THE ROLES OF OXYGEN IN AEROBIC ORGANISMS

Oxygen has several vital physiological roles:

1 Bioenergetics. Aerobic mitochondrial respiration accounts for 90% of oxygen consumption, generating adenosine triphosphate (ATP) by oxidative phosphorylation. Mitochondrial electron transfer oxidase systems provide the fundamental machinery, in particular the cytochrome oxidase of complex IV. Oxygen acts as terminal electron acceptor, combining with two protons to produce water.¹

2 Biosynthetics. Oxygen transferase systems incorporate oxygen into substrates, such as prostanoids, catecholamines and some neurotransmitters.

3 Biodegradation and detoxification reactions. These mixed-function oxidase reactions require oxygen and a co-substrate (e.g. NADPH). The cytochrome P-450 hydroxylases are examples.

4 Generation of reactive oxygen species. These are essential antimicrobial defences deployed by neutrophils and macrophages.²

TISSUE HYPOXIA

As tissue PO₂ falls, the biosynthetic and biodegradation systems are the first to succumb. Cell signalling by reactive oxygen species, released at mitochondrial complex III, activates hypoxia-inducible factor-1, a transcription factor upregulating genes important in hypoxic cell survival.³ Oxidative phosphorylation starts to fail at an intracellular PO₂ of 0.1–1 mmHg, equivalent to an extracellular PO₂ of around 5 mmHg. At this point oxygen-limited cytochrome turnover causes progressive ATP depletion, a process which has been termed ‘dysoxia’.⁴ Stopgap production continues by anaerobic glycolysis, but without correction of dysoxia there is progressive lactic acidosis and eventual cell death by apoptosis and necrosis. On reoxygenation, further release of reactive oxygen species causes oxidant stress, often overshadowing the hypoxic insult.²

THE OXYGEN CASCADE

In unicellular organisms, oxygen reaches the mitochondria across a short diffusion path with a steep partial pressure gradient. In multicellular animals the much longer diffusion path traverses a series of small partial pressure reductions known as the oxygen cascade. As a result, oxygen arrives at intracellular organelles at tensions above the anaerobic threshold.

Important steps in the oxygen cascade include:

6 mitochondria and other intracellular organelles

The cascade can be jeopardised at any step, with downstream oxygen deprivation of mitochondria and other intracellular organelles. In this chapter we will consider how oxygenation can be monitored at strategic points along the cascade.

INSPIRED GAS

Monitoring the fraction of inspired oxygen (FiO₂) is necessary to prevent both hypoxaemia and the adverse effects of excess oxygen. The inspired oxygen tension (PiO₂) of humidified gas is determined by the FiO₂, the barometric pressure (BP) and the saturated vapour pressure of water (47 mmHg).

Equation 14.1

Gas supply pressures are monitored continuously. Ventilators incorporate input pressure alarms and oxygen analysers within the inspiratory module to identify oxygen source failure. Direct measurement of circuit oxygen concentration can be performed.

TRANSFER OF INSPIRED GAS TO ALVEOLI

Communication between oxygen delivery system and pulmonary alveoli is open if:

1 There are no signs of upper-airway obstruction (Chapter 25).

2 Expired tidal and minute volumes and airway pressures for the ventilated patient are within correctly set alarm limits (Chapter 27).

3 There is an appropriate end-tidal CO₂ waveform (Chapter 34).

ALVEOLAR GAS

In a patient receiving 100% oxygen, alveolar PO₂ in individual lung units can range from < 40 mmHg to > 600 mmHg. Consequently, end-tidal PO₂ monitoring is of no value.

DISTRIBUTION OF ALVEOLAR VENTILATION

Clinicians routinely track chest movement, auscultate air entry and examine plain chest radiographs. Although computed tomography scanning can reveal occult overdistension,⁷ it has logistical disadvantages and is a significant radiation hazard. Electrical impedance tomography is under development as an alternative, and shows promise.⁸ Simple and non-invasive, it tracks lung volume changes in real time, with potential to optimise alveolar ventilation distribution while limiting overdistension.⁹

MATCHING OF VENTILATION AND PERFUSION

For efficient gas exchange, the majority of lung units must have well-matched alveolar ventilation and perfusion (V/Q ratios close to 1). Even in health there is a spread to lower and higher V/Q ratios, all clustered around unity. When lungs are diseased, V/Q scatter is much greater, with variable representation across the full spectrum from zero to infinity. Such complexity resists simple bedside quantification. The best method is the multiple inert gas technique (MIGET). MIGET generates a lung model with 50 compartments spanning the full range of V/Q ratios, by measuring the retention and elimination of six inert gases of varying solubility.^10,¹¹ Because MIGET is impractical at the bedside, simpler non-invasive modelling of shunt and V/Q mismatch is under evaluation, using FiO₂ as a forcing function while tracking haemoglobin oxygen saturation.¹² Predictive capacity¹³ and ease of application¹⁴ are encouraging.

THE IDEAL ALVEOLUS AND THE THREE-COMPARTMENT LUNG MODEL

Meanwhile the simplest model of all, a three-compartment model devised in the mid 20th century, is still in use. No manipulations such as FiO₂ switching or inert gas infusions are needed. However, the trade-off is that the model is overly simplistic, with poor predictive capacity in many respiratory disorders. The three compartments are:

1 the ideal compartment, consisting of alveoli with perfectly matched perfusion and ventilation (V/Q = 1)

2 the venous admixture or shunt compartment, containing perfused non-ventilated alveoli (V/Q = 0)

3 the alveolar dead space compartment, made up of ventilated non-perfused alveoli. (V/Q = ∞)

The alveolar PO₂ in the ideal compartment (PAO₂) is calculated from the alveolar gas:

Equation 14.2

where R is the respiratory exchange ratio, either measured by indirect calorimetry or assumed to be 0.8. PiO₂ is calculated as in Equation 14.1. PaCO₂ is arterial PCO₂.

Most clinicians use the following approximation:

It is important to remember that PAO₂ is not a physiological reality. It is an artificial construct. Other parameters based on the three-compartment lung model, such as the A-a gradient and venous admixture (see below) must be regarded in the same light.

TRANSFER FROM ALVEOLI TO ARTERIAL BLOOD (PULMONARY OXYGEN TRANSFER)

The MIGET technique has identified V/Q mismatch and intrapulmonary right-to-left shunt as the two main causes of reduced pulmonary oxygen transfer in critical illness.¹⁵ Intrapulmonary shunt predominates in the acute respiratory distress syndrome (ARDS), in lobar pneumonia and after cardiopulmonary bypass, whereas V/Q mismatch without shunt is more prominent in chronic lung disease.¹⁶

BEDSIDE INDICES OF PULMONARY OXYGEN TRANSFER

These are either tension-based or content-based.

TENSION-BASED INDICES

(Reproduced from Nunn JF. Oxygen. In: Nunn JF (ed.) Applied Respiratory Physiology, 4th edn. Oxford, UK: Butterworth-Heinemann; 1993: 264, with permission.)

Figure 14.2 Effect of varying FiO₂ on A-a gradient with mild, moderate and severe V/Q mismatch. No allowance is made for absorption atelectasis or alterations in hypoxic pulmonary vasoconstriction.

(Reproduced from D’Alonzo GE, Dantzker DR. Respiratory failure, mechanisms of abnormal gas exchange, and oxygen delivery. Med Clin North Am 1983; 67: 557–71, with permission.)

Pao₂/Fio₂ ratio

The PaO₂/FiO₂ ratio is used to define acute lung injury and ARDS,¹⁸ and is an input variable in the Simplified Acute Physiology Score (SAPS II)¹⁹ and lung injury scoring systems.²⁰ At sea level its normal value is ≥ 500 mmHg. In acute lung injury, PaO₂/FiO₂ < 300 mmHg, whilst in ARDS the ratio is < 200 mmHg.

Its only advantage is simplicity. There are several major disadvantages:

1 Barometric pressure alters the normal PaO₂/FiO₂ ratio. A ratio of 380 mmHg is unremarkable at 1600 metres elevation for a young adult breathing air, but not at sea level.

2 Unlike the A-a gradient, the PaO₂/FiO₂ ratio cannot distinguish hypoxaemia due to alveolar hypoventilation from other causes.

3 The ratio is markedly FiO₂-dependent, both in right-to-left shunt (the predominant ARDS abnormality) and in lungs with a wide V/Q scatter (chronic obstructive pulmonary disease).^17,²¹

4 The ratio is also highly dependent on CaO₂ – CvO₂,¹⁷ which tends to fluctuate markedly in sepsis.

CONTENT-BASED INDICES

Venous admixture (Q_s/Q_t)

Venous admixture, another construct based on the three-compartment lung model (see above), represents the proportion of mixed venous blood flowing through the shunt (V/Q = 0) compartment. It is determined according to the formula:

Equation 14.3

Cc’O₂, CaO₂ and CvO₂ are the oxygen contents of pulmonary end-capillary, arterial and mixed venous blood respectively. CaO₂ and CvO₂ are calculated using data from arterial and mixed venous blood gas analysis and CO oximetry (see Table 14.4, below). Cc’O₂ is derived differently, since pulmonary end-capillary blood cannot be sampled. is assumed to equal PAO₂ as derived from the alveolar gas equation (Equation 14.2). (normally close to 1) can then be computed from an algorithm for the HbO₂ dissociation curve.²²

Table 14.4 Oxygen dynamics – measured and derived indices

Disadvantages of venous admixture

1 Sampling mixed venous blood requires a pulmonary arterial (PA) catheter.

2 In V/Q mismatch without right-to-left shunt, venous admixture varies markedly with FiO₂ and virtually disappears at FiO₂ > 0.5 (Figure 14.3). Venous admixture is thus of little use in conditions where the dominant gas exchange abnormality is not intrapulmonary right-to-left shunt, such as chronic obstructive pulmonary disease.

Figure 14.3 Effect of varying FiO₂ on venous admixture in various combinations of V/Q mismatch and shunt. No allowance has been made for absorption atelectasis or alterations in hypoxic pulmonary vasoconstriction.

(Reproduced from D’Alonzo GE, Dantzker DR. Respiratory failure, mechanisms of abnormal gas exchange, and oxygen delivery. Med Clin North Am 1983; 67: 557–71, with permission.)

When determined at FiO₂ = 1, venous admixture is an accurate measure of right-to-left shunt. However, exposure to 100% oxygen causes absorption atelectasis of unstable low V/Q units and increases intrapulmonary shunt.