Oxygen transport and gas exchange during exercise in health and disease

The oxygen transport pathway  describes the physiological steps that bring atmospheric oxygen into the body where it is delivered and consumed by metabolically active tissue. 

Oxygen molecular biology requires a transport and gas exchange system to move oxygen from the air to the tissues and support continuous generation of adenosine triphosphate via oxidative metabolism. 

The oxygen transport pathway  sustains vast increases in oxidative metabolism during exercise, high altitude, and insults to key elements of the system associated with disease. 

The partial pressure of oxygen in air at sea level is ∼150 mm Hg, but in the mitochondria of exercising skeletal muscle the partial pressure of oxygen can be ∼100-fold lower without significant engagement of anaerobic energy metabolism. 

In healthy young adults, resting metabolic rate is approximately 3.5 mL O2/kg of body weight/min, and it can increase to more than 90 mL O2/kg/min in at least some of the most aerobically trained elite athletes.

In patients with diseases that hinder the ability to take up, transfer, and utilize oxygen, there are physiologic changes including  tachypnea or tachycardia.

In such impaired patients even modest levels of exercise in chronic obstructive pulmonary disease or congestive heart failure results in physiologic changes.


In addition there is a marked redistribution of blood flow away from inactive tissues to the active muscles.

The oxygen cascade is an anatomical map starting with the extra- and intrathoracic large airways and ending in the mitochondria. 

The lungs and alveolar pulmonary capillary membranes, are associated with the right and left heart by connections in series and pumps blood across the interface of the pulmonary capillaries and alveoli. 

Oxygenated blood leaves the left ventricle and via the systemic circulation oxygen is distributed to the microcirculation in the peripheral organs for use by the tissues. 

The venous system then returns the deoxygenated blood back to the right heart and the cycle continues. 

The overall behavior of the cascade is described via the Fick equation which simply states oxygen consumption = cardiac output × arteriovenous oxygen difference.

Resting oxygen consumption is 3.5 mL O2 kg-1 · min-1 or 1 metabolic equivalent (MET). 

A 4-MET peak exercise capacity (∼14 mL O2 · kg-1 · min-1) is generally thought to be required for most humans to successfully engage in activities of daily living without limitation.

During heavy exercise in untrained non-athletic humans, oxygen consumption can increase to 10 to 12 METS. 

Many young, trained healthy humans are able to sustain 15 METs with levels as high as 20-25 METs seen in elite endurance athletes.

In the oxygen cascade convective and diffusive steps alternate. 

There is a bulk transport of oxygen followed by diffusion across a membrane and then uptake by a tissue. 

Minute ventilation is a convective action that moves volumes of oxygen-containing air in and out of the lungs. 

The composition of the air changes as it is mixed with the gases already in the lungs. 

There is no gas exchanged until there is a diffusive step at the interface of the alveolar/pulmonary capillary membrane. 

There, oxygen is transferred to the red blood cells, and then distributed via the large blood vessels to the microcirculation in another convective step. 

Oxygen leaves the microcirculation by diffusion across the capillary tissue interface. 

Once in the tissue, it is used by the mitochondria for the purposes of oxidative metabolism. 

The partial pressure of oxygen decreases from around 150 mm Hg in inhaled air to potentially very low pressures in the tissues. 

Mitochondrial pO2 values in exercising skeletal muscles may be less than 1 mm Hg.

The oxygen molecule is nonpolar, and its solubility in water is poor. 

Oxygen’s low solubility means that plasma itself only carries ∼0.5 vol% of oxygen.

This minimal amount of dissolved oxygen  makes changes in oxygen demand unattainable. 

As an example, O2 of 3 L · min-1 would require a cardiac output of 660 L · min-1 without the hemoglobin in erythrocytes as an oxygen carrier. 

The  low solubility of oxygen in tissue means that the low concentrations of oxygen necessitate short diffusion distances to achieve the gradients required to supply the mitochondria in working muscle. 

If the oxygen consumption in muscle performing heavy exercise is 35 mL · O2 100 cm3 tissue-1 · min-1, which about a 100-fold increase above resting, the diffusion distance can be calculated to be at most 40 μm.

Oxygen must be brought by convection to within this distance of every point in the tissue, requiring a dense mesh of capillaries in the microcirculation needed to achieve this condition. 

The observed fiber diameters of ∼50 μm in skeletal muscle are consistent with this estimate of the maximum diffusion distance to sustain activity.

The low solubility of oxygen in plasma and alveolar tissue also limits diffusive exchange in the lung., 

In the lung, however, very large surface area for gas exchange in the healthy lung, combined with a very short diffusion distance between alveoli and blood (∼2 μm) provides adequate diffusion.

Healthy young humans, at rest, have a minute ventilation is 5 to 10 L/min with breathing frequencies of around 10 breaths per minute and tidal volumes of 0.5 to 1.0 L. 

The minute ventilation range is dictated by height/weight, but other factors can influence this.

The diaphragm is the primary muscle involved in moving air at rest. 

During exercise or excessive respiratory muscle work, other respiratory muscles such as the intercostals and sternocleidomastoid, become progressively more active, along with the diaphragm. 

Because of the in-out nature of breathing, gas is not exchanged in the large airways and is mixed with alveolar gas. 

The dead space in the large airways along with the reciprocating nature of ventilation explains the drop in oxygen partial pressure from the atmosphere to the alveolar gas. 

Alveolar ventilation is always less than minute ventilation.

Ventilation is driven by complex neural circuits located in the brainstem, including a central pattern generator and chemosensor along with feedback from peripheral sensory nerves located in the carotid bodies, aortic arch, muscles, and lungs.

During rest and at low altitude, the primary feedback mechanisms that control minute ventilation are related to CO2 and pH. 

Hypoxia caused by either high altitude or disease can engage the carotid chemoreceptors which are powerful drivers of increased minute ventilation.

All anatomical and nervous tissue  elements involved with ventilation and its regulation can be subject to one or more disease processes: 

Lung diseases that increase dead space so that with each breath there is less gas exchange in the alveoli and more so-called wasted or dead space ventilation. 

Neurological and neuromuscular diseases that affect brainstem control of breathing and/or diaphragm function. 

Peripheral chemoreceptors that sense CO2, pH, and O2  may  be altered in many disease processes. 

In congenital central hyperventilation syndrome, also known as Ondine’s curse, requires the patient to engage in conscious efforts to breathe even at rest.

Each breath temporal pattern at rest: inspiration takes a second or more and is accomplished almost exclusively by contraction of the diaphragm, whereas expiration at rest is passive and occurs due to the elastic recoil properties of the lung and chest wall.

At rest, the tidal volume of each breath is roughly 500 mL. 

About 150 to 200 mL of this breath represents dead space with 300 to 350 mL of alveolar ventilation available for gas exchange. 

Most of the dead space is anatomical in nature and remains unchanged throughout exercise. 

Each resting breath is roughly 10% of vital capacity. 

With increased exercise intensity there is greater necessity for greater ventilation: tidal volume  increases first and plateaus at ∼40% to 60% of vital capacity and ∼60% of peak exercise capacity. 

Tidal volume increase is achieved by using both inspiratory and expiratory reserve volume and optimizes alveolar ventilation and minimizes mechanical work.

Exercise optimizes alveolar ventilation is because anatomical dead space is fixed and increasing tidal volume minimizes the dead space to tidal volume ratio, thus improving alveolar ventilation. 

Once tidal volume plateaus, greater breathing frequency plays a greater role in increasing total ventilation. 

During exercise, minute ventilation to rise to values of 90 to 100 L/min or more in healthy young subjects.

With very-high volumes of ventilation described above, inspiratory time progressively decreases from a second or more to as little as 0.5 seconds, but expiration becomes active and expiratory time decreases dramatically. 

Elite athletes may be observed to have 60 breaths per minute with an inspiratory and expiratory time of 0.5 seconds each and a tidal volume of 2.5 to 3.5 L per breath. 

Exercise hyperpnea occurs through feedback from the peripheral chemosensors and also types III and IV sensory afferents in the contracting respiratory and skeletal muscles.

There is evidence that oscillations in pH/CO2 may contribute to the hyperpnea of exercise.

The high respiratory frequencies, and flows, and tidal volumes of  heavy exercise cause some athletes to encroach upon the maximal capacity of their expiratory flow volume loops.

At the maximal capacity of expiratory flow volume loops expiratory flow is constrained by airway anatomy and elastic recoil such that even with additional respiratory muscle effort, higher expiratory flow cannot be attained at a given lung volume. 

When this occurs during exercise it can lead to relative hypoventilation, exercise-induced hypoxemia, and CO2 retention. 

Expiratory flow limitation and relative hyperinflation are especially prominent in healthy older individuals during exercise as aging reduces the maximal flows, yet the metabolic demands still require a considerable ventilation.

Unlike the cardiovascular or musculoskeletal systems, the pulmonary system shows minimal to no improvement with physical training.

The increasing demands placed on the respiratory system from physical training are met with a static capacity

Expiratory flow limitation and/or an increased operating lung volume, is seen in individuals with structural lung disease such as chronic obstructive pulmonary disease.

Older  healthy individuals have reduced expiratory flow, which results in flow limitation being common and often severe.

Structural factors in the lung limit peak flow during heavy exercise can limit exercise tolerance or performance.

The diaphragm and expiratory muscles can fatigue with some forms of exercise.

In the absence of exercise does not appear to elicit diaphragm fatigue.

There appears to be a need for the metabolic changes and potentially blood flow redistribution that occurs with exercise. 

Fatigue of the respiratory muscles impact performance.

Respiratory muscle fatigue is implicated in forms of respiratory failure and may play a role in the ability to wean patients from mechanical ventilation.

Genome wide association studies have failed to explain much if any of the population variability in human lung function. 

At rest, the partial pressure of oxygen in the venous blood entering the lungs is ∼40 mm Hg and 75% saturated while the partial pressure of oxygen in the blood leaving the lungs is ∼90 to 100 mm Hg and 95% to 98% saturated. 

Oxygen cascade:

Ventilation takes oxygen from the air and delivers  it to the alveoli. 

Oxygenation of the blood, with its diffusion across the alveolar pulmonary capillary membrane and binding  to hemoglobin in red blood cells. 

Compared with CO2, oxygen is somewhat less diffusible and it takes about 0.3 seconds for the oxygen tension in the blood flowing through the lungs to equilibrate with the oxygen levels in the alveolar gas. 

There is normally at rest a small alveolar-to-arterial O2 gradient of 1 to 5 mm Hg.

This mild gas exchange impairment  is most likely the result of ventilation-perfusion mismatch or a small amount of shunted blood.

The most notable diagnoses associated with arterial hypoxemia in patients are various forms of interstitial lung disease such as idiopathic pulmonary fibrosis. 

Chronic inflammation increases the thickness of the alveolar pulmonary capillary membrane, which limits the diffusion of oxygen from the alveoli to the blood. 

Interstitial lung disease and COPD are commonly associated with ventilation-perfusion mismatches that are related to disease severity and the inherent heterogeneity of the disease.

Arterial hypoxemia can be caused by shunts, as seen in congenital heart disease when some of the venous blood is not pumped through the lungs and is directed back to the left heart.

Hemoglobinopathies and conditions like carbon monoxide poisoning, limit the ability of the red blood cells to bind oxygen once it has diffused across the pulmonary capillary membrane.

All individuals develop some degree of gas exchange impairment during exercise through ventilation-perfusion mismatch and diffusion limitation, with the former is more pronounced early on in exercise.

In the absence of disease, environmental hypoxia, and with the exception of heavy exercise in some elite athletes, the blood is successfully oxygenated at the alveolar pulmonary capillary interface. 

At the left heart it is pumped to the systemic circulation by the left ventricle. 

Systemic oxygen delivery is the simple product of cardiac output and arterial oxygen content. 

The determinants of cardiac output are heart rate × stroke volume. 

Heart rate is determined by the intrinsic cardiac pacemaker activity of the heart along with the activities of the cardiac parasympathetic and sympathetic nerves. 

The determinants of stroke volume include preload, afterload, and contractility along with the chamber size of the ventricle.

Oxygen is not very soluble in blood, arterial oxygen content is essentially the product of blood hemoglobin concentration and arterial saturation based on the properties of the O2-hemoglobin dissociation curve.

At rest, cardiac output is roughly 5 L/min and arterial oxygen content is roughly 20 mL per 100 mL of blood. 

About 1 L of oxygen leaves the left ventricle each minute at rest in a generic healthy young person. 

In the absence of any disease, females typically have ∼10% lower hemoglobin concentrations than males of similar size and stature.

Systemic oxygen delivery at rest is about 1 L/min and systemic oxygen consumption is on the order of 250 to 350 mL/min at rest. 

Therefore, excess oxygen is delivered to the peripheral tissues in resting humans: cardiac output can decline markedly and still supply sufficient oxygen delivery provided the extraction of oxygen from the arterial blood is able to compensate for any fall in cardiac output. 

Compensating  a reduction in cardiac output explains why humans are able to survive marked reductions in oxygen delivery during acute conditions such as blood loss and when left ventricular function is compromised during chronic forms of heart failure.

During exercise, cardiac output can increase roughly four-fold in young, healthy humans: primarily due to a three-fold increase in heart rate from 60 to 70 beats/min at rest to around 200 beats/min during maximal exercise. 

This increase in heart rate is accompanied by a 20% or 30% increase in stroke volume. 

With exercise the increase in heart rate occurs because parasympathetic tone to the heart is withdrawn and sympathetic activity to the heart increases dramatically.

With exercise stroke volume increases as a result of increased venous return from the periphery.

With exercise skeletal and respiratory muscle pump blood to the central circulation along with increased cardiac contractility caused by activation of the cardiac sympathetic nerves and circulating catecholamines. 

These factors leads to a cardiac output of 20 L/min with a systemic oxygen delivery of 4 L/min to support an oxygen consumption of about 3 L/min in young men.

In contrast to the case at rest, a much higher fraction (∼75 %) of the oxygen delivered from the heart to the periphery is used by the tissues with exercise.

In elite athletes, stroke volume can be double that seen in average humans with peak cardiac outputs of 35 to 40 L/min or more have been observed.

This means that 7 to 8 L of oxygen leave the heart each minute to support a systemic oxygen uptake as high as 6 or even 7 L/min. 

In congestive heart failure, the heart rate can rise, unless compromised by damage in the cardiac conduction system or drugs, but. stroke volume is reduced and systemic oxygen delivery is very limited.

There  is a linear relationship between peak cardiac output and peak oxygen consumption ranging from very low values in patients with congestive heart failure or conditions such as mitral stenosis to very high values in the elite athletes.

Activation of the sympathetic nervous system leads to a redistribution of blood flow away from inactive and relatively over-perfused tissues such as the kidney and liver so that a very high fraction of cardiac output can be directed to the exercising skeletal muscles. 

During heavy exercise, visceral blood flow can be reduced by 75% compared with values measured during rest.

In healthy individuals, during dynamic exercise there is an intensity dependent rise in systolic blood pressure with minimal, if any, change in diastolic pressure. 

The rise in systolic pressure is largely due to the enhanced contractility and cardiac output.

 The maintenance of diastolic blood pressure with exercise is due to the progressive fall in total peripheral resistance. 

The mean arterial pressure and its regulation is controlled,  in part,  by arterial and cardiopulmonary baroreceptors, which continuously monitor blood pressure/volumes and alter autonomic activity to ensure arterial pressure is maintained within a narrow range. 

With an increase in arterial blood pressure, there is a reduction in sympathetic activity and increase in parasympathetic activity with the end result being a lowering of blood pressure to previous levels.

Arterial baroreceptors are functional during exercise, but are reset to defend a higher arterial blood pressure.

As exercise intensity increases, the operating point of the baroreceptors also increases.

Hemoglobin in red blood cells is responsible for carrying oxygen in blood. 

With anemia reduced hemoglobin content can potentially compromise oxygen delivery. 

Normally hemoglobin content is 12 to 16 g/dL of blood in healthy young women and men. 

At rest, anemia is associated with an increase cardiac output so that oxygen delivery remains constant in the face of mild anemia. 

During severe anemia, cardiac output can double or even triple, and increased oxygen extraction also operates to preserve tissue oxygenation when hemoglobin content are reduced to values of ∼ 5 g/dL.

During anemia there is a shift in the oxygen hemoglobin dissociation curve which facilitates the off-loading of oxygen at the tissues. 

When anemic subjects are not hypoxic, desaturated venous blood can be re-saturated in the pulmonary capillaries.

Additionally, in many tissues, oxygen delivery is not compromised until hematocrit values exceed ∼70%.

Blood volume is also a determinant of oxygen delivery. 

One’ total blood volume influences filling pressures in the heart, and as a result can also affect cardiac output. 

Exercise training can increase total blood volume and red cell mass.

Total body hemoglobin and red blood cell mass are key determinants of maximal exercise capacity. 

This relationship along with the relationship between cardiac output and peak exercise capacity highlights the central role of oxygen delivery in exercise, especially heavy exercise: 

the use of transfusion or erythropoietin increase performance in sport.

The oxygen-hemoglobin dissociation curve (ODC) describes the curvilinear relationship between the partial pressure of oxygen and the fraction of hemoglobin that is saturated with oxygen in the blood. 

The oxygen-hemoglobin dissociation curve (ODC) is a result of cooperative interactions of the four hemoglobin chains that make up the quaternary structure of hemoglobin and the way their affinity for oxygen changes as oxygen is loaded and unloaded from them. 

ODC is influenced by pH, temperature, and CO2 — and 2-3 bisphosphoglyceric acid.

Lower pH, higher temperature, and higher CO2 causes a decrease in affinity or right shift and making it easier to unload oxygen at the tissues, especially active skeletal muscle. 

ODC property of hemoglobin facilitates oxygen delivery to tissues when demand is high as in exercising muscles, or when there is tissue ischemia. 

Hemoglobin is almost completely saturated at relatively modest partial pressures of oxygen, and unless an individual is at high altitude or has some pathophysiologic condition in the lung that reduces alveolar PO2 or pulmonary diffusion, there is typically adequate partial pressure of oxygen to almost fully oxygenate even right shifted hemoglobin as it passes through pulmonary capillaries. 

A right shift in the ODC is generally protective against hypoxia.

At rest, the majority of the 5 L of cardiac output is directed to the brain, heart, and visceral organs and oxygen extraction in the visceral organs is low. 

During exercise, the skeletal muscle metabolic rate increases as does its relative share of blood flow. 

During exercise in a young healthy individual, nearly 85% of cardiac output is directed to active skeletal muscles while blood flow to the heart increases, cerebral blood flow is maintained or increases slightly and visceral blood flow is reduced dramatically.

This blood flow redistribution occurs as a result of local vasodilation in the contracting muscle coupled with increased global sympathetic activity. 

The  increased sympathetic activity that does not result in vasoconstriction in the active muscles is termed “functional sympatholysis.

Maximal muscle blood flow conductance is restrained during maximal exercise.

When exercise is in isolation, such as a single leg, maximal blood flow and vascular conductance is greater compared with when multiple muscle groups are active. 

This vascular constraint preserves arterial blood pressure because the maximal dilatory capacity would outstrip the cardiac output’s ability to compensate. 

Sympathetic restraint of maximal conductance occurs mainly at or around maximal exercise in healthy subjects.

In chronic heart failure this redistribution of blood flow during exercise occurs at much lower intensities, about 60% peak work.

A mismatch of vasodilation and cardiac output can been seen in sepsis where cardiac output can be high and there is marked peripheral vasodilation with  a limited vasoconstrictor response to catecholamines. 

During exercise, vasodilation with limited vasoconstrictor responses in skeletal muscle drives blood flow to the contracting muscles while preserving blood pressure.

In sepsis, inappropriate responses drive blood flow to tissues out of proportion to their demand for oxygen and threaten blood pressure.

Although not all skeletal muscle can be maximally perfused during intense exercise: respiratory muscles appear to receive adequate blood flow at the expense of other skeletal muscles via sympathetically mediated redistribution.

During intense exercise oxygen cost of breathing, the respiratory muscles will command 10% to 15% of total cardiac output, at the expense of other active skeletal muscles. 

The microcirculation adjusts flow and oxygen delivery by actively varying vessel diameters in a process termed blood flow regulation to maintain an adequate tissue PO2.

Capillaries lack smooth muscle and have a limited ability to control their diameter.

Hypoxia detected at the capillary level generates a signal that is conducted upstream to feeding arterioles that vasodilate, resulting in increased flow and oxygen delivery.

If hypoxia persists, long-term changes in oxygen pressures lead to remodeling of the vascular network: structural adaptation of existing vessels and formation of new vessels.

In small vessels such as capillaries, the blood cells tend to migrate toward the center, surrounded by a plasma sleeve.

The viscosity of blood in small vessels becomes diameter-dependent as well as hematocrit-dependent,

This separation is the reason blood cells and plasma tend to distribute unevenly at bifurcations, leading to variations in hematocrit throughout the network. 

This separation can result in capillaries with low hematocrit or even plasma channels carrying no blood cells at all, which can lead to local areas of hypoxia: areas of hypoxia that persist can lead to organ damage or even failure.

The interface of the capillaries and tissues is where oxygen diffuses from the blood to the tissues. 

Off-loading of oxygen from hemoglobin at the local tissue site is facilitated by the oxygen disassociation curve and physical factors: the thickness of membranes, the number of capillaries around a given cell, and the diffusion distance path of oxygen from the capillaries to the mitochondria. 

Poorly functioning microcirculation and capillaries can limit vasodilation and delivery of red blood cells to metabolically active tissues. 

This can be seen in diabetes and inflammatory diseases with notable effects on tissues such as the retina, heart, and kidney.

The fundamental response to exercise is increased ventilation and cardiac output, both of which ensure sufficient oxygen is taken up at the lung and transported to the metabolically active tissue. 

In disease that hinders the ability to uptake oxygen, the typical response is for ventilation and cardiac output to increase to compensate and maintain homeostasis. 

Specific diseases, may stress one part of the oxygen cascade to a point where the regulatory mechanism is at its sustainable limit:

severe interstitial lung disease where it may not be feasible to sustain the increased ventilation required to maintain arterial oxygenation

Such pathology actually overlaps with elite some highly trained athletes have such a metabolic demand for oxygen uptake that they are unable to sustain the required pulmonary ventilation to achieve this. 


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