Hypoxia and hypoxemia are common reasons for hospital admission, usually in the context of a primary respiratory illness¹. An understanding of the evaluation, diagnosis, and monitoring of patients with hypoxemia can improve patient care and resource utilization.

PATHOPHYSIOLOGY

The Oxygen Cascade

The process of delivering oxygen (O₂) to tissues is complex, but knowledge of this process facilitates an understanding of the clinical aspects of hypoxemia and hypoxia. Providing adequate tissue oxygenation involves the pulmonary, cardiovascular, and hematology systems and is hampered by the relatively slow tissue diffusion of O₂. O₂ always moves down its partial pressure gradient from dry atmospheric air (partial pressure of O₂ [PO₂] 160 mmHg at sea level) to the mitochondria in tissues (PO₂ 3–20 mmHg). The gaseous waste product of aerobic metabolism, carbon dioxide (CO₂), is assisted in its transport to atmospheric air like O₂, but unlike O₂, diffuses readily across tissues.

Alveolar Oxygen

The fraction of inspired O₂ (Fio₂) in atmospheric air is 21%, but the partial pressure of inspired O₂ (P_IO2) is also dependent on barometric pressure (P_B), primarily as a function of altitude. O₂ entering the alveolus is “diluted” by humidification (PH₂O = 47 mmHg), and CO₂ in the alveolus. Arterial partial pressure of CO₂ (PaCO₂) approximately equals alveolar partial pressure of CO₂ (PAco₂) due to ready diffusion across capillary and alveolar membranes. PACO₂ is a function of energy metabolism (production of CO₂) and minute ventilatory volume (elimination of CO₂). CO₂ production reflects the respiratory quotient (RQ); RQ of a balanced diet is ~0.83. CO₂ elimination is reflected by the PACO₂. CO₂ is also involved in acid–base balance, which can impact its rate of elimination.

The simplified alveolar gas equation calculates an estimate of alveolar partial pressure of O₂ (PA_O2): PA_O2 ~ P_IO2 – (Pa_CO2/RQ). At sea level in atmospheric air, P_B is 760 mmHg. The resulting Pio₂ is Pio₂ = (F_IO2 *(P_B–PH₂O), or (0.21*(760 – 47)) = 149 mmHg. In the alveolus, CO₂ is present in proportion to the RQ and minute ventilation, and the P_IO2 is diminished by the factor Pa_CO2/RQ. With a PA_CO2 = paco₂ of 40 mmHg and an R of 0.83, the ideal PA_O2 at sea level is 149 mmHg – (40/0.83) = 101 mmHg. In contrast, in Salt Lake City, Utah, 1280 m above sea level, the P_B is 647 mmHG, and the ideal PA_O2 is 77 mmHG. Hyperventilation, environment, diet, and disease can influence PA_O2 through their impact on F_IO2, Pa_CO2, and RQ in different ways. For example, hyperventilation to a Pa_CO2 of 30 mmHg increases PA_O2 from 77 to 89 mmHg in Salt Lake City. Hyperventilation refers to an increase in minute ventilatory volume by increasing tidal volume, respiratory rate, or both.

Arterial Oxygen

Diffusion of O₂ across the alveolar and pulmonary capillary membranes takes time and is affected by diffusion distance and Pao₂–pulmonary venous Po₂ gradient. Uptake of O₂ in pulmonary capillary blood is a function of diffusion time, transit time/amount of blood flow through the capillary bed, and O₂–hemoglobin affinity. The complex air and blood flow control processes in the lungs include mechanisms to regulate matching of ventilation (V) and perfusion (Q). The partial pressure of arterial O₂ (Pao₂) is also influenced by deoxygenated blood that bypasses the alveolar capillary bed, referred to as the shunt fraction. Together, these result in a “normal” alveolar-arterial (A-a) oxygen gradient, or difference between Pao₂ and Pao₂. The anatomic, or fixed, shunt fraction is about 2% of cardiac output and combines with a variable physiologic shunt fraction in part reflecting imperfect ventilation-perfusion (V/Q) matching to create the A-a gradient. Accordingly, the normal (measured) Pao₂ of blood at sea level is ~95 mmHg and in Salt Lake City, ~72 mmHg. A Pao₂ of 60 mmHg is thought to trigger physiologic mechanisms to acclimate to chronic hypoxemia.² Diseases altering diffusion, lung ventilation, pulmonary perfusion, V/Q matching, and fixed shunt fraction can impact Pao₂.

Once O₂ crosses the alveolar-pulmonary capillary membranes, a minimal amount is dissolved in plasma (0.003 mL per dL of blood for each mmHg of Pao₂). The majority is transported bound to hemoglobin reversibly as oxyhemoglobin. When 100% of the O₂ binding sites are occupied, hemoglobin carries 1.34 mL (at standard temperature and pressure [STP]) of O₂ per gram. The O₂ binding relationship with hemoglobin tetramers is complex, generating an S-shaped curve of O₂ percent saturation of hemoglobin binding sites when viewed graphically (Figure 28-1). This hemoglobin saturation–desaturation relationship facilitates O₂ uptake across the alveolar-pulmonary capillary membranes and O₂ release in tissues, where PO₂ ranges between 3 and 20 mmHg. Several substances and conditions can “shift” the oxyhemoglobin saturation curve rightward, toward decreased pulmonary O₂ uptake and improved tissue release, or leftward, leading to improved pulmonary O₂ uptake and inhibited tissue release (see footnote, Figure 28-1). The capacity of blood to carry O₂ (CaO₂) is dependent on hemoglobin content and is a combination of dissolved O₂ and that carried by hemoglobin.

Disease processes that impact CaO₂ include anemia, impeded hemoglobin O₂ binding, and any disease or other condition resulting in a reduction in PAO₂ or PaO₂ (see above). For example, the majority of O₂ carried by the blood is bound to hemoglobin, therefore anemia results in decreased CaO₂. Acute isovolemic anemia is tolerated to a hemoglobin level of 5–7 g/dL or CaO₂ of 7–10 mL O₂/dL blood.^3-5 Chronic anemia is tolerated below 5 g/dL, but the “low threshold” in chronic anemia that is incompatible with life is unknown, with levels as low as 1.5 g/dL documented.⁶ Cyanosis, which is clinically visible deoxyhemoglobinemia, is detected at a capillary deoxyhemoglobin concentration of 4 to 6 g/dL, or arterial hemoglobin saturation of about 80% with hemoglobin of 15 g/dL; however, cyanosis is a function of perfusion, tissue O₂ extraction, and other factors apart from arterial hemoglobin O₂ saturation.^7-9 In a polycythemic individual, such as a newborn, the threshold for clinically visible cyanosis may occur at higher overall hemoglobin O₂ saturations.

Tissue Oxygen

Delivering oxygen to tissue beds (DO₂) is dependent on CaO₂ × cardiac output (CO; a function of stroke volume and heart rate) and requires an open vascular supply. In the capillary beds, O₂ delivery is dependent on oxyhemoglobin dissociation, capillary–tissue PO₂ gradient, and distance from the capillary vessel to the tissue cells. Once O₂ is delivered, there must be viable, functional cells/mitochondria to ensure O₂ use. Tissue hypoxia results when delivery of O₂ cannot meet O₂ demand which may reflect impaired delivery or increased metabolic needs, or both. Generalized tissue hypoxia is reflected in the mixed venous O₂ partial pressure indicating maximal O₂ extraction in the capillary beds along a steep O₂ partial pressure gradient. Examples of clinical disease affecting DO₂ include heart failure, septic shock, peripheral arterial occlusion, and anything affecting CaO₂. Common physiologic responses to impaired DO₂ include tachycardia and hyperventilation to maximize Pao₂.¹⁰

Background Summary

The need for oxygen in tissue beds drives the complex process of delivering O2 from atmospheric air, along its partial pressure gradient, to tissues. Understanding the process helps in understanding clinical physiologic responses to hypoxia (hyperventilation/tachypnea, increased cardiac output/tachycardia, polycythemia, V/Q matching, etc.) and pathophysiologic disequilibrium (V/Q mismatch, increased shunt fraction, shock, hyperventilation, respiratory failure, etc.). The most common clinical manifestations of disease resulting in a risk for tissue hypoxia result in blood hypoxemia as well, although important exceptions exist.

The history related to hypoxemia includes a complete pulmonary systems review, including infectious symptoms; this covers most clinical presentations. A history of possible toxic exposure or inhalation can help diagnose some conditions not easily detected by pulse oximetry (e.g. carbon monoxide poisoning; see Chapter 184). Review of the history with regard to underlying lung disease, cardiovascular disease, medication use, prior thoracic surgery, chest wall deformity or restriction (e.g. scoliosis), allergy, prior or current O₂ baseline use, prior need for artificial ventilatory support, and results of prior blood gas testing, pulmonary function tests, or other studies of cardiopulmonary function are also essential. Generalized symptoms of hypoxemia, such as poor feeding, altered mentation, and decreased level of activity should be sought.

PHYSICAL EXAMINATION

The physical examination should include a critical evaluation of the patient’s vital signs (including pulse oximetry, SpO₂) based on norms for age and altitude (Table 28-1), since tachycardia and tachypnea can compensate for relatively mild hypoxemia resulting in a normal SpO₂ reading. An initial impression of the patient’s degree of illness is beneficial, because hypoxia (with or without hypoxemia) may be present if the patient looks ill or uncomfortable. A careful cardiopulmonary examination should include a search for peripheral evidence of hypoperfusion or regional or systemic hypoxia and for chest wall abnormalities. A neurologic evaluation with regard to respiratory drive, strength of the muscles of respiration, and level of consciousness (as the brain is the most sensitive tissue to hypoxia) is applicable. If the patient has been placed on O₂, the degree of impairment may be masked, leaving a false impression of less acute illness. A review of findings prior to initiating O2 therapy with persons who observed or examined the patient can be helpful. It should also be noted that significant deoxyhemoglobinemia cannot be easily achieved in an anemic patient, so cyanosis is not a reliable physical finding of hypoxemia with coexistent anemia. A number of studies have undertaken the objective of identifying clinical findings that will predict hypoxemia. No history or physical examination findings, or combination of findings, have been shown to have sufficient sensitivity and specificity to reasonably predict hypoxemia; however, findings that consistently appear as better predictors include cyanosis (lower sensitivity, high specificity), increased work of breathing (retractions, grunting, head bobbing, nasal flaring), tachypnea >50–70 depending on age, poor feeding, and altered mentation (lethargy, decreased alertness, sleepy) (the latter 4 with high sensitivity, lower specificity).^12,13

Pulse Oximetry—”The Fifth Vital Sign”

Pulse oximetry combines the principles of spectrophotometry and optical plethysmography, taking advantage of the differential absorption of light in the red and ultraviolet wavelengths of deoxy- and oxyhemoglobin, and differentiating arterial flow as pulsatile flow¹⁴. The probe includes two light-emitting diodes and a photo detector placed opposite across a perfused tissue bed. The resulting reading is converted using an empirically determined algorithm and reported as the Spo₂ percentage. It should be noted that each light source must transmit light across an equivalent perfused tissue bed, displayed values are delayed 3 to 6 seconds, artifacts are common, and several factors can affect the validity and accuracy of pulse oximetry (Table 28-2). Despite its limitations, pulse oximetry clearly exceeds the ability to detect hypoxemia by clinical examination.