| Introduction | Oxygen content |
The passage of oxygen from the atmosphere to the mitochondria is a complex process. Pathological conditions may affect this transfer at any step. The patient on the intensive care unit is particularly likely to be affected by disease or iatrogenic intervention. Hypoxia may be caused by an abnormal supply of oxygen, abnormalities of gas exchange, deficient transport in the blood or alterations in localized tissue utilization. An understanding of the principles involved will enable effective interpretation and subsequent management of the hypoxic patient.
Keywords: hypoxia, shunt, V/Q mismatch, ventilation
J.R.Coll.Surg.Edinb., 45, August 2000, 235-240
Hypoxaemia is defined as inadequate oxygenation of the blood. At a cellular level, hypoxia is the failure of tissue oxygenation with the cessation of oxidative phosphorylation due to inadequate mitochondrial tension of oxygen (PO2 which has kPa or mmHg as its units of measurement). Anaerobic tissue metabolism (when the PaO2 falls below 4.5 kPa) leads to reduced cellular function, lactic acidosis, cessation of the ATP dependent ion pumps within cell membranes and, subsequently, uncontrolled cell death.
Loss of function in cerebral tissue occurs after less than 1 minute of hypoxia; the heart can survive for up to 4 minutes with skeletal muscle surviving up to 2 hours. Irreversible loss of function occurs after four times the period of anoxia that results in loss of function. However, partial recovery can be expected with lesser periods of hypoxia.
The major causes of hypoxaemia are hypoventilation, diffusion impairment, shunt and ventilation-perfusion inequalities. Not all of these causes are necessarily amenable to treatment with mechanical ventilation. It is easy to assume that merely mechanically effecting oxygen flow within the lung will always correct pulmonary failure in much the same way that haemodialysis will correct any renal dysfunction.
An understanding of some basic physiological principles is essential to the interpretation of hypoxia in the intensive care setting.
THE OXYGEN CASCADE
The passage of oxygen from air to mitochondria is in the form of a cascade (Figure 1). It passes down a partial pressure gradient (PO2 of dry air at sea level is 21.2 kPa) through the respiratory tract and alveoli, the blood, tissues and finally the mitochondria (PO2 approximately 0.5-3 kPa). Interruption at any point on this cascade may lead to hypoxia.
Figure 1: The oxygen cascade; oxygen tensions fall down this cascade from the highest levels in the inspired gas to the lowest levels found in the mitochondria
ABNORMAL SUPPLY OF OXYGEN TO THE GAS EXCHANGE UNITS
Under normal circumstances air enters the lungs due to the negative pressure generated within the chest cavity as a result of downward movement of the diaphragm and expansion of the chest wall due to contraction of the intercostal muscles. Air flows into the lungs by bulk flow down the trachea, main bronchi and their branches until around the 16th or 17th branching. At this point, gas flow by bulk movement has ceased and air moves further out into the outer parts of the lung by diffusion. Gas exchange within the terminal respiratory units (terminal bronchi along with their alveoli), therefore, is all dependent on diffusion - an effect mainly governed by concentration gradients. Clearly, there are essentially two ways that this process can be affected -hypoventilation and altered inspired oxygen tension.
Hypoventilation
Hypoventilation is a reduction in the volume of gas delivered to the alveoli per unit time (alveolar ventilation). Hypoxia then results, assuming oxygen consumption remains unchanged. Hypoventilation always causes a rise in PaCO2 in accordance with the following equation:
Equation 1
PaCO2 = (V CO2 / VA ).K
where VCO2 is CO2 production, VA is alveolar ventilation and K is a constant. Thus, if the alveolar ventilation is halved, the PaCO2 is doubled.
The hypoxia of hypoventilation can be reversed by the administration of a higher inspired oxygen concentration as demonstrated by the alveolar gas equation:
Equation 2
PAO2 = PIO2 - (PACO2/R)
where PIO2 is the partial pressure of inspired oxygen.
Inspired oxygen tension
A rise in inspired oxygen concentration will produce a corresponding rise in alveolar PO2. Similarly a decrease in the inspired PO2 will inevitably decrease alveolar PO2. This is the situation most frequently observed on climbing to altitude and explains why normal people become breathless at around 10,000 feet and why climbers will use oxygen to climb Mount Everest at over 29,000 feet. The alveolar gas equation is also useful to understand abnormal gas exchange in patients who are hypoventilating postoperatively. Here PCO2 will rise as in Equation 1 and from Equation 2 it can be seen that if the patient is breathing air it is quite easy to reduce the PAO2 to very low levels:
PAO2 = (21 - 6) - (10/1) = 5kPa
where the patient is breathing air (21% oxygen, PIO2 = 21kPa) which is humidified (water vapour accounts for a further 6kPa) and has a PaCO2 of 10kPa; which results in a maximum PaO2 of 5kPa.
Dead space
The fraction of the tidal volume, which does not take part in gas exchange is called the dead space, while that which takes part in gas exchange is referred to as the alveolar ventilation. Dead space is divided into three components:
Anatomical dead space - relates to the volume of the conducting air passages and is influenced by the following factors:
Physiological dead space is alveolar dead space and anatomical dead space combined.
DIFFUSION IMPAIRMENT
Diffusion impairment occurs when there is failure of equilibration between alveolar gas and the pulmonary capillary blood. Equilibration is normally fast with blood PO2 almost reaching that in the alveolus after about one-third of the contact time of 0.75 second in the capillary. This leaves a large physiological window for gas exchange to take place and it only becomes a problem in disease states causing thickening of the alveolar membrane and in high cardiac output states where the contact time between the red cell and alveolar interface is reduced.
The significance of diffusion impairment to hypoxia in the setting of the intensive care unit is debatable. However, in conditions such as sepsis, with a high cardiac output and shortened transit times, then it may contribute to hypoxaemia.
Diffusion impairment does not affect carbon dioxide elimination. Carbon dioxide is more soluble in blood than oxygen and it is also carried in various forms in addition to the dissolved form - carbamino compounds as well as the main form as bicarbonate. Thus, the amount of carbon dioxide in blood at 40-60 ml/dl is considerably greater than that of oxygen (20 ml/dl).
Administration of 100% oxygen will overcome hypoxia caused by diffusion impairment. Since the CO2 tension of inspired air is almost zero it is not possible to enhance carbon dioxide elimination by this means.
True shunt
The term shunt essentially refers to blood entering the arterial circulation that has not taken part in gas exchange. Anatomical shunt is the venous blood that mixes with pulmonary end-capillary blood on the arterial side of the circulation. As well as bronchial and thebesian venous drainage, it includes blood flowing through atelectatic lung and areas of consolidation. Shunts also occur in congenital heart disease where blood moves from the right side of the heart directly to the left without first passing through the lungs - right to left shunting. All these forms of shunt are termed a true shunt to differentiate them from ventilation perfusion mismatch where the normal balance between lung ventilation and alveolar perfusion is disturbed. The difference between these two is important because the amount of ventilation perfusion mismatch is often given as a percentage shunt - Qs/Qt - just like in a true shunt.
Unlike other causes of hypoxaemia, administration of 100% oxygen to a patient with a true shunt fails to raise the arterial PO2 to normal levels, despite the end-capillary PO2 being high, because that of the shunted blood will be the same as venous blood. When the two mix, the oxygen concentration is reduced causing a large reduction in the arterial PO2. However, in the case of ventilation perfusion mismatch oxygen therapy can increase PaO2 - see below.
The degree of shunting may be calculated by referring to the shunt equation:
Equation 3
Qs/Qt= Cc - Ca/Cc-Cv
where Qs and Qt are the shunt and total blood flows, and Cc, Ca and Cv represent the oxygen concentrations of end-capillary, arterial and mixed venous blood. This equation assumes that the cardiac output is divided into two parts: one passing through ventilated lung and the other through the anatomical shunt. It should be remembered that the oxygen concentrations of the blood forming the venous admixture varies and is not necessarily equal to mixed venous blood (as measured by pulmonary artery catheter). The oxygen concentration of end-capillary blood is calculated from the alveolar gas equation and oxygen dissociation curve, and assumes complete equilibration between the alveolar gas and blood.
Ventilation-perfusion mismatch
This is an important cause of hypoxaemia affecting patients on the intensive care unit. Relative ventilation and perfusion, in different areas of the lung are unequal, resulting in inefficient gas transfer.
The distribution of ventilation in normal subjects varies depending on the mode of ventilation and position. More ventilation occurs in the right lung due to its larger size, both in the upright and supine positions. In the upright position there is greater ventilation towards the apex of the lungs than to the bases. In the lateral position, the lower lung is preferentially ventilated irrespective of which side is lain upon. This is due to the dependent diaphragm lying higher in the thorax, with increased length of muscle fibres providing more efficient contraction during inspiration. In the anaesthetised patient, however, irrespective of the mode of ventilation, the upper lung receives more gas flow.
Pulmonary blood flow is greater at the bases than at the apices in the erect subject. The distribution of flow through the lung is uneven due to the relatively low pressures in the pulmonary circulation and gravity assumes a very important role. Similarly, in the lateral position, the dependent lung is perfused more than the upper lung.
Although both perfusion and ventilation increase from the apices to the bases the increase in ventilation is less than that of perfusion and, in order to understand the relationship between the two is described as the ventilation/perfusion ratio (V/Q). The resting values are approximately 4 l/min for ventilation and 5 l/min for pulmonary blood flow, giving a ratio of 0.8 throughout the whole lung (assuming ventilation and perfusion of all alveoli are equal). However, some alveoli will receive no ventilation and some will receive no perfusion. Thus, the ratios will range from zero (effectively the same as a true shunt) to infinity (effectively the same as dead space) in these cases (Figure 2).
Figure 2: O2 - CO2 diagram showing the effect of variations in ventilation-perfusion ratio. The PO2 and PCO2 of lung units varies along the line between the two fixed points - mixed venous blood (lowest O2 and highest CO2) and inspired gas (highest O2 and lowest CO2)
Ventilation perfusion mismatch is responsible for the hypoxaemia seen in pulmonary oedema, chronic obstructive airways disease, pulmonary embolism and interstitial lung disease. The hypoxaemia worsens with increasing V/Q mismatch for two reasons. Firstly, with V/Q mismatch, a greater percentage of the cardiac output passes through lung units with lower V/Q ratios (perfusion > ventilation) so that less well saturated blood makes a greater contribution to total pulmonary blood flow. Secondly, as mentioned above in relation to shunts, the oxygen content of blood from lung units with low V/Q ratios exerts a greater effect on the saturation of blood flowing to the left side of the circulation because of the shape of the oxygen dissociation curve (Figure 3).
Figure 3: Depression of arterial PO2 by shunting when the alveolar PO2 is raised. The addition of a small amount of shunted blood lowers the arterial oxygen content and this greatly reduces the arterial PO2 because the curve is flat at this top end. Raising inspired oxygen tension will not correct hypoxia due to the shunt. However, in case of pure ventilation perfusion inequality, raising the inspired oxygen tension will always increase PaO2
Hypoxic pulmonary vasoconstriction (HPV) is a potent regulator of the distribution of blood flow to match areas of ventilation. HPV normally acts to improve gas exchange by reducing the blood flow to lung regions with low V/Q ratios.
In conditions producing inflammatory mediators such as sepsis and trauma, HPV is impaired with blood flowing to poorly ventilated lung resulting in hypoxia. Drugs such as sodium nitroprusside and nitroglycerine can also impair HPV. Hypoxic pulmonary vasoconstriction can also be abolished in the presence of raised pulmonary artery pressures leading to V/Q mismatch and hypoxia.
OXYGEN TRANSPORT IN THE BLOOD
Clearly the patient may be hypoxic because of abnormalities in oxygen transport within the blood. Oxygen is carried in the blood by two methods: the majority in combination with haemoglobin and a very small proportion dissolved in solution. Dissolved oxygen obeys Henry's law so that the amount in solution is proportional to the partial pressure. For each 1 kPa of gas tension 0.023 ml (0.003 ml/100 m/1.mm Hg-1) of oxygen is dissolved in each 100ml of blood. Thus, arterial blood, with a PaO2 of 13kPa has 0.3ml in solution in each 100ml of blood. This is so small that a 20 fold increase in cardiac output would be needed to give an adequate delivery of oxygen in the resting state. This level rises to about 2ml/dl on administration of 100% oxygen. Under hyperbaric conditions of 3 atmospheres breathing 100% oxygen the amount of oxygen dissolved increases to about 6ml/dl, which is just about sufficient for survival assuming everything else was normal (Figure 4).
Figure 4: Oxygen dissociation curve for a haemoglobin concentration of 15g/dl. The effect of alterations in PaO2 on the mixed venous PO2 for a fixed oxygen consumption (whole body oxygen consumption is normally around 5ml O2/100 ml blood)
The oxyhaemoglobin dissociation curve
Haemoglobin consists of four polypeptide chains each with a haem group which combines with molecular oxygen. Each molecule of haemoglobin is able to combine with four molecules of oxygen. The velocity and equilibrium constants of the four reactions differ, giving the characteristic oxyhaemoglobin dissociation curve. The theoretical maximum oxygen carrying capacity is 1.39ml O2/g haemoglobin but direct measurement gives a capacity of 1.34 ml O2/g haemoglobin and this difference is due to some of the haemoglobin being in various forms, such as methaemoglobin, which cannot combine with oxygen. The latter figure is normally used in calculations of oxygen content.
The oxyhaemoglobin dissociation curve is shown in Figure 4. The sigmoid shape is a result of differing affinity for oxygen, depending on how many molecules are bound to the haem complexes. The shape of the curve has several physiological advantages. The flat upper portion enables uptake of oxygen even if alveolar PO2 falls. The steep lower part of the curve enables peripheral tissues to take up large amounts of oxygen for only a small drop in capillary PO2.
The curve may be shifted to the right by an increase in temperature, carbon dioxide tension, hydrogen ion concentration and 2,3-diphosphoglycerate. A shift to the right causes reduced uptake of oxygen in the lungs but allows increased uptake by the tissues. A reduction of these factors shifts the curve to the left which causes increased uptake of oxygen from the lungs but reduced uptake by the tissues for the same oxygen delivery. The position of the curve is described by the PO2 at which haemoglobin is 50% saturated. This is termed the P50 and is normally 3.5 kPa in the adult.
Oxygen content (CO2) of blood is calculated from the sum of dissolved oxygen and that bound to haemoglobin where SO2 is the percentage saturation of the haemoglobin with oxygen, as is shown by:
Equation 4
CO2(ml/100ml) = 0.023 x PO2(kPa) + 1.34 x Haemoglobin x SO2(%)/100
The normal value for oxygen content is about 20 ml/dl.
The amount of oxygen made available to the body in one minute is known as oxygen delivery (DO2) or oxygen flux and is equal to the cardiac output x arterial oxygen content.
Equation 5
DO2 (ml/min) = Cardiac output x CO2
If the cardiac output is 5 l/min for then approximately 1000ml/min of oxygen is delivered to the tissues. The resting oxygen utilization is about 250 ml/min. This correlates with the normal value of 65-70% saturation of mixed venous blood i.e. the combined blood from the superior vena cava, inferior vena cava and coronary sinus. Thus, there is normally considerable reserve in the system.
In understanding why a patient may be hypoxic the balance of oxygen delivery and tissue consumption should be borne in mind. Anaemia, arterial hypoxaemia, low cardiac output, and increased oxygen consumption may each play a part in the hypoxic patient. The effect of each variable, however, is not linear. A 2 l/min decrease in cardiac output causes a 40% reduction in oxygen delivery, while a decrease in arterial oxygen saturation from 100 to 90% only decreases oxygen delivery by 10%.
A total of approximately 1500 ml of oxygen is stored in the body with about 50% combined with haemoglobin, 30% in the lungs and the rest bound to myoglobin. The oxyhaemoglobin dissociation curve shows that not all of this is available to the tissues since severe hypoxia must occur before even half the oxygen stored on haemoglobin and myoglobin is released. There is normally only 3-4 minutes of available reserves. Breathing 100% oxygen increases the stores (mostly in the lungs by 'washing out' nitrogen within the functional residual capacity) to about 4250 ml, enabling up to 10 minutes of apnoea.
TISSUE HYPOXIA
This may be divided into four categories:
In each case, tissue hypoxia is associated with anaerobic metabolism and the hallmark of inadequate tissue perfusion or hypoxia are the characteristic biochemical changes of efflux of hydrogen ions, lactic acidosis and loss of intracellular potassium.
A patient being on a ventilator is not synonymous with adequate delivery of oxygen to the tissues enabling oxidative phosphorylation to occur. Hypoxia may be present due a variety of causes. An understanding of the principles underlying extraction of oxygen from the atmosphere and subsequent delivery to the tissues is essential to the management of patients. The basic physiological processes have been outlined the basics, especially relating to problems encountered in the intensive care setting, enabling a logical, systematic approach to interpreting hypoxia. Providing higher oxygen concentrations to the lungs, either with or without mechanical ventilation, may not necessarily improve oxygenation. Indeed, the deleterious effects of positive pressures on decreasing venous return and hence cardiac output may mean that blood pressure, tissue perfusion and, hence, oxygenation may deteriorate even further.
SUGGESTED FURTHER READING
Copyright date: 3rd July 2000
Correspondence: NR Webster, Anaesthesia and Intensive Care, Institute of Medical Sciences, Foresterhill, ABERDEEN AB25 2ZD, UK
Email: n.r.webster@abdn.ac.uk
©2000 The Royal College of Surgeons of Edinburgh, J.R.Coll.Surg.Edinb.