Chapter 11 Respiration

The fundamental concept for respiration is that the concentration of $O_2$ and $C{O}_2$ dissolved in the fluid the ECF (plasma) creates partial pressure gradients of $O_2$ and $C{O}_2$ to create pressure driven flow. Pressure driven flow for gases is called diffusion. There is a relationship between concentration and partial pressure. The higher the concentration of a particular molecule in a gas (as a fraction of all the molecules), the higher the partial pressure.¹¹1Note: if there is a higher concentration but all gases in the mixture have also increased their concentration so that the fraction of any particular gas is the same, the the partial pressure is higher because the total pressure is higher. Specifically, the partial pressure of a particular molecule in a gas is proportional to the quantity of particular molecules as a fraction of the total molecules of the gas multiplied by the total pressure of the gas. The partial pressure of $O_2$ being:

$$P{O}_2=F{O}_2\times TotalPressure(mmHg)$$

(11.1)

Where $F{O}_2$ is the fraction of $O_2$ in the gas resulting in total pressure ($mmHg$). The fraction of air in the environment (atmoshere, atm) that is $O_2$ is 0.21 (21%). Air in the environment is inspired so it is called the fraction of inspired $O_2$ ($F_i{O}_2$). At sea level the total air pressure is 760 $mmHg$ (barometric pressure). Therefore, the $P_{atm}{O}_2=0.21\times 760mmHg$, so $P_{atm}{O}_2=159.5mmHg$.

Figure 11.1 is copied from Chapter 7. The gradients for $O_2$ and $C{O}_2$ are partial pressures ($P{O}_2$ and $PC{O}_2$). The partial pressure of each compartment is further noted with a subscript, with partial pressure of $O_2$ in the cell being $P_c{O}_2$ and in the tissue as $P_t{O}_2$. The gradient for $P{O}_2$ is from the arterial end of the capillary (partial pressure of arterial blood, $P_a{O}_2\approx 100mmHg$) into the tissue ($P_t{O}_2\approx 40mmHg$), and into the cell ($P_c{O}_2\approx 20mmHg$). Of these values the $P_c{O}_2$ is most variable and depends on the rate of utilization of $O_2$ in the mitochrondria (aerobic metabolism). The partial pressure driven diffusion of cellular respiration relies on the continuous use of $O_2$ in the mitochondria; and the continuous use of $O_2$ in the mitochondria depends on the availability of $O_2$ diffusing in from the arterial blood in the capillary. If aerobic metabolism in a cell stopped then the $P_c{O}_2$ would quickly equilibrate with the $P_a{O}_2$ at 100 $mmHg$. If blood flow stopped (ischemia), or if there was a lower partial pressure of $O_2$ in the arterial blood ($P_a{O}_2\le 60mmHg$) (hypoxemia) then diffusion of $O_2$ would be slower and the rate of aerobic metabolism would be limited (hypoxia). The difference between arterial blood $P_a{O}_2$ and the venous blood $P_v{O}_2$ is due to diffusion of $O_2$ out of capillary blood into the interstitial fluid and cells. Internal respiration creates venous blood (blood with less $O_2$ and more $C{O}_2$ than arterial blood).

The factors influencing diffusion are provided in the following equation:

$$\dot{D}=\frac{A}{T}\times d\times (P_1-P_2)$$

(11.2)

• •

  $\dot{D}$ is diffusion as a rate (amount of substances over time)

• •

  A is the surface area that diffusion can occur

• •

  T is the thickness of the membrane through which diffusion can occur

• •

  d is a diffusion coefficient that is related to the solubility and molecular weight of the substance diffusing

• •

  $P_1-P_2$ is the partial pressure gradient ($\mathrm{\Delta }P$)

Equation 11.2 assumes that the membrane is permeable to the substance being diffused. Which means there are no membrane restrictions to diffusion other than the surface area or thickness in the equation. Since that is the situation for the diffusion of $O_2$ and $C{O}_2$ across the cell membrane, capillary membrane and alveolar-capillary membrane this assumption is appropriate for respiration.²²2Note, if the membrane was only semi-permeable to $O_2$ and $C{O}_2$ then to model the situation more accurately the equation would need a permeability coefficient, as we have seen for filtration across the capillary.

{tips}

Only for those interested in what happened to Ohm’s law Equation 11.2 appears to jump away from the convention of Ohm’s law. But it’s in there.
Resistance for diffusion is:

$$R_D=\frac{T\times MW}{A\times S}$$

(11.3)

With $T$ representing the thickness of the membrane; MW the molecular weight; A the surface area; and S the solubility coefficient for the molecule. In Equation 11.2 the diffusion coefficient includes the solubility and the molecular weight. When you consider them separately, along with thickness and surface area, there’s a parameter for resistance.
So that:

$$\dot{D}=\frac{\mathrm{\Delta }P}{R_D}$$

(11.4)

So, no worries - Ohm’s law is in there underlying pressure driven flow.

The diffusion of $O_2$ into the tissue (interstitial space) reduces the partial pressure of $O_2$ in the blood (See Figure 11.2). The $P{O}_2$ at the venous end of the capillary is the $P_v{O}_2$ and reflects how much $O_2$ has been taken in by the cells. An important concept is that the $P_v{O}_2$ from different areas of the body can be quite different. The regional $P_v{O}_2$ depends on the regional metabolism. While the $P_a{O}_2$ is the same throughout the arterial circulation, the $P_v{O}_2$ is different throughout the venous circulation, but continues to mix and become similar until the final mixing chambers of the right atrium and ventricles are reached. In other words, the $P_v{O}_2$ in the right ventricle represents a weighted mean from the entire body. And the $P_v{O}_2$ from the right ventricle is what gets sent to the lungs, which means all of the alveoli receiving blood get blood with the same $P{O}_2$. Under resting conditions approximately 5 $mL{O}_2/100mL$ of blood is taken in by tissues [hall_guyton_2020]. However, this is an average and the true value is variable across the body with tissues such as the heart, brain and breathing skeletal muscles being slightly higher at rest, and inactive skeletal muscle lower when at rest (per unit volume).

Partial pressure driven diffusion of $C{O}_2$ follows the same reasoning as with the diffusion of $O_2$ but in the opposite direction (See Figure 11.2). The cellular partial pressure of $C{O}_2$ ($P_{c}C{O}_2$) is the highest partial pressure which drives diffusion of $C{O}_2$ out of the cell into the interstitial fluid. The $P_{t}C{O}_2$ is higher than the $P{a}_C{O}_2$ in the arterial blood at the arterial end of the capillary, which drives $C{O}_2$ into the capillary. The $P_{c}C{O}_2$ is variable based on the rate of $C{O}_2$ produced during aerobic metabolism (TCA). The diffusion of $C{O}_2$ into the blood increases the $PC{O}_2$ in blood flowing through the capillary. At the venous end the $P_{v}C{O}_2$ equilibrates to whatever is in the tissue which is higher than the $P_{a}C{O}_2$. There tends be wider fluctuation in $P_{a}C{O}_2$ than in $P_a{O}_2$ due to the much lower atmospheric partial pressure of $C{O}_2$. For reasons that will be partially elucidated in this chapter and more fully explained in Chapter 12 on Ventilation, variation in ventilation (breathing rate and volume) can create large fluctuations in $P_{a}C{O}_2$ with relatively little change in $P_a{O}_2$. Under resting conditions approximately 4 $mLC{O}_2/100mL$ of blood is released from the tissues.

The RER, introduced in Chapter 6 on Energetics, is based on the volume of $C{O}_2$ produced and released into the blood (and eventually expired by breathing); and the volume of $O_2$ taken in from the blood and utilized in the mitochondria.

$$RER=\frac{\dot{V}C{O}_2}{\dot{V}{O}_2}$$

(11.5)

With mixed substrate utilization for energy (fats and carbohydrates) the RER is approximately 0.8, which is based at a cellular level on the release of approximately 4 $mLC{O}_2/100mL$ and the uptake of approximately 5 $mL{O}_2/100mL$. With a purely carbohydrate metabolism the RER = 1.0 and with purely fats it is $\approx$ 0.7.

Red blood cells (RBCs), also referred to as erythrocytes, constitute approximately 45% of the total blood volume (Hematocrit, HcT). RBCs do not have a nucleus and therefore do not divide. They are regenerated and replaced regularly in the bone marrow through the process called erythropoiesis. Erythropoiesis is stimulated by the hormone erythropoietin (EPO) which is released from the kidneys.

EPO is secreted by the kidneys at a regular rate, possibly in response to bile filtration, to compensate for normal cellular turnover (See Figure 11.4). EPO release increases in response to cellular hypoxia and stimulates additional erythropoiesis as a compensatory mechanism in an attempt to solve the problem of cellular hypoxia. Common causes of cellular hypoxia resulting in elevated levels of EPO include altitude or low barometric pressure (hypobaric) exposure which reduce environmental and therefore arterial $P{O}_2$; anemia (reduced RBCs), and hypoxemia due to chronic lung disease. RBCs contain hemoglobin (HgB).

Hgb is an iron-containing oxygen-transport protein. While HcT is the percent of blood that is composed of RBCs, HgB is the number of grams per liter of HgB in blood (usually per deciliter or 100 milliliter⁴⁴41 $dL$ is equal to 100 $mL$). A normal HgB level is approximately 15 $g/dL$ with a range 12 to 20 $g/dL$.

HgB has an $O_2$-binding capacity of 1.34 $mL{O}_2/g$ which increases the total blood oxygen capacity seventy-fold compared to dissolved oxygen in blood. A HgB molecule can carry up to four oxygen molecules. When fully saturated with $O_2$ and with a HgB of 15 $g/dL$, there is approximately ($15\times 1.34=20.1mL{O}_2/100mL$ of blood. This estimate varies predictably and proportional to the amount of actual saturation and HgB.

Warning: Anemia

Anemia with HcT in the range of 0.3 - 0.4 is common following surgery and a cause of fatigue and reduced endurance that will recover in several days when kidneys are healthy due to an increase in EPO release and associated erythropoiesis (or sooner if facilitated by a blood, or RBC, transfusion). Causes of anemia that are not reversible, and that continue until anemia progresses until HcT is less than 0.1, can result in death. Anemia is a, but not the only, cause of hypoxemia. With anemia, there is reduced oxygen carrying capacity in the blood. Chronic renal conditions, including chronic conditions such as heart failure that cause chronic renal insufficiency, will often result in anemia. When this occurs treatment can include the medication Epoetin alfa (Epogen, Procrit) which is a human made form of erythrpoeitin that stimulates RBC production in the bone marrow.

There are three ways that $C{O}_2$ is transported in the blood (See Figure 11.6).

1. 1.

   $C{O}_2$ is transported directly in the blood in a small quantity (7%) which generates the partial pressure of $C{O}_2$ in the blood ($P_{a}C{O}_2$ in arterial blood, and $P_{v}C{O}_2$ in the venous blood).

2. 2.

   The majority of $C{O}_2$ is transported as bicarbonate ($HC{O}_3^{-}$) (approximately 70%) through the following chemical reaction within the red blood cells (RBCs). Within the RBC $C{O}_2+H_{2}O\to H_{2}C{O}_3$ which is facilitated by the enzyme carbonic anhydrase. To buffer this acid, a hemoglobin (HgB) will bind with $H^{+}$ to form $HgB-H^{+}$ (which stays in the RBC) and a molecule of $HC{O}_3^{-}$ which is released into the plasma through an exchange with $C{l}^{-}$ in a process known as the chloride shift.

3. 3.

   The remaining $C{O}_2$ (approximately 23%) binds directly with HgB to form $HgB-C{O}_2$ which is referred to as carbaminohemoglobin (not to be confused with carboxyhemoglobin which is $HgB-CO$ from the inhalation of carbon monoxide, the result being carbon monoxide poisoning).

These processes are facilitated by the movement of $C{O}_2$ into the RBCs which occurs due to the $PC{O}_2$ gradient between the plasma and the RBC. As the above reactions proceed the RBC $PC{O}_2$ drops and $C{O}_2$ will diffuse into the RBCs until the $PC{O}_2$ in the plasma and the RBC are equalized. As a reminder, gradient that pushes $C{O}_2$ into the plasma and then the RBCs originates in the mitochondria where $C{O}_2$ is being generated.

$O_2$ is transported directly in the blood in a small quantity (1-2%) which generates the partial pressure of $O_2$ in the blood ($P_a{O}_2$ in arterial blood, and $P_v{O}_2$ in the venous blood).

The majority of $O_2$ is transported in RBCs, attached to HgB. The partial pressure ($P{O}_2$) gradients facilitate the movement across membranes, including into the RBCs, which then allow $O_2$-HgB binding. The affinity for $O_2$-HgB binding is related to the $P{O}_2$ as well as to the number of binding sites of a HgB molecule already bound with $O_2$. With each binding site that has an $O_2$ bound to it, there is an increased affinity for the other binding sites to bind. The binding of $O_2$ to HgB is also influenced by the temperature (increased temperature reduces $O_2$-HgB affinity), and the pH (acidity reduces $O_2$-HgB affinity), as well as a 2,3-bisphosphoglycerate (BPG) (increased BPG reduces affinity). Of these factors that shift the curve, temperature and pH vary quickly based on body status (exercise vs. rest), and between parts of the body (working muscle vs. nonworking muscle; and between muscle and lungs). But BPG varies across longer time periods as a RBC adaptation. BPG is found in RBCs and preferentially binds to HgB when $O_2$ is not bound to HgB. If there is an increase in BPG there is reduced affinity of HgB to bind with $O_2$ so that oxygen unloads from HgB more quickly when $P{O}_2$ drops. At first this sounds negative. However, reducing the affinity of HgB for $O_2$ is helpful when the goal is to release $O_2$ so that it can diffuse into the metabolically active cells requiring $O_2$. Fluctuations in BPG tend to be RBC adaptations in response to chronic conditions such as chronic anemia, pulmonary disease and as an adaptation to high altitude.

The relationship between the $P{O}_2$ and the amount of $O_2$ bound to HgB expressed as the percentage of binding sites of HgB with $O_2$ (oxygen saturation, $S{O}_2$) is given in the oxyhemoglobin dissociation curve. The features of this curve depict, first, the relationship between $P{O}_2$ and $S{O}_2$; and shifts in the curve depict the influence of pH, $PC{O}_2$, temperature, and BPG. The curve is usually considered from the perspective of arterial blood and therefore the relationship between $P_a{O}_2$ and $S_a{O}_2$ and the diffusion of $O_2$ during loading of HgB with $O_2$. When considering $P_a{O}_2$ and $S_a{O}_2$ the oxygen content of arterial blood that is being delivered is being assessed, reduced values indicate hypoxemia. However, it is equally valid to consider the curve in the capillary or venous blood when considering the utilization of $O_2$ by the cells of the body; and the influence of the $O_2$-HgB affinity on releasing (unloading) $O_2$ into the tissues. When $S_a{O}_2$ is estimated with a pulsed oximeter it is abbreviated as $S_p{O}_2$.

Pulmonary artery pressure (PAP) is synonymous with arterial blood pressure (BP) and has both systolic and diastolic components. PAP is much lower than BP under normal circumstances, approximately 15-30 $mmHg$ / 5-10 $mmHg$ with pulmonary capillary pressures approximately 7 $mmHg$. Central pulmonary venous pressure is the pressure in the LA, approximately 0-2 $mmHg$, which is similar to the central systemic venous pressure in the RA.

Intensive (critical) care unit (ICU) monitoring for patients with cardiac or other blood flow or volume conditions are often monitored with a cathether that records pressure in the pulmonary artery for continuous PAP monitoring that can occasionally be pushed further into the pulmonary circulation to estimate the pulmonary capillary pressure with a measurement referred to as the pulmonary capillary wedge pressure (PCWP). The PAP and PCWP are utilized to assess whether left sided heart function is adequate for the current blood volume, or whether the pulmonary circulation pressures are rising. If the pulmonary circulation pressures are too high then the pulmonary microcirculation favors filtration which could result in pulmonary edema or effusion.

The same four pressures determine the microcirculation in the lungs as in peripheral capillaries and tissues with a few important differences. The pulmonary capillary hydrostatic pressure is lower and the interstitial fluid pressure is negative due to the loss of fluid through the alveolar membrane and resultant evaporation (incidental water loss through breathing). Alveolar capillary permeability is high, allowing extra amounts of protein to leak from the capillaries; therefore, interstitial fluid osmotic pressure is high. The alveolar walls are thin but are generally impermeable to the proteins and solute (but are permeable to water). Total microcirculation outward pressure moving out of the capillaries exceeds the inward pressure by about 1 $mmHg$ promoting a small continual loss of fluid from the pulmonary capillaries. The capillary fluid loss is removed from the area partly through lymphatic flow and partly through alveolar evaporation of water. Some of the fluid seeps through the lung interstitial tissue and ends up in the pleural cavity surrounding the lungs, where it is typically drained into the lymphatics that drain the pleural space.

The same safety factors exist to prevent edema as in the peripheral tissue, and the same factors can cause edema. An important difference between peripheral tissue edema and pulmonary tissue edema is that pulmonary tissue edema will become pulmonary edema (as in alveolar edema). Pulmonary (alveolar) edema is life threatening because it impairs pulmonary respiration and can cause hypoxemia. The most common cause of pulmonary edema is left sided heart failure.

If there is a slow accumulation (more often caused by reduced vascular osmotic pressure, or poor lymph function) of pulmonary tissue edema it may cross the pleural membranes and result in pleural edema (commonly referred to as a pleural effusion). The most common causes of pleural effusion include: blockage of lymphatic drainage from the pleural cavity; heart failure causes excessively high peripheral and pulmonary capillary pressures; decreased vascular osmotic pressure; increased capillary permeability caused by infection or any other source of inflammation of the pleural surfaces.

The quantity of pulmonary circulation equals the quantity and rate of systemic circulation. The venous return that enters the right side of the heart and flows to the pulmonary circulation must equal the output of the left ventricle. This equality does not have to be beat to beat, but certainly must be equal when integrated over time (i.e., minute by minute). Otherwise there would be an accumulation of blood in the pulmonary circulation that impairs blood flow, ventilation and respiration, if more entered the lungs than was ejected from the LV. Or, a continuous decrease in LV output, if more was ejected from the LV than came through the pulmonary circulation. Therefore, the overall regulation of pulmonary circulation quantity includes the same processes that regulate systemic circulation as covered in Chapters 8 and 9.

As with the peripheral circulation the distribution of pulmonary circulation is dependent on local regulation. One fundamental difference is that local regulation of pulmonary (alveolar) circulation through tone (vaso dilation and constriction) of arterioles is based on hypoxic vasoconstriction. This is the opposite of muscular arterioles. In the muscular (systemic circulation) arterioles local indications of low $O_2$ concentration and high metabolism result in vasodilation in an effort to increase blood flow to those capillaries. In the pulmonary circulation arterioles, low $O_2$ concentration results in arteriole vasoconstriction, in an effort to shift blood away from those capillaries. This makes complete sense for the distribution of circulation in the lungs, where the reason for blood to be delivered to capillaries surrounding alveoli is to obtain $O_2$, not to deliver $O_2$. If some alveoli have poor airflow and low $P_A{O}_2$ then it is better for less blood to circulate to that alveolar-capillary network. Arterioles of alveoli-capillary networks that have high $P_A{O}_2$ vasodilate, to promote circulation to those alveoli with more $O_2$.

Chapter 12 on Ventilation considers the concept of ventilation - perfusion $\dot{V}/\dot{Q}$ matching, the impact of body position on $\dot{V}/\dot{Q}$ matching zones, and the impact of $\dot{V}/\dot{Q}$ matching on the $P_A{O}_2-P_a{O}_2$ gradient, otherwise known as the A-a gradient.

Warning: Respiratory Sinus Arrhythmia

Respiratory sinus arrhythmia (RSA) refers to the observation that in healthy individuals at rest there is cyclic variation in heart rate with the respiratory (breathing) frequency. With inhalation (inspiration) HR tends to go up a few beats per minute; with exhalation (expiration) HR tends to diminish a few beats per minute. The RSA is a dominant source of what is called high frequency heart rate variability (HRV) and is associated with parasympathetic nervous system activity (vagal cardiac tone). It has been hypothesized that RSA helps to maximize blood flow through the pulmonary circulation when alveoli have more ventilation as a feedforward (not feedback) system of control. This control is feedforward because the HR increases in response to the same trigger for inhalation, not in response to there being more oxygen in the lungs. There is evidence that RSA helps to maximize ventilation - perfusion matching at rest [hayano_hypothesis_2003].

A ventilated alveoli at sea level has a partial pressure of oxygen ($P_A{O}_2$) of approximately 104 $mmHg$. The atmosphere at sea level has a partial pressure of $O_2$ of approximately 159.5 mmHg. The $P{O}_2$ from the atmosphere to the arterial blood drops as it passes into the alveoli because air is humidified (some of the pressure is now due to water molecules); because $C{O}_2$ is being diffused into the alveoli (some of the pressure is due to $C{O}_2$); and because $O_2$ is being diffused out of the alveoli (there is a regular reduction in the concentration of $O_2$). Maintaining a $P_A{O}_2\approx 104mmHg$ requires continuous air exchange with the atmosphere (alveolar ventilation, $V_A$, the primary topic for the next Chapter 12 on Ventilation.

The full equilibration of blood at a single alveoli is depicted in Figure 11.8. Note that the $P_a{O}_2=P_A{O}_2$. This requires alveoli with normal membrane thickness and surface area in contact with capillaries, and normal capillary membranes. During equilibration of $O_2$ binding to HgB based on the $P_a{O}_2$ according to the oxyhemoglobin curve (Figure 11.7) ensures the blood $O_2$ carrying capacity is sufficient to support cellular respiration.

A ventilated alveoli at sea level will have a partial pressure of carbon dioxide ($P_{A}C{O}_2$) of approximately 40 $mmHg$. The $PC{O}_2$ drops dramatically from the arterial blood to the atmosphere ($P_{atm}C{O}_2\approx 0.3mmHg$). The full equilibration of blood so that the $P_{a}C{O}_2=P_{A}C{O}_2$ requires alveoli with normal membrane thickness and surface area in contact with capillaries, and normal capillary membranes (See Figure 11.8). During equilibration of $C{O}_2$ the processes discussed in the section on $C{O}_2$ transport in the blood in reverse to release $C{O}_2$ from the blood (See Figure 11.6).

Arterial Blood Gases (ABGs) are measured from a sample of arterial blood and provide information on the arterial (plasma) partial pressure of $O_2$ and $C{O}_2$, the arterial blood pH, and the arterial blood bicarbonate ($HC{O}_3^{-}$). There are several standards for reporting these values in tabular form. A common convention and normal values are depicted in Table 11.2

ABGs are extremely valuable measurements for the examination of respiration impairments. Some impairments reduce the $P_a{O}_2$ (hypoxemia) but do not impact the $P_{a}C{O}_2$ and therefore do not create acid base imbalance. Whereas other impairments reduce $P_a{O}_2$ and increase $P_{a}C{O}_2$ (hypercarbia, also known as hypercapnea) and therefore create acid base imbalances (respiratory acidosis).

Acid base balance is when pH is at it’s normal blood level of 7.35-7.45. Acid base balance is maintained due to buffering capacity in both ICF and ECF. The ECF buffering capacity of blood is related to renal functin (long term) and respiration (short term). Disorders of acid base balance are classified as acidosis when pH is below 7.35, and alkalosis when pH is above 7.45. There are two general causes of imbalances, respiratory (due to altered $P_{a}C{O}_2$), or metabolic (primarily renal) due to altered $HC{O}_3^{-}$. The four possible situations are:

• •

  Respiratory Acidosis: Decreased pH due to elevated $P_{a}C{O}_2$

• •

  Respiratory Alkalosis: Increased pH due to decreased $P_{a}C{O}_2$

• •

  Metabolic Acidosis: Decreased pH due to decreased $HC{O}_3^{-}$

• •

  Metabolic Alkalosis: Increased pH due to increased $HC{O}_3^{-}$

Respiratory and renal mechanisms can compensate for acid base disturbances created by the other system. Respiratory compensation refers to the use of respiratory adjustments to $P_{a}C{O}_2$ to compensate (normalize, but not completely, pH) when there is a metabolic disturbance. Renal compensation refers to the use of renal clearance adjustments to $HC{O}_3^{-}$ and $H^{+}$ to compensate (normalize, but not completely, pH) when there is a respiratory disturbance. Respiratory compensation is rapid since it simply involves changing breathing rate and depth (ventilation), it can occur in seconds to minutes. Renal compensation involves renal clearance and possibly production of more $HC{O}_3^{-}$, so it takes hours to days, depending on what is required, GFR, and urine output (which depends on fluid intake).

DLCO is a pulmonary function test that evaluates the diffusion capacity of the lung for carbon monoxide ($CO$)). It is used to evaluate the extent that $O_2$ diffuses across the alveoli-capillary membrane into the capillary blood impacting the $P_a{O}_2$. The test involves measuring the partial pressure difference between inspired and expired $CO$. It relies on the strong affinity and large absorption capacity of red blood cells for carbon monoxide and demonstrates gas uptake by the capillary blood. DLCO is also affected by the HgB, carboxyhemoglobin, age and sex. DLCO is measured in $ml/min/kPa$ ($kPa$ as an SI unit of pressure, the kilopascal). However, DLCO is usually reported as a percent of predicted value based on age and sex. Values between 80-120% predicted are generally accepted as normal. Values below 80% indicate possible limitations to $O_2$ diffusion in the lung. With a low DLCO it is less likely that capillary blood will equilibrate with $P_A{O}_2$ while in the alveolar capillary, and is therefore more likely that $P_a{O}_2$ will be reduced. DLCO may be reduced in individuals with conditions that impact the thickness or surface area of alveoli (Equation 11.2) such as emphysema, pulmonary fibrosis, or pulmonary hypertension. DLCO helps with examination of whether someone has a respiration impairment and the risk that they will have hypoxemia at rest, or become hypoxemic with exertion.

Pulsed oximetry indirectly monitors the $O_2$ saturation of arterial blood ($S_p{O}_2$) as opposed to a measurement directly from arterial blood ($S_a{O}_2$). A pulsed oximetry device is commonly referred to as an oximeter, or more colloquially a ”pulse ox”. Oximeters use an electronic processor and two small light-emitting diodes (LEDs) facing a photodiode through a translucent part of the skin, such as a fingertip or earlobe. Each LED emits a different wavelength of light. Absorption of light at these wavelengths differs significantly between $O_2$-HgB and HgB. The amount of light not absorbed from each LED is measured, and separate normalized signals are produced for each wavelength. These signals fluctuate in time because the amount of arterial blood that is present increases (literally pulses) with each heartbeat. The signals are used to calculate an estimate of $S_a{O}_2$ known as $S_p{O}_2$. Most units are accurate within 2.5% down to approximately 70% saturation. The signals also reflect the volume of pulsatile capillary flow (photoplethysmogram (PPG)) that pulses with left ventricular systole and can therefore also be used to determine pulse rate (as an estimate of heart rate), and indices related to blood flow volume and timing.

Poor blood flow to the extremity may cause erroneously low readings which can be as simple as a cold limb, or vasoconstriction (so not all low readings are low). There are no known causes of erroneously high readings (so normal / high readings tend to be accurate). This means that as an indicator of hypoxemia, oximetry has more false positives and limited false negatives. Such a diagnostic accuracy measurement is said to have low specificity and high sensitivity and are better for ruling out a situation than they are for ruling in a situation. For example, if $S_p{O}_2$ is normal then we are confident it is normal so we feel confident we have ruled out hypoxemia. If $S_p{O}_2$ is less than 89% we have less confidence about hypoxemia because there is a risk of a false positive, so we have less confidence to rule in hypoxemia. Other problems can include incorrect sensor application (such as not placing the LEDs on the thinner skin surface area); highly calloused skin; movement; finger nail polish; or higher skin pigmentation. Oximeters that include a PPG waveform are usually more expensive but allow an assessment of sensor accuracy by verification that the sensor is producing a steady pulse waveform. In the absence of a PPG waveform another approach to confirm accuracy is to verify the pulse rate estimate from the oximeter is the same as the radial pulse.

$S_p{O}_2$ helps to examine whether someone has hypoxemia at the time of measurement. Since it is easily measured, it provides continuous information about hypoxemia. For example, in someone with COPD that has a reduced DLCO but is not hypoxemic at rest, using an oximeter to monitor the $S_p{O}_2$ allows the clinician to know the point in time that the patient became hypoxemic, either due to exertion with exercise, ADLs, or position changes.

This chapter presents an incomplete story of overall pulmonary support for the mass balance of $O_2$ and $C{O}_2$. It leaves off with alveolar respiration, and only considers alveolar respiration at one alveolus. In the next chapter we consider ventilation (breathing) mechanics and the process of drawing air into and pushing air out of the alveoli. Without continuous alveolar ventilation ($V_A$) there is no alveolar respiration; and without ventilation ($V_e$), there is no $V_A$. We also consider the importance of the distribution of $V_e$ throughout the lungs that results in regional differences in $V_A$, and the distribution of pulmonary perfusion ($\dot{Q}$). Alveolar respiration cannot occur unless there is $V_A$ matched with capillary blood flow (perfusion).

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