\text{T}$ for the same data as in Figs 76.1 and 76.2. When the lung really does consist of two functional compartments—normal and shunt, as may happen in localized consolidation or atelectasis—the $\dot{\text{Q}}\text{S}/\dot{\text{Q}}\text{T}$ model accurately depicts the extent of shunt across the whole FiO_{2} range. However, when there is $\dot{\text{V}}\text{A}\text{/}\dot{\text{Q}}$ inequality, rather than shunt, $\dot{\text{Q}}\text{s}/\dot{\text{Q}}\text{T}$
can be very high at low FiO_{2}, but eventually falls to zero on 100% O_{2}. Thus, the shunt equation will underestimate the true extent of $\dot{\text{V}}\text{A}\text{/}\dot{\text{Q}}$ inequality at FiO_{2} above room air and may over-estimate true shunt at FiO_{2} < 1.0.

To use the equation, CaO_{2} is calculated from arterial PO_{2}, saturation, and [Hb], and Cc'O_{2} is correspondingly computed from alveolar PO_{2}. The weakness is in CvO_{2}. To measure this directly requires a pulmonary artery catheter, which is often unavailable.
Alternatively, CvO_{2} can be calculated from metabolic rate $(\dot{\text{V}}{\text{o}}_{2})$ and cardiac output $\left(\dot{\text{Q}}\text{T}\right)$
using the Fick principle:

Rearranging,

which can be combined with eqn 3 to yield:

However, if $\dot{\text{Q}}\text{T}$ and / or $\dot{\text{V}}{\text{o}}_{2}$ are not known, and must be assumed, application of the shunt equation can be considerably in error as Fig. 76.4 shows. The top panel shows how arterial PO_{2} would actually vary as cardiac output (and thus CvO_{2}) varies for a lung with a fixed shunt that was 20% of the cardiac output, the patient always breathing 100% O_{2}. The fall in PaO_{2} when cardiac output is low is due to the associated fall in mixed venous PO_{2} required to meet the unchanged metabolic needs of the tissues, and vice versa when cardiac output is elevated. The lower panel shows the shunt calculated from the arterial PO_{2} values in the upper panel if the venous O_{2} concentration was assumed constant at the value actually seen when cardiac output was 6 L/min. Only at that cardiac output will the correct shunt value (20%) be obtained (dashed lines). As cardiac output drops, the calculated shunt is erroneously high; when cardiac output is elevated, the shunt is underestimated. The errors may be considerable.

Mixed venous O_{2} saturation/Po_{2}

The preceding illustrates the risk of assuming mixed venous oxygenation when computing the shunt and a rationale for knowing the correct value. Another reason for estimating mixed venous PO_{2} and/or saturation is to better understand the relationship between O_{2} supply and demand. Using oximeter-tipped catheters placed in the pulmonary artery, mixed venous saturation is continuously available, and arterial saturation is also usually available. Thus, with [Hb], the arteriovenous O_{2} concentration difference, CaO_{2}—CvO_{2}, becomes available. From the Fick principle in eqn 5, the arteriovenous difference is numerically equal to the ratio $\dot{\text{V}}{\text{o}}_{2}/{\dot{\text{Q}}}_{\text{T}}$, which is the ratio of whole-body O_{2} demand $(\dot{\text{V}}{\text{o}}_{2})$ to supply $(\dot{\text{Q}}\text{T})$. A high arteriovenous difference implies high O_{2} demand in relation to supply, and vice versa, which may be clinically useful information. This concept is, however, complicated by a major uncertainty. Suppose $\dot{\text{V}}{\text{o}}_{2}/\dot{\text{Q}}\text{T}$ is high. Does that mean that demand is elevated or that supply is reduced? Measuring only the ratio cannot tell. We need the absolute value of either $\dot{\text{V}}{\text{o}}_{2}$ or $\dot{\text{Q}}\text{T}$ to resolve this. This is important because inappropriate therapy might otherwise be applied.

Physiological dead space, Vd/Vt

Just as for shunt, a two-compartment approach can estimate how much ‘dead space’ would have to exist to explain the mixed expired PCO_{2} value. The concept is again to imagine the lungs as one normal compartment performing all gas exchange, and a second that is ventilated, but completely unperfused, and not participating in gas exchange (hence, the name ‘dead space’ for the ventilation associated with it). Again, we use mass conservation, applied to CO_{2}, as follows:

Where $\dot{\text{V}}\text{E}$ is total minute ventilation (tidal volume $(\dot{\text{V}}\text{T})$ times breathing frequency), $\dot{\text{V}}\text{A}$ is ventilation of the normal compartment and Vd is ventilation of the unperfused compartment. Note that $\dot{\text{V}}\text{E}=\dot{\text{V}}\text{A}+\text{V}\text{D}.$ PeCO_{2} is the PCO_{2} in the mixed exhaled gas. PaCO_{2} is the alveolar PCO_{2} of the normal compartment, and PiCO_{2} is the inspired PCO_{2}, since that must be the alveolar PCO_{2} of the unperfused compartment. Replacing $\dot{\text{V}}\text{A}$ by $\dot{\text{V}}\text{A}-\text{V}\text{D}$, and rearranging eqn 7 yields:

If, as is commonly done, we substitute PaCO_{2} (arterial PCO_{2}) for PACO_{2}, because the latter is actually very difficult to measure, we end up with:

Vd/Vt is the fraction of the total ventilation passing to the unperfused compartment (without gas exchange), and thus ‘wasted’. It is a composite of three kinds of dead space: one is normal, and is the contribution from the conducting airway volume (from mouth to the last terminal bronchiole), called the anatomic dead space. The second is the tubing volume, if any, between a ventilated patient and the valve of the ventilator or fork in the ventilator tubing that separates inspired from expired gas. This includes the endotracheal or tracheostomy tube volume. The third is the ‘alveolar dead space’, which is a virtual volume of gas ventilating hypothetical alveoli that are completely unperfused. It is normally zero. Application of eqn 9 captures all three kinds inseparably as a single value, and what then has to be done is to subtract the first two kinds of dead space to arrive at the alveolar dead space, which is usually the number of interest. Tubing volume is calculated from its length and diameter. Anatomic dead space, rarely measured, is often taken as 1ml per pound (2 mL/kg), of lean body weight. It will be a little less if the pharynx is bypassed by an endotracheal or tracheostomy tube.

It is important to distinguish absolute dead space from percentage dead space. The latter is most frequently reported and, while useful, is affected directly by the tidal volume. A dead space of 200 mL with 500 mL tidal volume, yields 40% Vd/Vt, while the same dead space in a 1-L tidal volume reduces Vd/Vt to 20%. Therefore, reporting of alveolar dead space should also use absolute volume. In a normal lung, alveolar dead space (i.e. total, less anatomic, ventilator tubing volume) is essentially zero, but in lung disease with $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ inequality it can be substantial. In the cases presented in Figs 76.1–76.3, alveolar dead space is 17% when SDQ = 1.0, 35% when SDQ = 1.5, and 52% when SDQ = 2.0.

The popular perception is that only areas of above-normal $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio contribute to alveolar dead space. However, areas of low $\dot{\text{V}}\text{A}/\dot{\text{Q}}$ ratio and even shunt contribute to Vd/Vt when arterial PCO_{2} is used as in eqn 9 because such areas not only depress arterial PO_{2}, they elevate arterial PCO_{2}.

Conclusion

In conclusion, several longstanding approaches to gas exchange allow quantification of gas exchange disturbances in the ICU. Perhaps the key point is that, for all, assumptions are made that may critically affect their interpretation and lead to erroneous therapeutic decisions. This discussion is intended to illustrate those important assumptions and thereby mitigate their consequences.

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