Disorders of oxygenation: hypoxemia and tissue hypoxia

Introduction

Hypoxemia, a decreased partial pressure of oxygen in the blood, is a commonly encountered clinical problem among patients with acute or chronic cardiopulmonary disorders. Accurately characterizing the cause and severity of hypoxemia in a timely manner can have significant implications for clinical management and patient prognosis. The blood gas measurements play an integral part in the evaluation of the hypoxemic patient, as does the understanding of oxygen uptake, delivery, and consumption.

A small amount of oxygen is dissolved in the blood and the rest is bound to hemoglobin (Hb). Effective utilization of oxygen requires binding by Hb in the lungs, transport in the blood vessels, and release to tissues, where cellular respiration occurs. Hydrogen ion (pH), CO ₂ , temperature, and 2,3-DPG all play important roles in these processes.

A panel of blood gas measurements includes partial pressures of oxygen ( p O ₂ ) and carbon dioxide ( pC O ₂ ), percent oxyhemoglobin (%O ₂ Hb), and related parameters, which are used to detect and monitor oxygen deficits from a variety of causes. Measurement of blood gases and cooximetry may be done by laboratory analyzers, point-of-care testing, and transcutaneous blood gas devices.

Identifying the cause of an oxygen deficit requires an understanding of the measurements and calculations important in oxygen uptake and delivery, which include the Hb concentration, alveolar-arterial p O ₂ (A-a) gradient, p O ₂ :FiO ₂ ratio, oxygenation index (OI), O ₂ content, O ₂ delivery, pulmonary dead space, and intrapulmonary shunt.

Oxygen measurements are commonly done on arterial blood but are also done on capillary, venous, and mixed venous blood. It is important for both clinicians and laboratorians to understand the benefits and limitations that are inherent to the different measuring techniques and sample sources. Whether monitoring oxygenation is more beneficial when done in a clinical laboratory or at the point of care depends on a combination of factors, including clinical need, therapeutic urgency, proximity of the patient care areas to the clinical laboratory, and qualifications/cooperation of the nonlaboratorian testing personnel.

Parameters in oxygen monitoring

The oxygen-related parameters measured by a blood gas/cooximetry analyzer are p O ₂ , %O ₂ Hb, O ₂ saturation ( s O ₂ or “O ₂ sat”), and total Hb (and hematocrit). There are subtle but important differences between these individual measurements, which are discussed later in this chapter. Cooximeters measure several common forms of Hb in blood: oxyhemoglobin (O ₂ Hb), deoxyhemoglobin (HHb), carboxyhemoglobin (COHb), and methemoglobin (metHb).

The p O ₂ represents the tension of oxygen in the aqueous or plasma phase of blood. p O ₂ is reported in either mmHg in the United States or kPa in most other countries. The typical atmospheric pressure at sea level is 760 mmHg (101.3 kPa) and the atmosphere contains 21% oxygen. Thus, the p O ₂ of inspired air at sea level is 160 mmHg (21.3 kPa). If separate open containers of blood and water are exposed to the atmosphere, the p O ₂ should be the same for each, approximately 160 mmHg. However, the blood is not directly exposed to ambient atmospheric air. As the air is inspired through the nasopharynx and travels down the trachea and bronchi, it is humidified and the partial pressure of water increases from approximately 3 mmHg in ambient air to 47 mmHg at the level of the alveoli. Because of CO ₂ released from the blood, the partial pressure of CO ₂ in the alveolar space increases from 0.3 mmHg to approximately 40 mmHg in healthy individuals at rest. The presence of increased H ₂ O and CO ₂ in the alveolar space displaces p O ₂ and leads to an alveolar p O ₂ of approximately 104 mmHg. Thus, arterial p O ₂ should be close to equilibrating with alveolar p O ₂ in normal adults with only a small decrease accounted for by the transport across the alveolar-capillary membrane.

The amount of dissolved oxygen in the blood, as measured by the p O ₂ of the sample, contributes only a small amount to the overall oxygen content of the blood. The majority of the oxygen carried in the blood is bound to Hb. The amount of oxygen bound to Hb may be represented by either the percent oxygen saturation ( s O ₂ ) or the percent oxyhemoglobin (%O ₂ Hb). The s O ₂ is a measurement of the percentage of the O ₂ Hb relative to the total functional Hb (O ₂ Hb + HHb). It is calculated as follows:

If all Hb binding sites contain oxygen, then the s O ₂ would be 100%, although the normal range for s O ₂ is typically 94%–98%.

The %O ₂ Hb is the percent of the total Hb that contains oxygen. It is calculated as follows:

Because blood usually contains some COHb and metHb, the %O ₂ Hb never reaches 100% and typically ranges from about 92% to 96% in healthy individuals, slightly lower than the s O ₂ . In patients with elevated COHb or metHb, the %O ₂ Hb will be decreased, but the s O ₂ is unaffected.

The p O ₂ and the s O ₂ are related as illustrated in the oxyhemoglobin dissociation curve ( Fig. 4.1 ). As the p O ₂ increases up to about 100 mmHg, the s O ₂ also increases to about 99%–100% (i.e., all the hemoglobin oxygen binding sites contain oxygen). However, if a patient breathes supplemental oxygen (such as an FiO ₂ of 0.40), the arterial p O ₂ may increase well above 100 mmHg, while the s O ₂ remains at or near 100%.

The hematocrit is the percentage of the blood volume that is occupied by RBCs. The hematocrit is directly proportional to the hemoglobin concentration. The numerical hematocrit percent is generally about three times the hemoglobin concentration (in g/dL). The oxygen content is directly proportional to the s O ₂ percentage and the hemoglobin concentration (see “Measured and Calculated Parameters Used in Evaluating Arterial Oxygenation ”). The oxygen content and the cardiac output are used to calculate the oxygen delivery.

Measurement of oxygen levels (i.e., p O ₂ and %O ₂ Hb) in peripheral venous blood is of limited utility in assessing a patient's oxygenation status; however, pH and p CO ₂ measurements can still be quite useful in estimating a patient's acid–base status and level of ventilation. Mixed venous blood samples obtained from the pulmonary artery after all the blood returned from the body has been mixed and pumped into the pulmonary circulation from the right ventricle can give an estimate of oxygen consumption. For example, in the setting of sepsis, patients may have a high cardiac output, mitochondrial dysfunction and poor oxygen extraction. Therefore, they will have high mixed venous %O ₂ Hb, but this does not necessarily indicate that their tissue oxygen uptake is adequate. In patients with heart failure and low cardiac output, they will often have insufficient oxygen delivery but normal capacity for oxygen extraction and subsequently a low mixed venous %O ₂ Hb. These two conditions are frequently present together and can complicate the interpretation of mixed venous %O ₂ Hb and therefore limit its clinical utility.

Pulse oximetry has become universally utilized for continuously and noninvasively monitoring a patient's arterial hemoglobin saturation without needing to invasively measure s O ₂ with a blood gas analyzer. In the absence of more severe hypoxemia ( s O ₂ <90%) and states of poor perfusion, the measurements obtained with a pulse oximeter generally approximate blood s O ₂ with good accuracy ( ) . Because pulse oximetry will not measure the oxygen saturation correctly for other hemoglobins such as metHb or COHb, pulse oximetry will not detect CO poisoning. For example, if a patient has an elevated COHb, the %O ₂ Hb will be decreased, but the pulse oximeter may read a normal s O ₂ . A cooximeter, which requires a blood sample, will determine the %O ₂ Hb (and s O ₂ if desired), and the percentages of metHb and COHb.

Point-of-care testing for blood gases . Point-of-care testing (POCT) has the potential to deliver rapid blood gas and other critical care test results near the patient. When properly incorporated into the patient care process, POCT can translate to faster therapeutic intervention, reduced preanalytical errors, and improved patient care. However, POCT also requires a higher level of supervision and quality management to avoid the pitfalls of improper sample handling, test inaccuracy, training and continued competency assessment of nonlaboratorians, and justification of the additional costs of analyzers and test units or cartridges. The benefits of POCT are also dependent on the test volume and proximity of the care area to a clinical laboratory. For example, POCT becomes very labor intensive for high volume testing and may have limited benefit if a clinical laboratory is located near the patient-care area.

Transcutaneous monitoring . Transcutaneous monitors for p O ₂ (and p CO ₂ ) measure the p O ₂ at the skin surface ( p _tc O ₂ ), which gives an estimate of the arterial p O ₂ . Monitors typically warm the skin at the sensor site to increase blood flow. Since pulse oximetry has become a standard of care for noninvasive monitoring of oxygen levels, the p _tc O ₂ is used only infrequently and predominantly in neonates. When initiating transcutaneous monitoring, it is recommended that an arterial blood gas be drawn and measured for p O ₂ to ensure accurate calibration. Therefore, the clinical utility of transcutaneous monitoring is limited to a small subset of patients who either lack an arterial access site or require continuous monitoring of oxygen and carbon dioxide with minimal blood draws.

Structure and function of hemoglobin

The four most prevalent forms of normal hemoglobin in blood are oxyhemoglobin (O ₂ Hb), deoxyhemoglobin (HHb), carboxyhemoglobin (COHb), and methemoglobin (metHb). O ₂ Hb and HHb are both functional hemoglobin and represent the same molecules as they continually bind and release O ₂ . Both COHb and metHb are nonfunctional in O ₂ binding and release.

Four subunits join together to form the hemoglobin molecule ( Fig. 4.2 ). Each subunit contains a globin protein + heme + Fe ⁺⁺ that binds O ₂ . Both O ₂ and CO ₂ (carbaminohemoglobin) bind reversibly to hemoglobin. As one O ₂ binds to a subunit, the conformation of the remaining subunits changes slightly to favor more O ₂ binding. This is positive cooperativity.

There are several molecules, ions, and conditions that promote the timely binding of oxygen to hemoglobin in the lungs and release in the tissues and cells ( Table 4.1 ). These are hydrogen ions (H ⁺ ), measured as its negative log pH, p CO ₂ , temperature, and 2,3-DPG. Conditions of higher metabolic activity or oxygen consumption, as in cells, tend to produce higher [H ⁺ ] (acidity), higher p CO ₂ , and warmer temperatures that favor the release of O ₂ from Hb, while less [H ⁺ ] (alkalinity), lower p CO ₂ , and cooler temperature, as in the lungs, tend to favor binding of O ₂ to Hb.

The role of 2,3-DPG on Hb binding and release of O ₂ is more complex. 2,3-DPG is an ion largely contained in RBCs that “cooperates” with O ₂ and other molecules to control when Hb binds or releases O ₂ . Without any 2,3-DPG, Hb would stay in a conformation (R form) with a higher affinity for O ₂ that favors the binding of O ₂ . As blood enters the tissues, the increased H ⁺ ions and p CO ₂ promote the release of O ₂ , which then favors the binding of 2,3-DPG to Hb. This causes a conformational change to the T form of Hb that has a lower affinity for O ₂ , therefore leading to further release of oxygen to the tissues.

As blood enters the lungs, which have a higher p O ₂ , as some O ₂ binds to Hb, more 2,3-DPG is released, which then promotes more binding of O ₂ to Hb ( ) .

As a note, fetal Hb does not bind 2,3-DPG as well as adult Hb, so fetal Hb tends to stay in a conformation with a higher affinity for O ₂ than does adult Hb. This is essential so that the fetal blood can more effectively extract O ₂ from maternal blood.

Carbon monoxide is small enough to fit into the protein crevice and create very strong bonds with iron to form COHb, which is unable to release oxygen. The normal level of COHb in the blood is about 1%, but in heavy smokers COHb levels may be up to 10% of the total Hb. Because hemoglobin binding affinity for CO is 200 times greater than its affinity for oxygen, even when inspired air contains CO levels as low as 0.02%, headache and nausea occur ( , ) . If the CO concentration increases to 0.1%, unconsciousness will follow. While COHb is nonfunctional, if CO can be removed, the hemoglobin becomes functional again. CO releases very slowly from COHb once the source of CO (i.e., cigarette smoke) has been eliminated, but this process can be accelerated in the presence of higher p O ₂ in the blood obtained by providing either supplemental oxygen or hyperbaric oxygen to the patient. In CO poisoning, the affected person dies of asphyxiation because their blood is no longer able to carry enough oxygen to supply the needs of the tissues and brain.

MetHb has its Fe ⁺⁺ ions oxidized to Fe ⁺⁺⁺ , which renders the hemoglobin nonfunctional in oxygen transport ( ) . Methemoglobinemia can be congenital, due to genetic mutations in the enzyme cytochrome b5 reductase, which normally maintains the balance of metHb by reducing Fe ⁺⁺⁺ back to Fe ⁺⁺ forming HHb, or acquired, typically secondary to medications or exogenous chemicals. At metHb levels above 10%, symptoms due to tissue hypoxia may range from mild cyanosis, dyspnea, headache, or fatigue. As metHb levels progressively increase above 20%, hypotension, cardiac dysfunction, seizures, coma, and even death may occur at metHb levels above 50%. Treatment of severe, symptomatic methemoglobinemia involves removing any offending drugs and administering methylene blue or ascorbic acid to facilitate reduction of metHb back to HHb.

Another poisonous agent that binds to hemoglobin is the cyanide anion (CN ⁻ ). This toxic agent is inhaled as hydrogen cyanide gas. Once cyanide is taken into the bloodstream the majority (92%–99%) binds to hemoglobin in red blood cells. From there, it is taken to the cells and mitochondria where it binds to the enzyme cytochrome oxidase and inhibits mitochondria from metabolizing oxygen.