Oxygen therapy

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Chapter 24 Oxygen therapy

In mammals energy is provided by both anaerobic and aerobic respiration, the former being inadequate to provide adequate energy alone, so oxygen is the key ingredient to survival. Aerobic respiration is the most efficient mechanism for adenosine triphosphate (ATP) production. Absence or lack of ATP results in failure of energy-hungry enzyme systems, loss of cell homeostasis, and initially cellular and later organism death. A substantial part of critical care is targeted at treating and/or preventing hypoxia. An understanding of the common pathways that lead to cellular hypoxia from whatever cause is vital to providing appropriate support and treatment to the acutely unwell patient. This chapter will review the pathophysiology of oxygen delivery from atmosphere to cell; methods of assessment; types of therapy that can be acutely administered; and the potential hazards of oxygen use.

PATHOPHYSIOLOGY OF OXYGEN DELIVERY

The single-cell organism (e.g. amoeba) requires oxygen for its survival and obtains it from the environment from simple diffusion. This relies upon Fick’s first law of diffusion:

¹ where K is the diffusion constant for a particular gas, A is the surface of a membrane, T is the membrane’s thickness and ΔP the difference in partial pressure across the membrane. About 600 million years ago single-celled organisms evolved into multicellular organisms. As oxygen is poorly soluble in water, diffusion alone became insufficient to deliver oxygen to the cells, and novel methods of delivery evolved, most notably the cardiovascular system.² This provided the means to deliver oxygen around the body.

OXYGEN DELIVERY

Transport of oxygen to the cells can thus be divided into six simple steps reliant only on the laws of physics:

1 convection of oxygen from the environment into the body (ventilation)

2 diffusion of oxygen into the blood (oxygen uptake)

3 reversible chemical bonding with haemoglobin

4 convective transport of oxygen to the tissues (cardiac output: CO)

5 diffusion into the cells and organelles

6 the redox state of the cell

This chain of events is oxygen delivery ().

STEP 1: CONVECTION – VENTILATION

The first step occurs in the lung in the form of pulmonary ventilation. At sea level the partial pressure of oxygen in environmental air is approximately 160 mmHg. On inspiration the air is humidified and mixed with exhaled carbon dioxide (CO₂) such that at the alveolus the PaO₂ is 100 mmHg. This will vary in different environments and different conditions (Table 24.1). Much of oxygen therapy is based on increasing oxygen delivery into the lungs, whether it be by masks or other devices.

Table 24.1 Clinical significance of some PaO₂ and SaO₂ values

STEP 2: DIFFUSION – ALVEOLUS TO BLOOD

Oxygen within the alveolus diffuses across the alveolar–capillary membrane. The average thickness of the alveolar capillary membrane is 0.3 μm and the surface area of the respiratory membrane is 50–100 m². This leads to a PaO₂ in the pulmonary capillaries of approximately 90 mmHg. Herein lie many of the problems seen in the critically ill where two mechanisms predominate:

1 the thickness and barrier effect of the space between alveolus and capillary

2 the relationship between perfusion and ventilation at alveolar level (V/Q ratio)

Good ventilation and good perfusion is ideal while poor ventilation and poor perfusion is bad. Even in normal lungs the ratios vary across the lung. In disease states the situation is exaggerated. For example, in pneumonia ventilation may be impaired while in pulmonary embolus perfusion is disrupted. Positive-pressure ventilation may further alter the balance of ventilation and perfusion.

STEP 3: HAEMOGLOBIN BINDING

Oxygen is poorly soluble in water, having a solubility of 0.003 082 g/100 g H₂O. Having diffused across the alveolar capillary membrane, the oxygen binds rapidly to the respiratory pigment haemoglobin. The relationship between saturation of haemoglobin with oxygen (SaO₂) and PO₂ is not linear and forms a sigmoidal shape (Figure 24.1). The P50 is the PaO₂ at which 50% of the haemoglobin is saturated. Various factors are known to alter the affinity of haemoglobin for oxygen (Table 24.2). These have teleological advantages as, for example, a low pH or high CO₂ at tissue level could imply tissue hypoxia, and the reduction in oxygen-binding affinity, may increase oxygen availability. Similarly, hyperthermia (fever), hypercarbia and an increase in the concentration of 2,3-diphosphoglycerate (2,3-DPG) all move the curve to the right and increase oxygen availability. 2,3-DPG is a byproduct of glycolysis and therefore binds haemoglobin in predominantly hypoxic tissues, facilitating a release of oxygen. Conversely hypocarbia, alkalosis and low concentrations of 2,3-DPG result in a leftward shift of the curve and a higher affinity for binding for any given PO₂. Systemic interventions such as alteration in PCO₂ or pH will influence the curve and therefore oxygen dissociation and availability.

Figure 24.1 Haemoglobin oxygen dissociation curve. Normal curve at 40 nmol/l and shifts to left and right.

Table 24.2 Factors influencing the position of the oxygen dissociation curve

Factors increasing P50 (curve shifts to the right)	Factors decreasing P50 (curve shifts to the left)
Hyperthermia	Hypothermia
Decreased pH (acidaemia)	Increased pH (alkalaemia)
Increased PCO₂ (Bohr effect)	Decreased PCO₂
Increased 2,3-DPG	Decreased 2,3-DPG
	Fetal haemoglobin
	Carbon monoxide
	Methaemoglobin

2,3-DPG, 2,3-diphosphoglycerate.

STEP 4: CONVECTION – CARDIOVASCULAR

In humans the cardiovascular system is the solitary delivery system of oxygen to the cells. This is achieved by the convection (bulk flow) of oxygen – predominantly bound to haemoglobin (21 ml/100 ml) from the lungs via the heart and out into the systemic circulation by way of the arteries. These branch down to form the capillaries where the oxygen is offloaded to the tissues. Convection of oxygen by the cardiovascular system is influenced mainly centrally by CO and peripherally by local controls of the regional perfusion of the tissues.

The delivery of oxygen also relies on the concentration of oxygen in the blood (CaO₂). This is calculated by the following formula:

1 g of haemoglobin binds 1.34 ml of oxygen. Thus changes in the SaO₂ and haemoglobin concentration are important in determining the oxygen concentration. Delivery of oxygen is therefore summarised by the formula:

The normal resting is approximately 1000 ml/min. Oxygen consumption () at rest is approximately 250 ml/min.

where C is calculated as (1.34 × [Hb] × S) + (0.003 × P)

It can be seen that the amount of oxygen extracted is about 25% of that delivered at rest and that there is a large reserve. This obviously varies between organs. This ratio is referred to as the oxygen extraction ratio (OER).

During exercise this can increase by up to 70–80% at maximum. Oxygen that is not removed by the tissues returns to the heart and lungs. Globally the difference between that delivered and that returning is the consumption. This model can also be used to look at regional consumption. Hence the saturation of mixed venous blood (S), which is all the returning blood or central venous blood, can be used as an indicator of global and indirectly the adequacy of . If oxygen delivery by the microcirculation and cellular oxygen uptake are adequate, then a S value of 70% usually indicates that global is appropriate. Lower may indicate increased uptake but more often reduced or inadequate delivery. Mixed venous blood is useful for measurement of global , but it usually requires the presence of a pulmonary artery catheter. The use of central venous saturations has become an alternative surrogate which is usually adequate and considerably more practical.

The body cannot store large amounts of oxygen and is thus dependent on a continuous supply The excess ability to increase to match changes in is an adaptation that permits sudden changes in demand such as exercise in which can exceed 1500 ml/min in some cases.

STEP 5: DIFFUSION – BLOOD TO MITOCHONDRION

Ninety per cent of cellular aerobic metabolism takes place in the mitochondria. The rate of diffusion of oxygen from bound oxyhaemoglobin to the mitochondria follows similar principles to the diffusion of oxygen into the blood from the alveoli. Namely:

1 Fick’s law of diffusion, where the ΔP is dependent on

and the rate of cellular uptake and utilisation

2 the position of the oxygen haemoglobin dissociation curve

Once delivered to the cell, oxygen is utilised in the generation of ATP. This is achieved by the production of pyruvate from glucose via glycolysis. This produces only 2 ATP molecules per molecule of glucose. The pyruvate is converted to acetyl coenzyme A and in the mitochondrion enters the citric acid cycle (Krebs cycle), resulting in the production of reducing power to form NADH and FADH_2. These molecules are transferred to the electron transport chain and oxidation to water releases the cellular energy currency ATP.³

Originally at approximately 160 mmHg, the partial pressure of oxygen at the mouth falls to a PO₂ in some mitochondria which can be as low as 1 mmHg. Below this value, cellular demands for oxygen outweigh its delivery, and ATP production may be reduced.

STEP 6: THE REDOX STATE OF THE CELL

Conventionally oxygen delivery from atmosphere to cell is considered a cascade, implying that a high concentration at one end will cascade down and increase oxygen in the cell. It will increase oxygen available to the cell potentially but the driving force for oxygen to enter the cell and the mitochondrion is the gradient between the partial pressure of oxygen in the cell and outside. Increased oxygen utilisation will reduce that tension and increase the gradient. Conversely, adequate oxygen in the cell will reduce the gradient between the cell and outside and oxygen will not diffuse. The cell determines how much oxygen it uses by creating the gradient that sucks oxygen in – it is not a cascade. Similarly, it is the ATP/adenosine diphosphate (ADP) ratio and probably hydrogen ion concentration that drive ATP production and modify oxygen requirement, i.e. the cell is largely autonomous and uses what it needs.⁴ While ensuring adequate oxygen delivery is important, excess oxygen is at least theoretically of no benefit.

PATHOLOGY OF OXYGEN DELIVERY ()

Failure of oxygen delivery to the cells leads rapidly to cellular dysfunction, and can lead to cellular death and organ dysfunction, culminating in organism death. Failure of to match ( drives the requirement) results in reduction in aerobic metabolism and energy production and necessitates production of ATP by the less efficient glycolytic pathway.

The level of at which begins to decline has been termed the ‘critical ’ and is approximately 300 ml/min in an adult (Figure 24.2).⁵ ‘Shock’ is the usual term used in this situation, defined loosely as failure of delivery of oxygen to match the demand of tissue. Commonly this refers to failure of the circulation, but low can result from several pathological mechanisms which can occur as a single problem or in combination. Cellular hypoxia can result from each of the stages of oxygen delivery:

1 reduction in environmental oxygen, e.g. altitude: hypoxic hypoxia

2 failure to ventilate, whether from airway obstruction, loss of respiratory drive from the central nervous system, drugs or muscular failure – neuromuscular disease such as acute inflammatory demyelinating polyneuropathy (Guillain–Barré syndrome): hypoxic hypoxia

3 impaired gas exchange across the alveolar–capillary membrane, e.g. pneumonia, pulmonary embolus, acute asthma, pulmonary oedema: hypoxic hypoxia

4 abnormal or reduced binding to haemoglobin so there is inadequate oxygen carriage, e.g. severe anaemia, carbon monoxide poisoning or methaemoglobinaemia: anaemic hypoxia

5 reduced CO, e.g. left ventricular failure. Failure of oxygen delivery: stagnant or ischaemic hypoxia

6 impaired diffusion at the blood–tissue interface, e.g. tissue oedema due to sepsis: hypoxic hypoxia

7 cytochrome or mitochondrial poisoning. Cyanide, arsenic and some antiretroviral drugs: histotoxic hypoxia

Figure 24.2 The normal relationship between and . Above the value of ‘critical , is independent of oxygen delivery. Below this value, becomes supply-dependent and may be amenable to therapeutic interventions.

The above is summarised in Table 24.3 as the types of hypoxia.

Table 24.3 Types of hypoxia

Type of hypoxia	Pathophysiology	Examples
Hypoxic hypoxia	Reduced supply of oxygen to the body leading to a low arterial oxygen tension	1 Low environmental oxygen (e.g. altitude) 2 Ventilatory failure (respiratory arrest, drug overdose, neuromuscular disease) 3 Pulmonary shunt: (a) Anatomical – ventricular septal defect with right-to-left flow (b) Physiological – pneumonia, pneumothorax, pulmonary oedema, asthma

Anaemic hypoxia The arterial oxygen tension is normal, but the circulating haemoglobin is reduced or functionally impaired Massive haemorrhage, severe anaemia, carbon monoxide poisoning, methaemoglobinaemia Stagnant hypoxia Failure of transport of sufficient oxygen due to inadequate circulation Left ventricular failure, pulmonary embolism, hypovolaemia, hypothermia Histotoxic hypoxia Impairment of cellular metabolism of oxygen despite adequate delivery Cyanide poisoning, arsenic poisoning, alcohol intoxication

The impact of a low can be made worse by an increase in oxygen demand. Metabolic rate increases with exercise, inflammation, sepsis, pyrexia, thryotoxicosis, shivering. seizures, agitation, anxiety and pain.⁶ Therapeutic interventions such as adrenergic drugs, e.g. adrenaline (epinephrine)⁷ and certain feeding strategies can also lead to an increased .

In critical illness, where oxygen delivery is considered to be in jeopardy, there has been considerable interest in the relationship between and (see Figure 24.2). The presence of signs or markers of tissue hypoxia such as acidosis implies inadequate tissue oxygenation. This could either be from inadequate delivery failing to meet consumption requirements or due to a reduced ability of the tissues to extract oxygen. The former could be corrected by increasing delivery; the latter is more difficult. Historically this has led to the strategy for delivering ‘supranormal’ to ensure adequate supply.^8,⁹ There were some intrinsic problems in this approach. It is irrefutable that, if delivery is inadequate, it should be corrected to meet consumption, but much of the early work was based on the relationship between delivery and consumption trying to reach a point where delivery outstripped consumption. As both values are derived from the same root equation and same data, mathematical linkage was inevitable, so as one increased, so would the other.^10,¹¹ Also the inotropes used to increase delivery also increased consumption.

Clinical studies clearly show that adequate resuscitation to meet oxygen requirements is sensible. In the critically ill going beyond this is not helpful,^12,¹³ although there may be a place for supraoptimal values in the high-risk surgical patient.^8,⁹ In the acute situation the combined use of markers of tissue hypoxia, such as acidosis and lactate, in conjunction with surrogates of oxygen delivery, such as ScvO₂, and standard haemodynamic measurements of an adequate circulation have proved beneficial.^14,¹⁵ So-called early goal-directed therapy is now included in published guidelines for the treatment of severe sepsis (Table 24.4).¹⁶ The benefits of this new approach may well have as much to do with the prompt and aggressive improvements in haemodynamics and resuscitation as the values obtained. Timing is probably the significant difference when compared with other applications of the ‘supranormal’ technique. Targetedoxygen delivery is a major debate that is still evolving (Table 24.5