PaO₂ as an Index of Hypoxia

When available, the partial pressure of oxy- gen in the arterial blood (PaO₂) is a logical starting point in tissue oxygenation assessment. As described in previous chapters, the degree of hypoxemia in a given individual is a simple indicator of the likelihood of hypoxia. Hypoxia is unlikely in mild hypoxemia, possible in moderate hypoxemia, and likely in severe hypoxemia. In moderate hypoxemia, development of hypoxia depends mainly on the integrity of the cardiovascular system.

These guidelines represent clinical rules of thumb. There are, of course, exceptions to every rule. It has been shown that under certain conditions, hypoxia does not occur despite the presence of severe hypoxemia.^{378 379 380} For example, mountain climbers at the summit of Mt. Everest had PaO₂ levels below 30 mm Hg without apparent adverse consequences.³⁷⁸ Similarly, patients with congenital heart disease had PaO₂ levels averaging 37 mm Hg without notable physiologic impairment.³⁸⁰ Furthermore, these patients were capable of some exercise, during which PaO₂ levels decreased further to 28 mm Hg.³⁸⁰

Finally, despite the fact that a PaO₂ of less than 20 mm Hg is generally considered to be incompatible with life, 13 of 22 patients in one study recovered without permanent physiologic impairment despite PaO₂ levels of less than 21 mm Hg.³⁷⁹ Thus, PaO₂ alone, even when extremely low, is inadequate as an index of tissue hypoxia.

Also, one must not rely too heavily on PaO₂ alone because measurements in stable critically ill patients in one study varied as much as 13% from one reading to another.³⁸¹ This constitutes an average variance of about 16 mm Hg in PaO₂ measurements without a noticeable change in patient condition.

Prevention of Hypoxemic Hypoxia

The guidelines presented previously, notwithstanding the exceptions, represent a prudent approach to the classification of hypoxemia and the prevention of hypoxia. One must remember that in normal persons, when PaO₂ decreases to about 55 mm Hg, judgment and short-term memory may be impaired, presumably due to hypoxia.³⁸² Therefore, in all but unusual circumstances, it is unacceptable to allow moderate or severe hypoxemia (i.e., PaO₂ < 60 mm Hg) to persist.³⁸² This is true even in patients with chronic obstructive pulmonary disease (COPD), because a PaO₂ of 60 mm Hg is not associated with a great risk of increasing hypercarbia.³⁸²

As described in Chapter 10, there are some circumstances (e.g., paraquat poisoning, ARDS) when moderate degrees of hypoxemia may be considered acceptable or permissive. Indeed, a rebuttal of the traditional approach to treatment of hypoxemia has been presented.⁶⁹⁶ Nevertheless, treatment of moderate hypoxemia seems prudent until clear evidence suggests otherwise.

Methods available to treat hypoxemia have been discussed in detail in Chapter 10. Although the PaO₂ is a useful starting point in clinical hypoxic assessment, it is foolhardy to equate a normal PaO₂ with normal tissue oxygenation. The myriad other factors that may influence O₂ transport and internal respiration must also be evaluated.

SaO₂ Determination

The SaO₂ is the percentage of hemoglobin that is carrying oxygen in the arterial blood. It should be remembered that 98% of oxygen is carried in arterial blood combined with Hb. Regarding saturation, it is important for the clinician to note the technique that is being used to determine SaO₂, because the values obtained by different techniques may vary. Saturation may be calculated via a nomogram or measured by oximetry, CO-oximetry, or pulse oximetry.

SaO₂ as an Index of Hypoxia

SaO₂ is a better indicator of arterial oxygen content than is the PaO₂. Approximately 98% of blood oxygen is carried in the combined state (e.g., HbO₂); therefore, SaO₂ more accurately reflects the quantity of oxygen in the blood than the PaO₂. Clinically, as long as SaO₂ exceeds 90%, most clinicians are confident that the patient is not hypoxic. Usually a red flag is raised, however, when SaO₂ falls below 90%.

Furthermore, with the advent of routine SpO₂, understanding of the oxyhemoglobin curve assumes greater clinical importance. Important relationships between PO₂ and SO₂ must be committed to memory (i.e., PO₂ of 60 mm Hg = SO₂ of 90%; PO₂ of 40 mm Hg = SO₂ of 75%). The clinician must be able to mentally equate and interchange these two important parameters of oxygenation.

The PO₂–SO₂ relationships described earlier hold true given normal oxyhemoglobin affinity. A change in this relationship (e.g., PO₂ = 60 mm Hg; SO₂ = 80%) is indicative of a change in Hb–O₂ affinity (i.e., shift in oxyhemoglobin curve) that may be clinically important to recognize. For example, in the presence of alkalemia and hypocarbia, SpO₂ may remain above 90% even when PaO₂ is much lower than 60 mm Hg.

There is sometimes concern that a left-shifted oxyhemoglobin dissociation curve may cause tissue hypoxia because the hemoglobin will not release oxygen to the tissues. This phenomenon alone, especially in chronic conditions, is probably unlikely to cause tissue hypoxia as a patient with a p₅₀ of 11 mm Hg did not appear to show any evidence of hypoxia.⁴³⁶

Finally, the relative insensitivity of SaO₂ must also be recognized. Although SaO₂ is a superior index of quantitative oxygen content in the blood, it is inferior to PaO₂ as a sensitive index of pulmonary deterioration, mild hypoxemia, and/or hyperoxemia. Because the normal individual has an SaO₂ on the flat portion of the oxyhemoglobin dissociation curve, relatively large changes in PaO₂ result in minimal or no change in SaO₂.

SpO₂ and Abnormal Hb Species

As described earlier, SpO₂ measures functional saturation, not fractional saturation. Thus, abnormal Hb species (e.g., HbCO, MetHb) are not reflected. HbCO is recorded as HbO₂ because only two wavelengths of light are being measured. This could lead to a false sense of security regarding the patient with significant levels of abnormal Hb species. If, for example, an individual has an HbCO level of 20% and a fractional HbO₂ level of 70%, SpO₂ will read approximately 90%.

Thus, pulse oximetry may be misleading in the patient with recent exposure to carbon monoxide. With increased methemoglobinemia, SpO₂ readings tend to migrate toward 85%. As always, one cannot depend too heavily on any single technology as a replacement for thorough clinical evaluation.

Although pulse oximetry has some shortcomings as a true measure of oxygen saturation, it is useful particularly as a monitor of desaturation. In other words, when there is a fall in oxygen saturation from previous levels, it will usually be reflected. For this reason, pulse oximetry is an excellent method to monitor oxygen status on a real-time basis.

Maintenance of an Adequate SaO₂

In summary, SaO₂ values may vary substantially depending on the technique of measurement. The clinician must understand the method being used and its implications regarding patient management. When abnormal forms of Hb are suspected, SaO₂ should always be measured by using CO-oximetry.

When fractional SaO₂ is low, as determined by CO-oximetry, therapy is focused on decreasing the amount of any abnormal Hb species present in the blood and increasing blood oxygen content to satisfactory levels.

High levels of HbCO are treated with fraction of inspired oxygen (FIO₂) of 1.0 and, when available, hyperbaric oxygen. The half-life of HbCO is approximately 5 hours on room air. Thus, it takes the body about 5 hours to eliminate 50% of HbCO while breathing room air. Breathing 100% O₂ decreases the half-life to about 1 hour. Furthermore, the high levels of inspired oxygen maximally saturate available Hb and enhance dissolved O₂ concentration. In the case of very high MetHb levels, methylene blue is often useful to accelerate the reduction of MetHb to Hb.

In most clinical situations, conventional wisdom is simply to maintain the fractional SaO₂ above 90% to 92%. This usually equates to a PaO₂ > 60 mm Hg. When SaO₂ falls below this point, however, immediate action is usually indicated to restore SaO₂ to safer levels. One must remember that below 90% saturation, SaO₂ will fall precipitously with further PaO₂ reductions. Although this approach has been recently challenged,⁶⁹⁶ presently it is probably best to adhere to conventional wisdom.

Mean Corpuscular Volume

Normal RBCs are, for the most part, approximately 7 μm in diameter. Figure 11-2 shows a normal RBC film magnified 1000 times. Anisocytosis is said to exist when there are abnormal variations in cell size (Fig. 11-3). The presence of great numbers of large (>10 μm) RBCs is called macrocytosis. This condition is also seen in Figure 11-3. Conversely, the presence of great numbers of small (<5 μm) RBCs is called microcytosis (Fig. 11-4).

Cell size is measured in the clinical laboratory using the mean corpuscular volume (MCV) index. Normal MCV is 90 (±8) femptoliters (fL).³⁸⁸ Decreased [Hb] associated with an MCV less than 82 fL is called microcytic anemia; decreased [Hb] associated with an MCV greater than 98 fL is called macrocytic anemia.

Red Blood Cell Shape

Abnormalities in the shape of RBCs are called poikilocytosis. An example of a cell with an abnormal shape is the megaloblast. These cells are large (11 to 20 μm), nucleated RBCs that are oval and slightly irregular in shape (see Fig. 11-3). Megaloblasts are found in anemia due to vitamin B₁₂ deficiency (i.e., pernicious anemia) or in folic acid deficiency.

Immature Red Blood Cells

The presence of large numbers of immature RBCs in the blood suggests that anemia may be due to acute blood loss. Under normal conditions, between 0.5% and 1.5% of RBCs are in the immature form known as reticulocytes (Fig. 11-5).³⁸⁹ The presence of increased reticulocytes in the blood is called reticulocytosis. Reticulocytosis leads to rapid oxygen consumption in acquired blood samples and may lower blood PaO₂ if not measured promptly. Another type of immature RBC, the normoblast, is not normally found in the blood but may be observed in anemia secondary to acute blood loss. A normoblast is a nucleated RBC similar in size to a normal RBC.

Mean Corpuscular Hemoglobin Concentration

The percentage of the RBC volume occupied by Hb is another useful diagnostic aid in anemia. Normally, approximately one-third of the RBC consists of Hb. The clinical laboratory test used to evaluate RBC [Hb] is the mean corpuscular hemoglobin concentration (MCHC). Normal MCHC is 34±2%³⁸⁸ and is called normochromia. Hyperchromia (MCHC >36%) is rare; however, hypochromia (MCHC <32%) is seen commonly in iron deficiency anemia (see Fig. 11-4).

Summary

Table 11-1 compares MCV and MCHC.Table 11-2 summarizes many of the terms used in describing RBCs when diagnosing anemia. Common types of anemia associated with each laboratory finding are also shown in Box 11-3.

Bone Marrow Failure

Abnormal development (aplasia) of the bone marrow may occur without apparent cause, but more commonly this condition follows exposure to some chemical or physical agent. Chemical agents known to be associated with aplastic anemia include the drug chloramphenicol, insecticides such as DDT, and arsenic. Physical causes include excessive exposure to radiation.

Inadequate Hemoglobin Synthesis

The most common problem in Hb synthesis is iron deficiency. Iron supply is normally not a problem, because iron is recycled following the destruction of old RBCs. However, when iron is lost from the body, as in hemorrhage, or when additional iron is required, such as in pregnancy, it may be in short supply for Hb production.

Probably the most common cause of iron deficiency anemia is chronic blood loss. It may also be seen in infants or in mothers during pregnancy. An interesting diagnostic characteristic observed in some individuals with iron deficiency is pagophagia.⁴³⁸ Pagophagia is a type of “pica” or craving for unusual substances. Pagophagia is a strong craving for ice and is the most common type of pica seen in iron deficiency anemia. Pica occurs in up to 58% of patients with iron deficiency.⁴³⁸

In recent years, severe iron deficiency has become relatively uncommon. Nevertheless, mild iron deficiency is still far too common and can have damaging long-term consequences.⁴³⁹ Thus, we must continue to be vigilant in its identification and prevention.

Production of Hb may be abnormal in a genetic disorder called thalassemia. Thalassemia, also known as Cooley’s anemia or Mediterranean disease, may manifest itself in one of two forms: thalassemia major is a severe form of the disease that may be associated with severe anemia; thalassemia minor is a milder form.

Inadequate production of Hb is associated with hypochromia and the presence of small RBCs (microcytosis).

Inadequate Red Blood Cell Formation

Production of RBCs depends on an adequate supply of folic acid, vitamin B₁₂, and the hormone erythropoietin. Folic acid is plentiful in green leafy vegetables. Alcohol, however, interferes with the metabolism of folic acid. Therefore, poor diet or alcoholism may lead to folic acid deficiency.

Vitamin B₁₂, sometimes referred to as extrinsic factor, is normally absorbed in the stomach. This absorption is facilitated through a substance that has been labeled intrinsic factor. Individuals lacking in this intrinsic factor may develop anemia due to vitamin B₁₂ deficiency. Anemia that develops by this mechanism is known as pernicious anemia.

Anemia is also common in chronic renal failure and is due at least in part to decreased erythropoietin. Some loss of RBCs into the urine may also occur due to increased permeability of the diseased glomerulus.

Anemia due to folic acid or vitamin B₁₂ deficiency leads to a high number of large RBCs (i.e., macrocytosis). In addition, megaloblasts may be observed in the blood of these individuals.

Red Blood Cell Loss/Hemolysis

Immediately after acute blood loss, [RBC] may be normal. Soon after, however, fluid enters the blood from the interstitial space and thus leads to anemia.

Hemolysis is usually the result of the presence of toxins in the blood. Toxins may originate from infectious processes or may directly enter the blood, such as in poisonous snakebites. Many chemical agents may be associated with hemolysis. Finally, chronic hemolysis with acute exacerbation may occur in disorders such as sickle-cell disease (see Chapter 7) or thalassemia.

The pain rate (episodes per year) is a useful measure of the severity of sickle cell disease.⁴⁴⁰ Treatment, which has been discussed briefly in Chapter 7, may include bone marrow transplant, or more commonly, administration of pharmacological agents (e.g., hydroxyurea) aimed at increasing the amount of fetal Hb (HbF).⁴⁴¹ Increases in HbF have an ameliorating effect on the disease and symptoms. Many of these chemotherapeutic agents, however, may cause adverse effects and drugs with less potential of side effects (e.g., butyrate) continue to be explored.⁴⁴¹

Reticulocyte levels typically are increased in conditions associated with hemolysis or blood loss. In most long-term hemolytic anemias, reticulocytes exceed 5%.³⁹⁰ When evaluating the reticulocyte levels, however, one must keep in mind that reticulocytes are usually expressed as a percentage of total RBCs.

It is probably better to think in terms of the actual count of reticulocytes rather than the percentage. The normal actual count of reticulocytes is about 50,000 cells/mm³ or 1% of [RBC]. If [RBC] decreases from 5 million to 2.5 million/mm³, and the reticulocyte count remains constant (i.e., 50,000 cells), the percentage of reticulocytes would be 2%. If the actual reticulocyte count is not considered, this could be wrongly interpreted as an increase in RBC production.

The presence of normoblasts in the blood is abnormal and a sign of accelerated RBC production. Anemia secondary to the loss of RBCs is typically normocytic in laboratory analysis.

Clinical Symptoms

Restlessness, anxiety, or alteration in consciousness may be early signs of shock caused by decreased cerebral perfusion. Cyanosis, decreased urine output, and lactic acidosis may likewise suggest poor perfusion status. Rapid breathing and respiratory alkalosis are often observed with shock, presumably as a secondary response to hypoperfusion mediated through the peripheral chemoreceptors or as a result of high / in the lungs.

Vasoconstriction secondary to the release of norepinephrine and, to a lesser extent, epinephrine may also lead to cold, pale extremities. Sympathetic stimulation of the sweat glands in conjunction with the peripheral vasoconstriction tends to make the skin appear cold and clammy.