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Many textbooks on respiratory and critical care medicine begin with statements like, "Oxygen is the most necessary and basic building block of life." In clinical training, the early application of high-flow oxygen is taught as a life-saving maneuver in emergencies. In the emergency department and intensive care unit, much importance is placed on keeping the pulse oximeter reading over 90% (and usually over 95%); likewise, there is a compulsion to keep the PaO 2 in the normal range of 90-100 mm Hg.

At first glance, there is nothing wrong with this approach. Oxygen is indeed necessary for life, and avoiding hypoxemia is a core part of resuscitation. When treating patients with severe respiratory failure, however, attaining a normal PaO 2 may be either impossible or only possible by the application of injurious airway pressures. Therefore, a more complete understanding of oxygen delivery and consumption is necessary.

Each gram of hemoglobin can bind 1.34 mL of oxygen when fully saturated. A small amount of oxygen is also carried in the plasma in its dissolved form. This is represented by the PaO 2 . The solubility coefficient for oxygen in plasma is 0.003. Putting all of this together yields the oxygen content equation:

With normal hemoglobin of 15 g/dL, SaO 2 of 100%, and a PaO 2 of 100 mm Hg, the oxygen content of arterial blood is 20.4 mL O 2 /dL blood. It is important to note that the contribution made by the dissolved oxygen (PaO 2 x 0.003) is very small—0.3 mL O 2 /dL blood. The hemoglobin binds 98.5% of the oxygen content. The fraction contributed by the dissolved oxygen is negligible. If the FiO 2 on the ventilator were increased to bring the PaO 2 up to 500 mm Hg (keeping the SaO 2 at 100%), only 1.2 mL O 2 /dL blood would be added to the oxygen content.

Keeping the PaO 2 elevated beyond what's necessary for adequate saturation of the hemoglobin is unlikely to be consequential except in cases of profound anemia (Hgb < 5 g/dL) or hyperbaric conditions. In fact, the PaO 2 can often be ignored when calculating oxygen content and delivery in order to make the math easier. This leads us to the first rule of oxygen: The SaO 2 is what matters, not the PaO 2 .

Once the arterial blood is loaded with oxygen, it is delivered to the tissues to be used for metabolism. The amount of blood circulated per minute is the cardiac output, which is expressed in liters blood per minute. Since the CaO 2 is measured in deciliters, the units are converted by multiplying by 10. This yields the oxygen delivery equation:

If a normal cardiac output is 5 L/min, the DO 2 is 1020 mL O 2 /minute. In order to make comparisons among different patients of various heights and weights, this can be indexed by dividing the DO 2 by the body surface area. A "typical" body surface area is 1.7 m 2 , so the "typical" DO 2 I would be 1020/1.7, or 600 mL O 2 /min/m 2 .

The cardiac output has the greatest influence on oxygen delivery. Even during periods of arterial hypoxemia, an increase in cardiac output can be sufficient to deliver the necessary amount of oxygen to the tissues. The table below shows the effect that an increase in cardiac output can have on oxygen delivery, even with significant anemia or hypoxemia. It also shows that anemia has a more pronounced effect on oxygen delivery than hypoxemia. For the purposes of simplifying the calculations, the PaO 2 has been omitted. This leads us to the second rule of oxygen: An increase in cardiac output can offset hypoxemia .

During periods of rest, the body's consumption of oxygen (VO 2 ) is approximately 200-250 mL O 2 /minute. Indexed for body surface area, the resting VO 2 I is 120-150 mL O 2 /min/m 2 . Normal subjects can increase their VO 2 during peak exercise by a factor of 10, and elite athletes can reach a maximum VO 2 of 20-25 times their resting consumption. During critical illnesses like septic shock, multisystem trauma, or burn injury, VO 2 increases over baseline by approximately 30-50%.

The consumption of oxygen by the tissues (VO 2 ) varies by organ system. The brain and heart consume the most delivered oxygen, while hair, bones, and nails consume a negligible amount. This can be further complicated by the fact that different organ systems receive different amounts of the cardiac output—the brain consumes the most oxygen, for example, but also receives 15% of the total blood flow. The coronary circulation, on the other hand, accounts for only 5% of the total cardiac output so the percentage of delivered oxygen that is consumed is much higher. Fortunately for the clinician, this is not important because regional monitoring of oxygen delivery and consumption is practical only in laboratory animals. Measurement of the total body VO 2 , on the other hand, can be done rather easily with a pulmonary artery catheter (more accurate) or by using a combination of a noninvasive cardiac output monitor along with a measurement of central venous oxygen saturation (less accurate). While this is not as precise as directly measuring the content of oxygen in expired gas, it is a close enough approximation for clinical use.

As with the arterial oxygen content equation, the minor contribution made by the dissolved oxygen (in this case, the PvO 2 ), can be omitted from the calculation. Thus, for a hemoglobin of 15 g/dL and a normal SvO 2 of 75%, the venous oxygen content is 15.1 mL O 2 /dL blood. The difference between arterial and venous oxygen content is normally 3-5 mL O 2 /dL blood .

Knowing the DO 2 or VO 2 in isolation is not particularly useful. The clinical question is whether the delivery is adequate to meet the body's consumption requirements. To answer this, the DO 2 :VO 2 ratio is helpful. During periods of both rest and exercise, the DO 2 :VO 2 ratio is maintained at approximately 4:1 to 5:1 by changes in the cardiac output. This provides a reserve of sorts—after all, it wouldn't be very useful from a survival perspective to only deliver as much oxygen as the body absolutely needs at any given time. This lack of a physiologic reserve would mean that a person would have no ability to withstand a sudden change in circumstances like having to sprint away from an attacker, or deal with a high fever or pulmonary embolism.

As seen in the following figure, the DO 2 can vary widely as the VO 2 remains constant. This reflects the aforementioned physiologic reserve. As the DO 2 declines, however, it can reach a point at which further drops in oxygen delivery cause a drop in consumption. This point is known in physiology as the hypoxic, or anaerobic, threshold. It is at this point that the reserve is exhausted and the consumption becomes supply-dependent. A patient at or below this point for a prolonged period will become severely acidotic and, in most cases, will not survive.

It would make sense that the anaerobic threshold would occur when the DO 2 equals the VO 2 . Experimentally, however, it has been shown that the threshold is closer to the 2:1 mark, and is explained by the variable oxygen consumption of different organ systems. Cardiac output delivered to hair, teeth, and bones doesn't contribute much to meet the needs of the more vital organ systems.

If the SaO 2 is assumed to be 100%, then the SvO 2 correlates with the DO 2 :VO 2 ratio:

This correlation makes clinical estimation of the DO 2 :VO 2 relationship much easier, as the SvO 2 can be measured directly and continuously by a pulmonary artery catheter. If a pulmonary artery catheter is not present, a central venous oxygen saturation (ScvO 2 ) can be measured by obtaining a venous blood gas from a central venous line placed in the internal jugular or subclavian vein. The ScvO 2 is usually 5-8% higher than the SvO 2 . While not as accurate as the true mixed venous oxygen saturation obtained with a pulmonary artery catheter, the ScvO 2 can be used to estimate of the DO 2 :VO 2 relationship.

The SvO 2 , as a surrogate for the DO 2 :VO 2 relationship, can be used to identify when a patient has insufficient oxygen delivery to meet consumption requirements. The SvO 2 also has the advantage of not requiring continuous calculation of the actual DO 2 and VO 2 —any changes in the relationship between delivery and consumption will be reflected in the SvO 2 . The SvO 2 drops as oxygen delivery drops relative to consumption. An SvO 2 below 70% should warrant evaluation, and an SvO 2 below 60% is definitely concerning—it means that the patient is approaching the anaerobic threshold.

Looking back at the DO 2 equation, impaired oxygen delivery is always due to either low cardiac output, anemia, or hypoxemia. Correction of these should increase DO 2 , with a resultant increase in SvO 2 . Keep in mind that the cardiac output has the most significant effect on DO 2 , and conditions like congestive heart failure, hypovolemia, hemorrhagic shock, and cardiac tamponade will all reduce cardiac output. This leads us to the third rule of oxygen: The SvO 2 is low in low-flow states .

Patients with severe respiratory failure may have uncorrectable hypoxemia. A reduction in the SaO 2 will lead to a corresponding reduction in SvO 2 if the DO 2 :VO 2 ratio remains constant. Calculating the oxygen extraction ratio is a quick way to estimate the balance between oxygen delivery and consumption even when the SaO 2 is markedly reduced:

For a normal SaO 2 of 100% and SvO 2 of 75%, the O 2 ER is: (1.0– 0.75)/1.0 = 0.25/1.0 = 0.25, or 25%. This means that of the delivered oxygen, 25% was extracted and consumed by the tissues. A normal O 2 ER is 20-25%.

As an example, consider a patient with severe respiratory failure whose SaO 2 is 84%. His SvO 2 is 60%. According to the above figure, an SvO 2 this low would be concerning. However, the assumption in Figure 2 is that the SaO 2 is 100%. Calculating the oxygen extraction ratio:

As a second example, take a patient with severe respiratory failure with an SaO 2 of 86%. His SvO 2 is 49%. The O 2 ER is (0.86 – 0.49)/0.86, or 43%. This would correlate with an SvO 2 of 57% if the SaO 2 were 100%, and is certainly concerning for a low cardiac output state. An O 2 ER of 30% or higher should warrant investigation, and an O 2 ER higher than 40% indicates that the patient is approaching the anaerobic threshold .

Unfortunately for physiologists and writers of clinical algorithms, simply saying to keep the SvO 2 over 70% and all will be well doesn't work. This should come as no surprise to anyone familiar with the medical literature in critical care medicine—multiple studies proposing one physiologic manipulation or another have been consistently disproven. The combined processes of oxygen delivery, oxygen consumption, stress response, and cellular adaptation are far too complex to be summed up in this chapter, let alone a one-size-fits-all algorithm.

A normal PaO 2 while breathing ambient air at sea level is 90-100 mm Hg, but humans are able to tolerate much less over prolonged periods of time. The minimum necessary PaO 2 and SaO 2 is not known, and it is unlikely that any IRB will grant approval to a study aiming to withhold supplemental oxygen from critically ill patients. The degree of tolerable hypoxemia is also highly variable, and depends on factors such as the patient's age, comorbid conditions, living environment, genetic factors, and ability to cope with physiologic stress. What is known is that some people are able to survive moderate and even severe hypoxemia. Keep the following in mind:

• In septic shock, the problem is not inadequate oxygen delivery. It's the inability of the tissues to properly metabolize the delivered oxygen. That's why patients die despite having an SvO 2 of 80%. The reasons for this are (very) incompletely understood.

Using lactate levels is an appealing method of determining whether oxygen delivery is adequate, but it has its limitations as well. Most lactate production in critical illness is not due to anaerobic metabolism, despite common assumptions. Instead, it is a product of increased pyruvate production (with metabolism to lactate) in the setting of impaired or altered glycolysis and gluconeogenesis. Lactate is the preferred fuel for cardiac myocytes in the setting of adrenergic stimulation and is produced by aerobic cellular respiration. Thus, lactate should be viewed as a nonspecific marker of physiologic stress. If the lactate comes down following intubation, fluid resuscitation, etc., then it simply indicates that the patient is responding to therapy. It doesn't imply restoration of aerobic metabolism in previously anaerobic tissues. Likewise, an increasing lactate may indicate that the patient has a condition that is leading to an increase in sympathetic tone and cortisol-mediated stress response. Increasing oxygen delivery may or may not help the situation—it depends on what the underlying condition is.

This concept leads to the fifth rule of oxygen: SaO 2 , SvO 2 , O 2 ER, and lactate are all pieces of information and not goals in themselves . They must be taken into account along with urine output, peripheral perfusion, mentation, and other clinical information before any treatment decisions can be made.

The idea that supplemental oxygen can be toxic, especially in high doses, is not new. In neonates, high FiO 2 has been associated with retinopathy and bronchopulmonary dysplasia. In adults, there is evidence of worse outcomes with hyperoxia in the setting of acute myocardial infarction and following cardiac arrest. High FiO 2 in adults can cause irritation of the tracheobronchial tree and absorption atelectasis (due to the oxygen being absorbed without the stabilizing effect of nitrogen gas, leading to alveolar collapse).

Laboratory studies have demonstrated the increased presence of reactive oxygen species in the setting of infection, inflammation, and tissue reperfusion. The clinical significance of this is unclear, as the oxidative burst is a known component of inflammation and may be a part of the host response to infection. Reactive oxygen species can cause cellular injury and apoptosis in vitro but they rapidly combine with chloride and other ions in vivo , mitigating their effect. The degree to which the PaO 2 itself plays a role is also not fully understood, and it may be the case that the oxidative burst occurs as a part of inflammation or reperfusion under any kind of aerobic conditions (and not solely hyperoxic) .

The degree to which clinically significant oxygen toxicity occurs in humans is poorly understood, and the role that the PaO 2 itself plays is unclear. Just because we don't know that there is toxicity, however, doesn't mean that it isn't occurring. The safest practice, then, is to treat oxygen like any other drug and to only give the patient as much as he needs. A useful analogy is the administration of norepinephrine in septic shock. A normal mean arterial pressure is 93 mm Hg, but organ perfusion is adequate with a mean arterial pressure of 65 mm Hg. Norepinephrine is titrated to achieve the lower target since that's all that's necessary. Aiming for the higher, "normal" target would require higher doses of norepinephrine and expose the patient to the risk of harm (ischemic fingers and toes, splanchnic vasoconstriction, increased afterload leading to impaired cardiac function, etc.).

Avoiding hyperoxia is easy, and can be accomplished by reducing the FiO 2 . Even normoxia may not be necessary, and it may be prudent to tolerate a degree of permissive hypoxemia in order to avoid exposing the patient to high FiO 2 or ventilator pressures. Remember that cardiac output has a much more significant effect on oxygen delivery than the saturation, and focus on signs of adequate or inadequate oxygen delivery rather than strictly following the SaO 2 and PaO 2 . This approach leads us to the sixth and final rule of oxygen: Give the patient just as much oxygen as he needs. This may be less than you think .

Six Rules Of Oxygen

1. The SaO 2 is what matters, not the PaO 2 .

2. An increase in cardiac output can offset hypoxemia.

3. The SvO 2 is low in low-flow states

4. The DO 2 :VO 2 ratio, SvO 2 , and O 2 ER reflect the balance between delivery and consumption. They don't represent a specific target for intervention.

5. SaO 2 , SvO 2 , O 2 ER, and lactate are all pieces of information and not goals in themselves. They must be taken into account along with urine output, peripheral perfusion, mentation, and other clinical information before any treatment decisions can be made.

6. Give the patient just as much oxygen as he needs. This may be less than you think.

CO	Hgb	SaO 2	DO 2
3 L/min	15g/dL	100%	603 mL O2 /min
8 L/min	7 g/dL	100%	750 mL O2 /min
5 L/min	15 g/dL	100%	1005 mL O2 /min
8 L/min	15 g/dL	75%	1206 mL O2 /min

DO2 :VO2	SvO2
5:1	80%
4:1	75%
3:1	67%
2:1	50%