Medical School · Year 1 · Respiratory · includes a quiz and discussion video

Lecture 3: Pulmonary Gas Exchange

Unit 1.8: Respiratory System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the composition of atmospheric and alveolar gas
2. Explain the diffusion of gases across the blood-gas barrier
3. Describe the factors affecting diffusion capacity
4. Explain oxygen and carbon dioxide transport in blood
5. Describe the oxygen-hemoglobin dissociation curve and factors affecting it
6. Apply gas exchange concepts to clinical scenarios

Lecture Content

I. Gas Laws and Partial Pressures

Understanding gas exchange requires familiarity with the physical behavior of gases. Several fundamental laws govern how gases exert pressure, dissolve in liquids, and diffuse across membranes. These principles apply directly to oxygen and carbon dioxide transport in the respiratory system.

Dalton's law states that the total pressure of a gas mixture equals the sum of the partial pressures of each individual gas. Each gas contributes to total pressure in proportion to its fractional concentration. At sea level, atmospheric pressure measures 760 mmHg. Nitrogen, comprising 78 percent of air, exerts a partial pressure of approximately 593 mmHg. Oxygen at 21 percent contributes 160 mmHg. Carbon dioxide at 0.04 percent adds only 0.3 mmHg. Water vapor pressure varies with humidity in ambient air but becomes fixed at body temperature.

As inspired air travels through the upper airways, it becomes fully saturated with water vapor at body temperature. At 37 degrees Celsius, water vapor pressure equals 47 mmHg. This humidification reduces the partial pressures available for other gases. The partial pressure of inspired oxygen after humidification calculates as the fraction of inspired oxygen multiplied by the difference between atmospheric pressure and water vapor pressure. With room air at sea level, this yields approximately 150 mmHg.

The alveolar gas equation describes the partial pressure of oxygen in the alveolus, accounting for the exchange of oxygen for carbon dioxide. Alveolar oxygen partial pressure equals inspired oxygen partial pressure minus the ratio of arterial carbon dioxide partial pressure to the respiratory quotient. The respiratory quotient represents the ratio of carbon dioxide production to oxygen consumption, typically 0.8 on a mixed diet. With normal values, alveolar oxygen partial pressure calculates to approximately 100 mmHg.

This equation reveals an important relationship: alveolar oxygen partial pressure falls when arterial carbon dioxide rises, because carbon dioxide displaces oxygen in the alveolar space. Conversely, hyperventilation that lowers arterial carbon dioxide raises alveolar oxygen partial pressure. This inverse relationship becomes clinically important when evaluating patients with hypoxemia.

<image>Panel A: Column of atmospheric air showing gas composition percentages and partial pressures at sea level. Panel B: Upper airway adding water vapor at 37°C with water vapor pressure of 47 mmHg and recalculated partial pressures. Panel C: Alveolus showing oxygen entering and carbon dioxide exiting with alveolar gas equation. Panel D: Color-coded gas movement arrows with oxygen in red, carbon dioxide in blue, nitrogen in gray, and water vapor in light blue.</image>

II. Alveolar-Arterial Gradient

The alveolar-arterial oxygen gradient quantifies the difference between oxygen partial pressure in the alveolus and in arterial blood. This gradient serves as a valuable clinical tool for distinguishing among causes of hypoxemia.

In an ideal lung with perfect matching of ventilation and perfusion, blood leaving pulmonary capillaries would have the same oxygen partial pressure as alveolar gas, producing a gradient of zero. In reality, even healthy lungs demonstrate a small gradient due to physiological factors including a minor degree of ventilation-perfusion mismatch and small anatomical shunts from bronchial and coronary venous drainage.

The normal alveolar-arterial gradient measures 5 to 15 mmHg in young adults and increases with age. A clinical approximation calculates the expected gradient as age divided by four, plus four. Thus, a healthy 60-year-old might have an expected gradient of 19 mmHg.

Calculating the gradient requires first determining alveolar oxygen partial pressure using the alveolar gas equation, then subtracting measured arterial oxygen partial pressure from this calculated value. An increased gradient indicates that something between the alveolus and arterial blood impairs oxygen transfer.

Three mechanisms increase the alveolar-arterial gradient. Ventilation-perfusion mismatch, the most common cause of hypoxemia, occurs when some lung units receive more blood flow relative to ventilation while others receive more ventilation relative to blood flow. Blood from underventilated units remains poorly oxygenated and dilutes the well-oxygenated blood from normally ventilated regions. Shunt represents an extreme form of ventilation-perfusion mismatch where blood completely bypasses ventilated alveoli. Diffusion impairment, though less common, occurs when the blood-gas barrier thickens or when transit time shortens sufficiently to prevent equilibration.

Two causes of hypoxemia maintain a normal alveolar-arterial gradient. Hypoventilation reduces alveolar oxygen partial pressure by allowing carbon dioxide to accumulate, but gas exchange at the alveolar-capillary interface remains normal. Low inspired oxygen partial pressure, as at high altitude, similarly reduces alveolar oxygen without impeding gas transfer.

<image>Panel A: Central calculation showing PAO2 from alveolar gas equation minus measured PaO2 for A-a gradient. Panel B: Normal gradient causes including hypoventilation and low FIO2 with explanations of intact gas exchange. Panel C: Increased gradient causes including V/Q mismatch, shunt, and diffusion impairment with gas transfer problem descriptions. Panel D: Clinical pearl noting A-a gradient diagnostic utility with normal values by age at bottom.</image>

III. Diffusion Across the Blood-Gas Barrier

Gas exchange occurs by passive diffusion across the blood-gas barrier separating alveolar air from pulmonary capillary blood. The physical characteristics of this barrier and the properties of the diffusing gases determine the efficiency of gas transfer.

Fick's law of diffusion describes the factors governing gas movement across a membrane. The volume of gas diffusing per unit time equals the surface area times the diffusion coefficient times the partial pressure gradient, all divided by the barrier thickness. Each of these factors has clinical relevance.

The blood-gas barrier represents an engineering marvel of minimal thickness combined with enormous surface area. The barrier consists of three layers: the alveolar epithelium formed by type I pneumocytes, measuring 0.1 to 0.2 micrometers; a minimal interstitial space containing basement membrane components; and the capillary endothelium at approximately 0.1 micrometers. Total barrier thickness measures only 0.3 to 0.5 micrometers at its thinnest points, facilitating rapid diffusion. The alveolar surface area totals 50 to 100 square meters in adult lungs, approximating the area of a tennis court.

The diffusion coefficient for a gas depends on its solubility and molecular weight. Carbon dioxide, despite being heavier than oxygen, diffuses approximately 20 times more rapidly because of its much greater solubility in aqueous solutions. This difference explains why carbon dioxide elimination rarely becomes limited even when oxygen uptake is impaired.

Gas exchange can be characterized as either perfusion-limited or diffusion-limited. In perfusion-limited exchange, the gas reaches equilibrium across the barrier before blood exits the capillary. Under these conditions, increasing blood flow increases the total amount of gas transferred. Normal oxygen and carbon dioxide exchange operates in a perfusion-limited manner. In diffusion-limited exchange, the gas cannot equilibrate before blood leaves the capillary, and the barrier properties rather than blood flow constrain transfer. Carbon monoxide, which binds avidly to hemoglobin and maintains a very low partial pressure in blood, exemplifies diffusion-limited transfer.

Under normal resting conditions, blood spends approximately 0.75 seconds transiting pulmonary capillaries. Oxygen reaches equilibrium within the first 0.25 seconds, leaving substantial reserve capacity. During exercise, transit time shortens but normally remains sufficient for equilibration. In disease states with thickened barriers, oxygen may not equilibrate even during the available transit time, causing exercise-induced desaturation before resting hypoxemia develops.

<image>Panel A: Electron microscopy-style diagram showing blood-gas barrier layers with type I pneumocyte, basement membranes, and endothelium with thickness measurements. Panel B: Fick's law variables illustrated including surface area, diffusion coefficients for oxygen and carbon dioxide, and partial pressure gradients. Panel C: Emphasis on thin barrier thickness as key factor facilitating rapid diffusion. Panel D: Graph of oxygen partial pressure versus capillary transit time showing rapid equilibration in health versus incomplete equilibration in disease.</image>

IV. Diffusing Capacity

Diffusing capacity quantifies the efficiency of gas transfer across the alveolar-capillary membrane. Clinical measurement uses carbon monoxide because its diffusion-limited kinetics allow assessment of membrane function independent of perfusion effects.

The diffusing capacity for carbon monoxide, abbreviated DLCO, represents the volume of carbon monoxide transferred per minute per mmHg of partial pressure gradient. Normal values approximate 25 milliliters per minute per mmHg, though they vary with age, sex, height, and hemoglobin concentration.

Multiple factors influence DLCO. Surface area reduction, as occurs in emphysema where alveolar septa are destroyed, decreases DLCO by reducing the area available for diffusion. Barrier thickening from interstitial fibrosis increases the distance gases must travel, reducing DLCO. Hemoglobin concentration affects DLCO because hemoglobin serves as the final sink for carbon monoxide; anemia reduces DLCO while polycythemia may increase it. Ventilation-perfusion mismatch reduces effective diffusing capacity because poorly perfused regions contribute minimally to gas exchange. Pulmonary vascular disease reduces DLCO by decreasing the capillary blood volume available for gas uptake. Interestingly, exercise increases DLCO through recruitment of previously unperfused capillaries. Pulmonary hemorrhage paradoxically increases DLCO because hemoglobin in the alveolar space avidly binds carbon monoxide.

Clinical applications of DLCO measurement help differentiate among lung diseases. Emphysema characteristically shows reduced DLCO reflecting loss of alveolar surface area. Pulmonary fibrosis also reduces DLCO due to barrier thickening, but the pattern combines with restrictive spirometry. Pulmonary vascular diseases including pulmonary arterial hypertension reduce DLCO out of proportion to other pulmonary function abnormalities. Anemia reduces DLCO and requires correction when interpreting results. Pure asthma typically preserves DLCO because neither the alveolar surface nor the barrier is affected, helping distinguish asthma from emphysema in patients with obstructive spirometry.

<image>Panel A: DLCO test setup showing subject breathing dilute carbon monoxide and exhaling into collection apparatus with equation defining DLCO. Panel B: Factors reducing DLCO including emphysema with reduced surface area and fibrosis with thickened membrane. Panel C: Additional factors affecting DLCO including anemia with low hemoglobin and pulmonary vascular disease with reduced capillary volume. Panel D: Clinical interpretation table listing conditions with expected DLCO values and underlying mechanisms.</image>

V. Oxygen Transport

Oxygen delivery to tissues requires transport from the lungs via the bloodstream. Understanding how blood carries oxygen explains the relationship between oxygen partial pressure and oxygen content, and clarifies why hemoglobin concentration critically determines tissue oxygen availability.

Oxygen exists in blood in two forms. Dissolved oxygen obeys Henry's law, with the amount proportional to partial pressure. At normal arterial oxygen partial pressure of 100 mmHg, dissolved oxygen amounts to only 0.3 milliliters per deciliter of blood, calculated as 0.003 times the partial pressure. This small quantity alone would be grossly insufficient to meet metabolic demands.

The vast majority of oxygen travels bound to hemoglobin within red blood cells. Each gram of hemoglobin can bind 1.34 milliliters of oxygen when fully saturated. With normal hemoglobin concentration of 15 grams per deciliter and nearly complete arterial saturation, hemoglobin carries approximately 20 milliliters of oxygen per deciliter. Hemoglobin thus increases blood oxygen-carrying capacity nearly 70-fold compared to plasma alone.

The oxygen content equation calculates total oxygen per unit volume of blood. Arterial oxygen content equals 1.34 times hemoglobin concentration times saturation, plus 0.003 times the partial pressure. The hemoglobin-bound component dominates this equation. Changes in hemoglobin concentration or saturation affect oxygen content far more than equivalent changes in partial pressure, explaining why anemia causes tissue hypoxia even with normal arterial oxygen tension.

Oxygen delivery to tissues equals cardiac output times arterial oxygen content. With normal values of 5 liters per minute cardiac output and 20 milliliters of oxygen per deciliter, oxygen delivery approximates 1000 milliliters per minute. This far exceeds normal oxygen consumption of approximately 250 milliliters per minute, providing substantial reserve capacity.

Oxygen consumption can be calculated using the Fick principle as cardiac output times the arteriovenous oxygen content difference. Mixed venous blood normally retains about 15 milliliters of oxygen per deciliter, representing a 5 milliliter per deciliter extraction from arterial blood. The oxygen extraction ratio, the fraction of delivered oxygen actually consumed, normally approximates 25 percent. This extraction can increase substantially during metabolic stress, representing an important compensatory mechanism for maintaining tissue oxygenation.

<image>Panel A: Test tube of blood showing dissolved oxygen in plasma versus hemoglobin-bound oxygen in red blood cells with volumes labeled. Panel B: Oxygen content equation with each term defined and typical values calculated. Panel C: Oxygen delivery cascade from cardiac output through arterial oxygen content to tissue delivery with Fick principle equation. Panel D: Bar graph comparing oxygen delivery to oxygen consumption illustrating reserve capacity and 25% extraction ratio.</image>

VI. Oxygen-Hemoglobin Dissociation Curve

The relationship between oxygen partial pressure and hemoglobin saturation follows a sigmoid curve that has profound physiological significance. The curve's shape and its modulation by various factors optimize oxygen loading in the lungs and unloading in the tissues.

The sigmoid shape arises from cooperative binding between oxygen and hemoglobin's four subunits. Binding of the first oxygen molecule increases the affinity for subsequent molecules, while release of the first molecule facilitates release of the others. This cooperativity creates the steep middle portion of the curve.

Several key points on the curve deserve recognition. At arterial oxygen partial pressure of 100 mmHg, hemoglobin saturation reaches 97 percent, operating on the flat upper portion of the curve. This flat region provides a safety margin: substantial drops in alveolar oxygen partial pressure produce minimal decreases in saturation. The clinically important threshold occurs at 60 mmHg, where saturation drops to 90 percent and the steep portion of the curve begins. Below this point, small decreases in partial pressure cause large decreases in saturation. Mixed venous blood at 40 mmHg partial pressure maintains approximately 75 percent saturation. The P50, defined as the partial pressure at 50 percent saturation, normally equals 27 mmHg and serves as an index of hemoglobin's oxygen affinity.

Multiple factors shift the dissociation curve, affecting how readily hemoglobin binds and releases oxygen. A rightward shift increases P50, indicating decreased oxygen affinity and enhanced oxygen release to tissues. Increased temperature, as occurs in exercising muscle, shifts the curve right, appropriately enhancing oxygen delivery where metabolic demand is highest. Increased carbon dioxide partial pressure and decreased pH both shift the curve right through the Bohr effect, again promoting oxygen release in metabolically active tissues where carbon dioxide and acid accumulate. Increased 2,3-diphosphoglycerate, a red blood cell metabolite that accumulates during chronic hypoxia and anemia, also shifts the curve right.

A leftward shift decreases P50, indicating increased oxygen affinity and impaired tissue oxygen delivery. Decreased temperature, decreased carbon dioxide, and increased pH reverse the Bohr effect. Decreased 2,3-diphosphoglycerate, as in stored blood, shifts the curve left. Carbon monoxide binding creates carboxyhemoglobin that both reduces available hemoglobin for oxygen transport and shifts the curve leftward, doubly impairing tissue oxygenation. Fetal hemoglobin, which cannot bind 2,3-diphosphoglycerate, has an intrinsically left-shifted curve that facilitates placental oxygen transfer. Methemoglobin, with oxidized iron that cannot bind oxygen, also shifts the curve left.

<image>Panel A: Main graph plotting hemoglobin saturation against oxygen partial pressure showing sigmoid curve with key points labeled at arterial, threshold, and mixed venous values. Panel B: Rightward shift arrows with causes including increased temperature, PCO2, and 2,3-DPG and decreased pH. Panel C: Leftward shift arrows with causes including decreased temperature and PCO2, increased pH, fetal hemoglobin, CO, and methemoglobin. Panel D: Inset diagrams illustrating Bohr effect at tissues promoting oxygen release and at lungs promoting oxygen loading.</image>

VII. Carbon Dioxide Transport

Carbon dioxide transport from tissues to lungs involves multiple mechanisms, each contributing to the total carrying capacity of blood. Understanding these mechanisms explains the clinical relationships between ventilation, carbon dioxide levels, and acid-base status.

Carbon dioxide travels in blood in three forms. Dissolved carbon dioxide, following Henry's law, accounts for approximately 7 percent of total transport. Despite this small percentage, dissolved carbon dioxide directly determines the partial pressure and drives diffusion gradients for loading and unloading.

Bicarbonate represents the largest fraction, carrying approximately 70 percent of blood carbon dioxide. The conversion occurs primarily within red blood cells where carbonic anhydrase catalyzes the combination of carbon dioxide and water to form carbonic acid. Carbonic acid rapidly dissociates to hydrogen ion and bicarbonate. Hemoglobin buffers the hydrogen ion, preventing significant acidification. Bicarbonate exchanges for chloride across the red cell membrane through the chloride-bicarbonate exchanger, moving bicarbonate into plasma for transport while maintaining electrical neutrality.

The chloride shift, also called the Hamburger phenomenon, describes this chloride-bicarbonate exchange. In tissue capillaries, as carbon dioxide enters red blood cells and generates bicarbonate, chloride moves in while bicarbonate moves out to plasma. Water follows osmotically, causing slight red cell swelling. In pulmonary capillaries, the process reverses: bicarbonate enters red blood cells, regenerates carbon dioxide for exhalation, and chloride moves back to plasma.

Carbaminohemoglobin contributes approximately 23 percent of carbon dioxide transport. Carbon dioxide binds to terminal amino groups on hemoglobin, not to the heme iron where oxygen binds. This binding does not compete directly with oxygen but is influenced by hemoglobin's oxygenation state through the Haldane effect.

The carbon dioxide dissociation curve has a more linear shape than the oxygen curve over the physiological range. This linearity means that carbon dioxide content changes more proportionally with partial pressure changes, facilitating carbon dioxide elimination through ventilation adjustments.

<image>Panel A: Red blood cell in tissue capillary showing carbon dioxide entry, carbonic anhydrase activity, and chloride-bicarbonate exchange with transport percentages. Panel B: Chloride shift at tissue capillary with CO2 loading, chloride entry, bicarbonate exit, and RBC swelling. Panel C: Reverse chloride shift at pulmonary capillary with CO2 unloading and RBC shrinking. Panel D: CO2 dissociation curve with linear shape and Haldane effect showing deoxygenated hemoglobin carrying more CO2.</image>

VIII. Bohr and Haldane Effects

The Bohr and Haldane effects describe reciprocal interactions between oxygen and carbon dioxide binding to hemoglobin. These complementary phenomena optimize gas exchange at both tissue and pulmonary capillary levels.

The Bohr effect describes how carbon dioxide and hydrogen ion concentration affect hemoglobin's oxygen affinity. Increased carbon dioxide and the resultant decrease in pH reduce hemoglobin's affinity for oxygen, shifting the dissociation curve rightward. This effect has clear physiological benefit at the tissue level. Metabolically active tissues produce carbon dioxide and organic acids, creating a local environment of elevated carbon dioxide partial pressure and reduced pH. The Bohr effect enhances oxygen release precisely where oxygen consumption is greatest.

The reverse Bohr effect operates in the lungs. As carbon dioxide is eliminated and pH rises, hemoglobin's oxygen affinity increases. This leftward shift promotes oxygen loading onto hemoglobin at the gas exchange surface, optimizing saturation before blood returns to the systemic circulation.

The Haldane effect describes the reciprocal phenomenon: hemoglobin's oxygenation state affects its capacity to carry carbon dioxide. Deoxygenated hemoglobin binds carbon dioxide more avidly than oxygenated hemoglobin, both as carbaminohemoglobin and through enhanced hydrogen ion buffering that shifts the bicarbonate equilibrium.

At the tissue level, oxygen release from hemoglobin creates deoxyhemoglobin, which can then bind more carbon dioxide and hydrogen ions. This facilitates carbon dioxide uptake precisely where carbon dioxide is produced. At the pulmonary level, oxygen binding creates oxyhemoglobin, which releases carbon dioxide and hydrogen ions, facilitating carbon dioxide elimination.

These coupled effects work synergistically. In tissues, carbon dioxide production simultaneously promotes oxygen release through the Bohr effect while oxygen release promotes carbon dioxide uptake through the Haldane effect. In the lungs, oxygen uptake promotes carbon dioxide release while carbon dioxide elimination promotes oxygen uptake. The two effects create a positive feedback loop that enhances gas exchange efficiency at both sites.

<image>Panel A: Tissue capillary events showing metabolizing cells producing CO2 and acid triggering Bohr effect with right-shifted curve promoting oxygen release. Panel B: Haldane effect at tissues where oxygen release enables deoxyhemoglobin to bind more CO2 and hydrogen ions. Panel C: Pulmonary capillary events showing reverse Bohr and Haldane effects with oxygen loading and CO2 release. Panel D: Central diagram showing circular reinforcing relationship between both effects at both locations with hemoglobin color changes.</image>

IX. Causes of Hypoxemia

Hypoxemia, defined as reduced arterial oxygen partial pressure, results from one of five pathophysiological mechanisms. Distinguishing among these mechanisms guides appropriate diagnosis and treatment.

Low inspired oxygen partial pressure occurs at high altitude, where barometric pressure decreases while the fractional concentration of oxygen remains 21 percent. It also occurs in confined spaces where oxygen is consumed or displaced by other gases. The alveolar-arterial gradient remains normal because gas exchange is intact; only the driving pressure for oxygen is reduced. Supplemental oxygen rapidly corrects hypoxemia from this cause.

Hypoventilation reduces alveolar ventilation, allowing carbon dioxide to accumulate and, through the alveolar gas equation, reducing alveolar oxygen partial pressure. Causes include central nervous system depression, neuromuscular weakness, and severe airway obstruction. The alveolar-arterial gradient remains normal because the gas exchange membrane functions normally. Arterial carbon dioxide rises in proportion to the decrease in oxygen. Supplemental oxygen corrects the hypoxemia, though the underlying hypoventilation and hypercapnia require separate intervention.

Ventilation-perfusion mismatch represents the most common cause of hypoxemia in clinical practice. Some lung regions receive more perfusion relative to ventilation, functioning as partial shunts that contribute poorly oxygenated blood. Other regions receive more ventilation relative to perfusion, functioning as partial dead space that wastes ventilation. The net effect reduces arterial oxygenation and increases the alveolar-arterial gradient. Supplemental oxygen effectively treats this hypoxemia because even poorly ventilated units receive some additional oxygen.

Diffusion impairment occurs when the blood-gas barrier thickens or when pulmonary capillary transit time decreases sufficiently that oxygen cannot equilibrate. Interstitial lung diseases represent classic examples. The alveolar-arterial gradient increases. Hypoxemia may manifest only during exercise initially, when shortened transit time combines with increased oxygen demand. Supplemental oxygen corrects this hypoxemia by increasing the diffusion gradient.

Shunt refers to blood that completely bypasses ventilated alveoli. Anatomic shunts include intracardiac defects with right-to-left flow and pulmonary arteriovenous malformations. Physiologic shunts occur when alveoli are completely filled with fluid or collapsed, as in pneumonia, atelectasis, or acute respiratory distress syndrome. The alveolar-arterial gradient increases substantially. Crucially, supplemental oxygen provides minimal benefit because shunted blood never contacts ventilated alveolar gas regardless of its oxygen content. This poor response to oxygen distinguishes shunt from other causes of hypoxemia.

The shunt equation quantifies the fraction of cardiac output bypassing gas exchange. This calculation compares the oxygen content difference between ideal pulmonary capillary blood and actual arterial blood to the difference between ideal capillary blood and mixed venous blood. A rough clinical estimate relates arterial oxygen partial pressure on 100 percent inspired oxygen to shunt fraction: values above 500 mmHg suggest less than 5 percent shunt, while values below 150 mmHg indicate greater than 20 percent shunt.

<image>Panel A: Flowchart beginning with low PaO2 branching on A-a gradient to normal or increased categories. Panel B: Normal gradient causes including low FIO2 and hypoventilation with distinguishing features and oxygen response. Panel C: Increased gradient causes including V/Q mismatch, diffusion impairment, and shunt with oxygen response characteristics. Panel D: Summary table of five causes with A-a gradient, PaCO2, and oxygen response columns highlighting shunt's poor response.</image>

X. Clinical Applications

Clinical assessment of gas exchange integrates physiological principles with practical diagnostic tools. Pulse oximetry, arterial blood gas analysis, and understanding of specific toxicities enable appropriate patient evaluation and management.

Pulse oximetry estimates arterial oxygen saturation by measuring differential light absorption through perfused tissue. The device distinguishes oxyhemoglobin, which absorbs more infrared light, from deoxyhemoglobin, which absorbs more red light. The ratio of absorption provides a continuous, noninvasive estimate of saturation.

Pulse oximetry has important limitations. Accuracy degrades below 80 percent saturation. Motion artifact and poor perfusion reduce signal quality. Most significantly, pulse oximetry cannot detect carboxyhemoglobin or methemoglobin, which absorb light differently and may produce falsely normal or falsely low readings respectively. In carbon monoxide poisoning, pulse oximetry may read normally despite severely compromised oxygen delivery.

Arterial blood gas analysis directly measures pH, oxygen partial pressure, and carbon dioxide partial pressure in arterial blood. From these values, bicarbonate concentration and oxygen saturation can be calculated or measured. Normal ranges include pH 7.35 to 7.45, carbon dioxide partial pressure 35 to 45 mmHg, oxygen partial pressure 80 to 100 mmHg, bicarbonate 22 to 26 milliequivalents per liter, and saturation 95 to 100 percent.

Carbon monoxide poisoning exemplifies a gas exchange emergency where standard monitoring may mislead. Carbon monoxide binds hemoglobin with 200 times greater affinity than oxygen, forming carboxyhemoglobin incapable of oxygen transport. Additionally, carboxyhemoglobin shifts the oxygen-hemoglobin dissociation curve leftward, impairing oxygen release from the remaining functional hemoglobin. Patients may appear pink and have normal pulse oximetry readings while suffering severe tissue hypoxia. Diagnosis requires co-oximetry, which measures carboxyhemoglobin directly. Treatment involves high-flow oxygen to displace carbon monoxide, with hyperbaric oxygen indicated for severe cases.

Methemoglobinemia occurs when hemoglobin iron is oxidized from the ferrous to ferric state. Ferric iron cannot bind oxygen. Additionally, methemoglobin shifts the dissociation curve leftward, impairing oxygen release from functional hemoglobin. Common causes include exposure to oxidizing drugs such as dapsone, benzocaine, and nitrites. Pulse oximetry characteristically reads approximately 85 percent regardless of actual saturation, as methemoglobin absorbs light equally at both wavelengths. Co-oximetry confirms the diagnosis. Treatment with methylene blue reduces the oxidized iron, restoring normal hemoglobin function.

<image>Panel A: Pulse oximetry with finger probe showing two-wavelength principle and limitations including poor accuracy, motion artifact, and inability to detect dyshemoglobins. Panel B: Arterial blood gas report with normal values, alveolar gas equation, and A-a gradient calculation with interpretation guidelines. Panel C: Carbon monoxide poisoning showing normal SpO2 with low oxygen content, symptoms, and treatment options. Panel D: Methemoglobinemia showing characteristic SpO2 of 85%, chocolate-brown blood, drug causes, and methylene blue treatment with co-oximetry examples.</image>

Summary

Gas exchange in the lungs depends on partial pressure gradients established according to Dalton's law and the alveolar gas equation. Alveolar oxygen partial pressure normally approximates 100 mmHg after accounting for humidification and carbon dioxide exchange. The alveolar-arterial gradient, normally 5 to 15 mmHg, increases when ventilation-perfusion mismatch, shunt, or diffusion impairment interfere with gas transfer, while remaining normal in hypoventilation and low inspired oxygen.

Diffusion across the blood-gas barrier follows Fick's law, depending on surface area, barrier thickness, partial pressure gradient, and diffusion coefficient. The DLCO measurement quantifies gas transfer efficiency and decreases in emphysema, fibrosis, and pulmonary vascular disease.

Oxygen transport occurs primarily bound to hemoglobin, with oxygen content calculated from hemoglobin concentration, saturation, and dissolved oxygen. Oxygen delivery depends on both cardiac output and oxygen content, while oxygen consumption reflects the product of cardiac output and arteriovenous oxygen content difference.

The oxygen-hemoglobin dissociation curve has a sigmoid shape with a P50 of 27 mmHg. Rightward shifts from increased temperature, increased carbon dioxide, decreased pH, and increased 2,3-DPG enhance tissue oxygen delivery. Leftward shifts from opposite conditions, carbon monoxide, and fetal hemoglobin impair tissue oxygenation.

Carbon dioxide transport occurs as dissolved gas (7 percent), bicarbonate (70 percent), and carbaminohemoglobin (23 percent). The Bohr and Haldane effects describe reciprocal interactions whereby carbon dioxide promotes oxygen release and deoxygenation promotes carbon dioxide uptake.

The five causes of hypoxemia differ in alveolar-arterial gradient and response to supplemental oxygen. Low inspired oxygen and hypoventilation maintain normal gradients. Ventilation-perfusion mismatch, diffusion impairment, and shunt increase the gradient, but only shunt responds poorly to supplemental oxygen.

Key Terms

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