pulmonology1 Flashcards
Pleura
Movement of the lungs within the thoracic cavity during inspiration and expiration is facilitated by a space between the two structures, the pleural space. The pleural space is created by the apposition of the inner lining of the chest wall, the parietal pleura, and the outer lining of the lung, the visceral pleura. A thin film of fluid separates the visceral and parietal pleura and acts as a lubricant. Disruption of this space either by air (pneumothorax), fluid (pleural effusion), or scarring can impair lung function.
Conducting Airways
The airways are a series of dichotomously branching tubes (i.e. a ‘parent’ airway divides into two ‘offspring’ airways) starting with the trachea and ending at the terminal bronchioles (the last conducting airway). On average there are 23 generations of airways in humans (from trachea to the last respiratory bronchiole). The first 16 are the conducting airways because they form a conduit for gas transfer to and from the respiratory exchange units of the lung. The structure of the airway wall changes depending on the generation of the airway. The walls are made up of three principal structures: the inner mucosal surface (epithelial cells, cilia, and goblet cells), the smooth muscle layer, and the outer connective tissue layer. Alterations in any of these layers can have an impact on airway resistance. Morphology of the airway wall changes as generation increases. Note specifically that the loss of cartilage in the outer tissue layer represents the transition from bronchi to bronchioles. Hence disease such as bronchitis and bronchiectasis refer to airways with cartilage whereas bronchiolitis affects the bronchioles or non-cartilagenous airways. Since the conducting airways by definition do not exchange gas, they are known as “anatomic deadspace.” Deadspace refers to parts of the lung that do not exchange gas. It can be anatomically defined or physiologically defined.
Gas-Exchange Regions
This region must permit efficient diffusion of oxygen and carbon dioxide across alveolar and capillary walls. The gas-exchange region (the acinus) begins distal to the terminal bronchiole and includes the respiratory bronchiole, the alveolar ducts, and the alveoli. The simple epithelium of the bronchioles gives way to two different types of alveolar epithelial cells, squamous lining cells (type I cells or pneumocytes) and secretory cells (Type II cells). Type I cells account for 95% of the alveolar surface area and fuse with the capillary endothelium to create a sufficiently thin membrane for adequate gas transfer. These cells can be injured in many diseases [such as the acute respiratory distress syndrome (ARDS)] impairing gas-exchange. Type II cells have two primary functions: 1) to repair or replace injured Type I pneumocytes, and 2) to secrete surfactant, a substance which lowers alveolar surface tension. Other cells found in the acinus (alveolar macrophages). Note that in the lung the pulmonary arteries (and arterioles) run with the bronchi (and bronchioles). Gas-exchange occurs at the capillary-alveolar interface. The pulmonary veins do not run with the airways but are more peripheral. Lymphatics run near the pulmonary arteries and veins to help cope with extravascular lung water.
Development of the Lung
The lungs develop from the lung bud of the gut tube endoderm. This bud eventually branches multiple times into the mesenchyme. The pulmonary circulation develops from the surrounding mesenchyme. The overlapping stages in embryogenesis on the lung include this initial branching, called the embryonic phase (26 days to 6 weeks gestation), the pseudoglandular phase lasting through 16 weeks where 14 more rounds of branching to the terminal bronchioles occurs, and the cannicular phase where the terminal bronchioles branch into respiratory bronchioles (to age 28 weeks). At about 26 to 28 weeks, if a premature infant is born, it has a reasonable chance of survival owing to the production of surfactant that begins at the end of the canalicular stage. Between 28 and 36 weeks, during the saccular phase, the respiratory bronchioles branch into terminal sacs and after 36 weeks, the alveolar phase occurs with maturation of the alveoli, increased surfactant secretion, etc. The lung continues to grow after birth into childhood (with growth occurring with formation of terminal sacs and then alveolarization taking place). Understanding lung development helps us understand why infants born after 36 weeks rarely have respiratory distress due to prematurity
Embryonic stage of lung development
at around 26 days to 6 weeks. The foregut endoderm extends into surrounding mesenchyme and 3 rounds of branching establish lung lobes. Initially asymmetric branching then a dichotomous branching pattern. This forms the proximal structure of the tracheobronchial tree to the level of the subsegmental bronchii and begins to fill bilateral pleural cavaties. Branching pattern determined by mesoderm. At branch points epithelia cell division stopped and collagen is produced. At developing buds, growth factors are produced to induce epithelial mitosis. Other mesodermal and epithelial factors stabilize and develop airways.
Pseudoglandular stage of lung development
6 to 16 weeks. 14 rounds of branching form terminal bronchioles. There is differentiation of conducting airway epithelium. It has a glandular appearance surrounded by mesenchyme. Formation of conduction airways is completed at end of this stage. The presence of cartilage, smooth muscle cells and mucous glands develop from the splanchnic mesenchyme
Canclicular stage of lung development
16 to 28 weeks. Terminal bronchiole divides into 2+ respiratory bronchioles. Surfactant production begins and increases as weeks progress. This stage is characterized by formation of respiratory bronchioles with delineation of pulmonary acinus. Initial development of pulmonary capillary bed. Expansion of airspaces at expense of mesenchyme. Fetal breathing is detected. Epithelial cell differentian beings and it is possible to survive but with respiratory distress problems.
Saccular stage of lung development
28 to 36 weeks. Respiratory bronchioles subdivide to produce terminal sacs (these continue to develop well into childhood. Distal growth and branching of terminal saccule with thinning interstitial space and decrease in cell proliferation. Now have type II and type I epithelial cells
Aveolar stage of lung development
36 weeks to early childhood (4 to 6 years). Lungs grows and alveoli mature: septea thin, single capillary network in alveolar wall, gas exchange unit established. Secondary septal formation. Presence of true alveoli. Type II cells proliferate and differentiate into type I cells. Lengthening and sprouting of capillary network. Fusion of the double capillary network and mature respiration surface for gas exchange.
Type I pneumocytes
90-95% by surface area but 33% by cell number (compared to Type II pneumocytes). Has a flat, thin squamous structure for gas diffusion. Poorly replicative. Form tight junctions with one another which prevent passage of large molecules
Type II pneumocytes
areclustered cuboidal cells that cover ~ 5% of the surface area of the lower area, but comprise ~ 2/3of all the cells in the lower airway(by cell number).Type II pneumocytes contain secretory cytoplasmic inclusions called lamellar bodies which secrete pulmonary surfactant. In addition to secreting surfactant,type II pneumocytes also act as stem cells. They are capable of mitotic division and replace damaged type I and II pneumocytes. The lower airway also contains several other cell types, including: Alveolar macrophages, Mast cells, Club cells (formerly known as Clara cells), and Lymphocytes. Neutrophilsare not normally found in the lower airway, but can be found in there in patients following anacute lung injury (ex: active smokers). In embryology, type II pneumocytes appear at 6 mongths
Surfactant
secreted by type II pneumocytes, acts to decrease alveolar surface tension, leading to an increase in compliance. Surfactants act to decrease surface tension in the alveoli, which ultimatelydecreases the work of inspiration (remember Laplace’s law). Surfactant synthesis does not begin until around week 26 of development. Mature levels of surfactant are not achieved until week 35 of development. Pulmonary surfactant is composed of dipalmitoyl phosphatidylcholine (a type of lecithin). A lecithin-sphingomyelin ratio of > 2.0 in amniotic fluid suggests that the fetal lungs are mature.
An acinus
refers to any cluster of cells that resembles a many-lobed berry, such as a raspberry (acinus is Latin for “berry”). The berry-shaped termination of an exocrine gland, where the secretion is produced, is acinar in form, as is the alveolar sac containing multiple alveoli in the lungs.
Lung embryology
Lung development begins in week 4 and continues until birth, with the majority of development takes place in the third trimester. The respiratory system arises from the embryonic endoderm in the pharyngeal and foregut region. Epithelial cells of primitive foregut invade the splanich mesenchyme. Primitive lung bud develops from an outpouching between the 4th and 6th brachial arches, called the laryngotracheal groove. The respiratory diverticulum is a ventral outgrowth of the foregut that grows anteriorly and inferiorly, developing into the: Trachea, Bronchi, and Bronchioles. Right and left lung bud push into primordial pleural cavity called the pericardioperitoneal. Portions of mesoderm from the paired pericardioperitoneal canals become the visceral and parietal pleura. As the lung buds develop, they push the visceral peritoneum outward expanding to meet the parietal peritoneum against the body wall, shrinking the pericardioperitoneal canals. As the lungs (and the heart) descend into the thorax, the pleuroperitoneal foramen closes. The downward growth of the lungs is halted from the liver. The lungs remain contained within the visceral peritoneum. The lungs develop through progressive division in a sequential order: Main bronchi, Bronchioles, Alveoli. The tracheoesophageal folds on either side of the respiratory diverticulum grow medially to become the tracheoesophageal septum, which separates the foregut into the laryngotracheal tube and the esophagus. The respiratory diverticulum maintains a small, superior communication with the distal pharynx, which will become the laryngeal inlet.
Pulmonary arteries
arise from the 6th aortic arch and muture into pulmonary arch. Pulmonary veins are out growths to left atrium.
General Overview of structure and Anatomical Terms of the Lungs
The lungs are contained within the pleural cavity and are connected via the trachea to the region of the larynx. The conduction system, beginning with the trachea, distributes air in up to about 20 generations of branching to the gas exchange system of the lung. Branching of the trachea to the left and right primary bronchi permits air to enter the left and right lungs, respectively. The primary bronchi branch to the secondary or lobar bronchi (three in the right lung, two in the left) that enter the five lobes of the lung (Upper right, middle right, and lower right, up- per and lower left). These then branch into segmental bronchi that respectively aerate individ- ual segments of the lung (10 in the right lung, 8 in the left). The medical relevance of segments is that each has its own air and blood supply and function as separate subunits. Should disease be restricted to one seg- ment, it can be surgically resected.
Pleura
The lung is contained in the pleural cavity and is covered by a thin elastic layer (the visceral pleura), which is com- prised of elastic fibrocol- lagenous tissue embed- ded with small amounts of smooth muscle, and contains nerves, lymphat- ics and blood vessels, covered by a surface layer of mesothelial cells.
The parietal pleura
lies against connective tissue that is continuous with the periosteum of the ribs and connective tissue of the intercostal muscles. The potential space between the pleural linings is normally negative in pressure relative to the atmosphere, hence, a puncture of the pleural cavity can lead to partial collapse of the lung.
Conduction System of the Lungs
The segmental bronchi further branch, giving rise to smaller bronchi, then to the bronchioles, which can further branch to terminal bronchioles which connect with the respiratory bronchioles of the exchange system.
Histology of the trachea and bronchi
The trachea contains about 20 “c-shaped” cartilagenous rings along its length, connected posteriorly by the trachealis muscle, whereas primary bronchi have segmented cartilagenous plates around their entire diameter. They are similar in their histologic structure, having an inner pseudostratified epithelial layer and a lamina propria that comprise the mucosa, an underlying submucosa of connective tissue, the cartilagenous layer and an adventitia connecting them to surrounding tissues. Larger bronchi contain a circumferential layer of smooth muscle, the muscularis, between the epithelial layer and the submucosa, which is not continuous in smaller bronchi or in the trachea. The tracheal and bronchial epithelium is similar. It is primarily comprised of ciliated epithelial cells, goblet cells, and basal cells. Also present are neuroendocrine cells, albeit in less abundance. The submucosae of the trachea and bronchi contain glands that contribute mucous and serous secretions to the mucosal surface.
Neuroendocrine cells
have small granules and secrete serotonin, bombesin, and other regulatory peptides. They sometimes cluster near nerve terminals and are thought to play roles in reflexive control of vascular or airway diameter.
Goblet cells
secrete mucins and other proteins which accumulate on the surface of the epithelium. A major proportion of incoming particulates bind to the sticky surface of the mucous layer, which therefore serves as the first line of defense against infection and congestion. The degree of hydration of the mucous layer is regulated by ionic channels. The ciliated cells contain 100-200 cilia which move in synchrony, the wave-like action continually pushing the mucous layer, in conveyor-belt fashion, toward the esophagus where it is swallowed. The basal cells are progenitor cells for the goblet and ciliated cells.
Mucosal associated lymphoid tissue
In addition, nodes of lymphocytes (mucosal-associated lymphoid tissue, or MALT) are present in the submucosa and serve as a second line of defense against infectious agents which might have obtained a “foothold” on the epithelial lining.
Bronchioles
Branching of bronchi leads to smaller air- ways which, when the diameter is about 1 mm, no longer have cartilage or glands, called bronchioles. Bronchioles have smooth muscle underlying the lamina pro- pria. They have ciliated cells and goblet cells in the epithelial layer and actively move mucous toward the larger bronchi. As bronchioles branch they give rise to a terminal bronchiole which leads to the ex- change system. Toward the exchange sys- tem, the terminal bronchiole epithelium contains comparatively more club cells, which secrete surface-active substances.
Cystic fibrosis
a chronic congestive disease associated with a defect in control of chloride transport in epithelial cells. Patients are homozygous recessive for the disease which results in a more viscous mucous which is less easily removed. It results in chronic infections and respiratory failure, usually resulting in early death.
Kartagener’s syndrome
a severe genetic defect characterized by chronic respiratory congestion and infections. It results from immotile cilia, usually due to defects in dynein arms. iii. Excessive smoking and/or air pollution leads to a progressive loss of ciliated cells, starting with a loss in synchrony of the cilia “wave”. Ciliated cells become gradually replaced with squamous cells as chronic coughing is used to clear congestion.
The Distal Tract
The terminal bronchioles lead to respiratory bronchioles which begin to open into individual alveoli. They are still primarily bronchioles, containing a smooth muscle layer and an epithelial layer primarily comprised of club cells. These branch giving rise to alveolar ducts which are really alveolar-bounded channels that permit penetration of air into the outermost regions of the lung. Most of the gaseous exchange occurs in the alveolar saccules, which are dead-end, grape-like clusters of alveoli. Pores between alveoli also permit air equilibration be- tween them. This is believed to be important in permitting oxygenation of adjacent regions should individual respiratory bronchioles become blocked.
The Alveoli
The estimated number of alveoli is between 500 million to 1 billion giving rise to about 75 square meters of surface area for exchange. Individual alveoli are small chambers separated by interalveolar septa which are comprised of fibroelastic basal laminae and cells. Interpenetrating the interalveolar septa is an extensive network of capillaries, which approach the number present in the rest of the body.
The two main types of pneumocytes
Two main types of cells, the type I and type II pneumocytes, are found on the side of the alveolar septa that faces the air supply. They are present in roughly equal numbers, but the flat, thin type I cells cover 90% of the surface directly next to the air supply. Type II cells are rounded. Capillary endothelial cells are also very thin in regions of gas exchange, and are tightly apposed to the same basal lamina to which type I cells are bound. The passage of dissolved gases occurs through the air-blood barrier which consists of the surfactant layer, the plasma membranes and cytoplasm of the very thin type I cell, the common basal lamina between the type I cell and the capillary epithelium, and the plasma membranes and cytoplasm of the endothelial cell. Thus, molecules of oxygen must diffuse through plasma membranes five times before reaching the hemoglobin in a RBC.
Type I cells
terminally differentiated and do not divide. They are replenished through division of their progenitors, the type II cells. The type I cells bear considerable oxidative stress and are replaced about every 20 days. The factors that promote type II cell division are not clear, but these cells can be grown in culture where they divide in the presence of alveolar fluid, epidermal growth factor and insulin.
Type II cells
contain granules having multilamellar contents as viewed by the EM. The granules contain surfactant, which lowers surface tension in alveoli and prevents both lung collapse and excessive drying. The surfactant coats the inner (type I) cell surfaces exposed to the air surface. The primary component of surfactant is phospholipid (about 85%), mainly satu- rated phosphatidylcholine. At least 4 surfactant-specific proteins have been cloned (SP-A to D). They have different functions-biophysical, protective and regulatory. For example, SP-A binds to phospholipids and is required for formation of the tubular myelin form of surfactant, whereas SP-D binds to bacteria and inactivates endotoxins. The secretion and removal of surfactant is regulated, with turnover estimated at 5-10 hours. Some components are recycled by type II cells. The molecular organization of surfactant is dynamic. For instance, during long periods of shallow breathing the more peripheral alveoli are not used and the surfactant rearranges leading to increased surface tension. With a few deeper breaths the surface area is expanded with concomitant surfactant rearrangement, decreasing surface tension and enabling ventilation of the previously closed alveoli. Lack of adequate surfactant is a major problem in premature births, where infants who would normally still be receiving placental oxygenation suddenly have to ventilate through the lungs.
Alveolar Defense
In addition to type I and II pneumocytes, the alveolar septa contain, within the loose connective tissue, monocytes, neutrophils and fibroblasts. Monocytes differentiate into alveolar macrophages which can enter the alveolar space. Alveolar macrophages serve as a third line of defense. They phagocytose, right within the air spaces of the alveoli, small inhaled particles and bacteria. They can enter the respiratory bronchioles where they get swept along in the mucous flow, by the millions daily. They can also pass out into lung lymphatics and enter lymph nodes where they function as antigen-presenting cells. Chronic exposure to excessive dust that is undigestable by macrophages is usually workplace-related. In black lung (coal miners), silicosis (fiberglass workers) or chronic exposure to asbestos fibers, macrophages en- gulf particles but cannot digest the material and die in the alveoli. Other macrophages ingest the dead macrophages but also die in the process. An overwhelming amount of undigestible material that cannot be cleared up the respiratory bronchioles accumulates, leading to alveolar damage and less surface area for exchange.
The elasticity of the alveolar septa
is very important to normal ventilation. Expansion through stretching enables exhalation to occur without effort. Loss of elasticity occurs in em- phasema, and is often accompanied by destruction of alveolar septa. Patients especially prone to this disease have an 〈antitrypsin defiency (an inhibitor of trypsin). They display a continued lysis of elastin in alveolar septa which is fatal in homozygotes. In addition, fibrotic dis- eases in which fibroblasts in the septa produce excessive collagen lead to impairment of expansion and gas exchange. The collagen also further separates the normally close apposition of capillary endothelial cells and type I pneumocytes, further limiting gas exchange.
Vasculature of the Lung
The lung receives blood from both systemic arteries (bronchial arteries from the aorta) and the pulmonary arteries from the right ventricle. The pulmonary system is relatively low pressure (about 20-25 mm Hg systole). Pulmonary arteries course along the respective bronchi and terminate in the extensive interalveolar network of capillaries. They do not supply oxygen to the conduction system, but pick up oxygen in alveoli. Oxygenated blood returns to the heart via the pulmonary veins, which sweep up toward the hilus and bring oxygenated blood from the capillaries surrounding the alveoli via the visceral pleura and intersegmental connective tissue back to left atrium of the heart. The bronchial arteries also follow the branches of the bronchi and supply oxygen only to the conduction system. Most of the blood of this system mixes with the pulmonary supply through anastamoses with small pulmonary arterioles and pulmonary capillaries. Bronchial veins drain only the connective tissue of the hilar region of the lungs to the azygous vein.
Respiratory muscles
Inspiration is an active process, which is carried out by the contraction of the inspiratory muscles. It expands the thoracic cavity by moving the diaphragm and the ribs. The most important inspiratory muscle is the diaphragm, which is innervated solely from the phrenic nerves. It contracts during inspiration and as a result the domes of the diaphragm descend and the lower ribs elevate and rotate. When the diaphragm contracts alone, the upper ribs are drawn inwards. During normal breathing the excursion of the domes of the diaphragm is 1.5 cm, increasing to 6-7 cm during deep breathing. Other muscles active during inspiration are the external intercostals, which function by pulling the ribs forward and outward. The sternomastoids and scalenes are generally silent during normal breathing and they are thus considered accessory inspiratory muscles. They become relevant when ventilation or the respiratory load is increased, as during exercise. Their function is to elevate the rib cage.
Active vs. passive respiration
During normal breathing, expiration is passive, as no muscle movement is necessary for it to occur. Active expiration may become necessary at minute volumes higher than 40 lt./min, or in the face of significant expiratory resistance. The most important expiratory muscles are those of the abdominal wall. Their use in breathing is complicated by their role in the maintenance of posture. So, the abdominal muscles are normally active in the upright position, but silent during quiet breathing in the supine position. During active expiration, they act by pushing the diaphragm upwards. The internal intercostals may also assist by pulling the ribs inward and downward and decreasing the thoracic volume.
Diaphragm’s role in disease
The status of the main respiratory muscles, specifically the diaphragm, can contribute directly to problems in breathing during disease. Consider that, in general, the force generated by muscle is a function of its length. The relationship for the diaphragm is shown in. Note that maximal tension (maximal force) for the diaphragm is achieved at 130% of its resting length, and decreases quite steeply for reductions in length. For chronic obstructive diseases such as asthma, chronic bronchitis, and emphysema, there is a tendency to breath at higher-than- normal lung volumes (you’ll hear why later), which is a condition in which the diaphragm is more contracted and reduced in length. Thus, the diaphragm in these patients operates at a mechanical disadvantage. An additional mechanical disadvantage arises out of the fact that the diaphragm at high lung volumes operates at a greater radius of curvature (this reduces the pressure generated by the muscle).
Intrapleural pressure and lung expansion
The critical factor that translates the movement of the thoracic cavity into expansion of the lung is the pressure outside of the lung, called the intrapleural pressure PIP. This pressure develops in the intrapleural space, which is a thin film of fluid interposed between the lung and the chest cavity. The source of PIP is the intrinsic elastic properties of the lung and the chest wall, together with the fact that, in a healthy person, the lung and chest wall deviate significantly from their “intrinsic” equilibrium positions (i.e., what their volumes would be if the lung and chest wall were separated from each other). The lung is more inflated than its intrinsic equilibrium position, and thus there is a force that tends to make the lung deflate. The chest wall, in contrast, is more deflated than its intrinsic equilibrium position, and thus there is a force for it to expand. The two opposing forces on the intrapleural space result in a negative PIP (a vacuum). This essentially acts to “glue” the lung to the chest cavity. During inspiration, the expanding chest cavity thus pulls the lung open, resulting in a larger lung volume. If the connection is broken, as in the case of pneumothorax when air enters the pleural cavity, the chest wall springs out and the lungs collapse.
Measurement of interpleural pressure
Intrapleural pressure can be measured by placing a needle into the pleural cavity and connecting the needle to a water manometer. PIP is generally reported as a difference from atmospheric pressure (in cm H2O). At least within healthy individuals, PIP is negative throughout the breathing cycle, varying between about –5 cm H2O at the end of expiration and –30 cm H2O at the end of inspiration. The heightened (more negative) intrapleural pressure near the end of inspiration is mainly the result of the tendency of the lung to recoil towards its intrinsic equilibrium position and the resulting forces on the intrapleural space; these are their largest when the lung is maximally inflated.
Air-flow during inspiration and expiration
Whether air flows into and out of the lung depends on the gradient between the air pressure at the mouth (Pmouth) and the air pressure in the lung (PL). During inspiration, air flows into the lung because the lung pressure becomes negative with respect to Pmouth (always at atmospheric pressure), while during expiration, air flows out of the lung because the lung pressure becomes positive with respect to Pmouth.
Air flow during inspiration
At the end of both expiration (just before inspiration), there is no air-flow because the lung pressure is zero. To understand how PL becomes negative with respect to Pmouth during inspiration, we need to introduce an additional pressure term, the transpulmonary pressure PTP (sometimes called the transmural pressure), which is the difference between PL and the intrapleural pressure PIP (PTP = PL - PIP). As we will see below in the discussion of lung compliance, PTP provides the driving force for changing lung volume during breathing. Here it is relevant because if we rearrange the equation for PTP to solve for PL, the resulting expression, PL = PTP + PIP, allows us to see that PL will be a function of PTP and PIP. It turns out that during inspiration, both PTP and PIP are rapidly changing, both becoming more negative, but the increase in negativity for PIP happens more quickly than for PTP. This causes PL to transiently achieve negative values. Understanding why the change in PTP lags behind that of PIP requires a full understanding of lung compliance; it basically has to do with the time it takes for the airflow to occur that is associated with lung inflation. One needs to remember mainly that the cause of PL achieving negative values during inspiration is the increase in negativity in PIP that occurs as a result of the lung inflating.
Air-flow during expiration
At the end of inspiration, air-flow stops because air has already flowed into the lung, increasing its pressure back to be the same as Pmouth. During expiration, the chest wall begins to contract, which effectively “releases” the lung from its more inflated state acquired during inspiration. The inherent tendency of the lung to recoil back toward its intrinsic equilibrium position produces a transient positive pressure inside of lung, often referred to as a lung’s elastic recoil pressure. In essence, the deflating lung acts to push air out of the lung. It should be mentioned that we can also explain the generation of the transiently positive lung pressure during expiration as a function of the changing values for PTP and PIP, as we did for inspiration, but this more intuitive explanation should suffice.
Compliance
Compliance, C, provides a measure of the elastic properties of the lung. Compliance is defined as the change in volume per unit change in pressure, C = ⊗V/⊗P. For the lung, compliance can be determined by plotting the volume of air inside the lung as a function of the pressure difference between the outside and the inside of the lung, defined above already as the transpulmonary pressure PTP. The lungs have high compliance at their volume at rest, so that it is easier for them to inflate during normal breathing. At high volumes, the compliance decreases, making expansion more difficult. Compliance is inversely proportional to the elasticity of the lung. A highly compliant lung is one that has lost its elasticity, while a non-compliant lung is highly elastic. Elastance is the reciprocal of compliance. The compliance of the lung differs during inspiration and expiration, with a greater change in transpulmonary pressure being required to effect a given volume change during inspiration. This behavior, known as hysteresis, is a property of all elastic structures. Hysteresis in the lung is due to a combination of the elastic properties of pulmonary cells and surface forces.
Respiratory diseases associated on abnormal lung compliance
Numerous respiratory diseases are associated with abnormal lung compliance. One of these, fibrosis, a disease caused by the infiltration of connective tissue, is associated with low lung compliance, making inspiration difficult. In contrast, emphysema is a disease caused by the loss of elastic tissue, which results in high lung compliance. Although the high compliance makes expansion of the lungs, and therefore inspiration, easier, it creates problems for expiration. Recall from above that, at the end of inspiration, the expanded lungs utilize the stored elastic energy (elastic recoil pressure) to push the air out during expiration. A high compliance will provide less elastic recoil pressure, making it difficult to expire.
Contribution of chest wall compliance
The thoracic cage has to move during breathing, too. The elastic properties of the chest wall are therefore crucial for respiration, and abnormalities in the chest wall compliance can cause respiratory problems. Examples include abnormalities of the bony thorax and of the soft tissue (extreme obesity). Old age is characterized by a general reduction in chest wall compliance. The main impact that this has on breathing is a reduction in the change in volume that the lung undergoes during normal breathing (the tidal volume). Reduced tidal volume ultimately results in reduced air-flow in the lung.
FEV1/FVC
the ratio of the volume of air exhaled in the 1st second of a forceful exhalation to the functional vital capacity. A normal FEV1/FVC ratio is 80%. In obstructive lung diseases, the FEV1/FVC ratio is typically less than 80%. In restrictive lung disease, the FEV1/FVC ratio is greater than 80%.
The A-a (alveolar-arterial) gradient
the difference between the partial pressure of oxygen in the alveoli (PAO2) and the arterial (PaO2) circulation. A normal A-a gradient is generally 5-15 mm Hg, and can be estimated by age using the formula (Age/4) + 4. In order to calculate the A-a gradient, a few other variables need to be figured out.
The alveolar gas equation
PAO2 = PiO2 – (PaCO2/R). PAO2=alveolar PO2in mmHg. PiO2= pressure of inspired oxygen in mmHg (can sometimes be approximated to 150). PaCO2=arterial PCO2in mmHg. R = respiratory quotient, which= (CO2eliminated)/(O2consumed). The alveolar gas equation allows us to calculate thePAO2from an arterial blood gas sample, whichcan beused to ultimatelyestimate the A-a gradient. When breathing environmental air at sea level, the PiO2can be approximated to ~150 (shown below as an example). However, if there is a known altitude change, to calculate the altitude adjusted PiO2:Take the atmospheric pressure (ex: 760 if at sea level) and subtractthe H2O vapor pressure (normally ~ 47) which is the moistureadded to inspired air as it is humidified by the respiratory mucosa. For example, at sea level this would be:(760–47) = 713. Then multiplythe result by the FiO2, which is thepercentage of O2in the air (normally 21%). So continuing with the example at sea level, (713) x(.21) = 149.73. Therefore, theFiO2of room air is 0.21 and thePiO2of room air is 150 mmHg. The A-a gradientis a value that reflects theintegrity of oxygen diffusionacross the alveolar and pulmonary arterial membranes. The A-a gradient can be calculated by subtracting that arterial oxygen concentration and subtracting that from the alveolar oxygen concentration(PAO2 – PaO2)
PAO2= alveolar oxygen pressure PaO2= arterial oxygen pressure
A normal resting A-a gradient in healthy middle aged adults~5-10 mmHg. A-a gradient is normal during conditions of hypoxia caused by: Hypoventilation, Decreased FiO2(experimentally, or at high altitudedue to decreased PiO2). Increased A-a gradient may occur in: Shunting, V/Q mismatch, Aging, Diffusion impairments(ex:interstitial fibrosis or pulmonary edema)
Ventilation
depends on both airway resistance and compliance. In general, ventilation is the amount of air-flow in the lungs. Pulmonary physiologists usually refer to two specific types of ventilation: minute ventilation, which is the volume of air that flows into or out of the lung in one minute, and alveolar ventilation, which is the volume of air that flows into or out of the alveolar space in one minute. Because minute ventilation includes air flowing in the conducting paths, as well as alveoli, it will always be larger than alveolar ventilation. Typical values for minute and alveolar ventilation under resting conditions, respectively, are 6 L and 4.2 L. Alveolar ventilation is usually designated V ̇A .
Factors that influence alveolar ventilation
bronchodilators and constrictors, exercise, altitude, obstructive disease and restrictive diseases, and gravity
Bronchodilators and constrictors affect of alveolar ventilation
Recall from above the list of chemical factors that can influence airway resistance. The same factors that influence airway resistance also alter ventilation. Bronchodilators increase alveolar ventilation, whereas bronchoconstrictors reduce ventilation.
Exercise affect of alveolar ventilation
During moderate exercise, ventilation can increase ~10-fold in order to meet the demands of increased CO2 production.
Altitude affect of alveolar ventilation
Ventilation increases to meet the increased demands of O2. Obstructive diseases and restrictive diseases. These can reduce ventilation by increasing airway resistance or altering lung compliance. A good example is emphysema, which reduces ventilation by increasing airway resistance (owing to dynamic airway collapse) and increasing lung compliance (which makes it more difficult to expire). For many obstructive diseases, especially for mild-to-moderate forms, overall ventilation does not go down, but there are reductions in ventilation regionally that are balanced by increases elsewhere. This condition can be just as bad for exchange of oxygen.
Gravity affect of alveolar ventilation
This factor is also an important contributor to regional differences in ventilation. To understand the role of gravity in ventilation, recall again the concept of intrapleural pressure (PIP), the pressure outside of the lung. Previously, we considered PIP as if it were uniformly distributed. But, PIP is not uniform; it is smaller at the base than the apex of the lung. A cause for this difference is the weight of the lung, which would result in a stronger pull from the chest wall at the apex. Because the intrapleural pressure is larger (more negative) at the apex, the bronchioles and alveoli there will have larger volumes (the vacuum in the intrapleural space essentially pulls them open). Somewhat counter-intuitively, the larger volume means that they will be less well ventilated. The reason for this can be understood by considering again the pressure-volume curve for the lung, here altered to consider the volume of individual alveoli. As for the entire lung, the curve for alveoli is steep at low volumes, but becomes considerably less so at high volumes, meaning that they are less compliant at high volumes. The smaller compliance of alveoli at the top of the lung means that they will undergo a smaller change of volume with each breath, thus ventilating much less. The bottom of the lung, on average, ventilates ~2.5 times more than the top.
Work of breathing
The combined impacts of lung compliance and airway resistance not only affect the magnitude of air flow in the lung (ventilation), but they also impact how we breath. By this, we mean the frequency of breathing and the volume of air in each breath (called the tidal volume, for quiet breathing). Do we breath at high frequencies with low tidal volumes or at low frequencies and large tidal volumes? The answer can be obtained by considering that breathing involves a certain amount of “work” that is done by the respiratory muscles on the lungs. The work done in moving the lungs has two major components: (a) work done against the elastic recoil of the lungs and (b) work done against airway resistance. An increase in the work of breathing can occur because of an increase in elastic recoil (decreased compliance) of the respiratory system, because of an increase in airway resistance, or a combination of the two. The different components of work terms vary under normal conditions for different types of respiration, as defined by frequency and tidal volume (VT). For small tidal volumes (the right side of the x-axis) the work required to overcome elastic recoil is small, but the work required to overcome airway resistance is large. The larger work combating airway resistance results from the fact that when you breath at high frequencies, you will not inflate your lung to large lung volumes during inspiration, a condition which, as discussed above, opens up the airways. For large tidal volumes, the reverse is true. The work to overcome elastic recoil increases, while the work required to overcome airway resistance drops for much of the breathing cycle. Somewhere in the middle (the low point on the “Total Work” curve) is the point of least amount of work, which is where a person typically breathes. Irregularities in the compliance and resistance during disease produce deviations in the plot. Someone who has a decrease in respiratory compliance (e.g., with pulmonary fibrosis) would breath at a smaller tidal volume with an increase in respiratory rate, in order to reduce the elastic work. In contrast, someone whose primary problem is an increase in airway resistance would want to breath with larger tidal volumes in order to reduce the resistance work.
Dead-Space
A last remaining issue related to airflow in the airways is the concept of dead-space. As discussed above, not all of the air that is taken in with each breath actually reaches the alveoli, the sites of gas exchange. Of the 500 ml of air in each breath (the average tidal volume), about 150 ml (or 30%) remains in the conducting path. This air is termed anatomic dead-space. In some sense, this airflow is wasted, insofar as it does not engage in gas exchange. Thus, an increase in the relative proportion of the anatomic dead-space can profoundly impact the efficiency of breathing. Such increases can happen under conditions in which we breath rapidly and at small tidal volumes (when much of the tidal volume fails to reach alveoli) or during snorkeling (which increases the total conducting path for air).
alveolar dead space
Apart from anatomic dead space, there is also alveolar dead space. These are alveoli that are well-ventilated but nevertheless do not participate in gas exchange. Such alveoli do not eliminate CO2, just like the conducting airways. Such alveoli would be those that are in unperfused regions of the lung, i.e., regions that lack blood flow (we will come back to the issue of lung perfusion in a later lecture). As with anatomical dead-space, increases in alveolar dead- space leads to wasted ventilation and decreases in the efficiency of breathing. The sum of the anatomic dead-space and the alveolar dead-space is called the physiologic dead-space. Physiologic dead space is, in general larger, than anatomic dead space, though for healthy individuals the difference between the two volumes is too small to be measured. Significant differences between anatomic and physiologic dead space are an indication of disease. Both anatomic and physiologic dead-space can be measured with relatively straightforward pulmonary function tests.
residual volume RV
The smallest lung volume of interest is the residual volume RV, which is the volume of air remaining in the lungs after a maximal expiration. This is on the order of 1.5 liters.
functional residual capacity, FRC
The volume of gas present in the lung and upper airways at the end of a normal expiration is called functional residual capacity, FRC, and is ~ 2.5 liters.
total lung capacity, TLC
The volume of air inside the lungs at the end of a maximal inspiration is the total lung capacity, TLC. This is the maximal volume that can be obtained by the lung and is ~7.5 liters.
tidal volume, VT
There are also important volumes that reflect differences in lung states. For example, tidal volume, VT, is the difference in lung volume between a normal inspiration and normal expiration. Tidal volume is, thus, also the volume of air that enters and exits the lungs in one normal breathing cycle. A typical value for VT is 500 ml.
vital capacity, VC
The volume of air exhaled after a maximal inspiration followed by a maximal expiration is called vital capacity, VC. VC = TLC - RV.
minute ventilation or minute volume (ml/min)
The tidal volume (ml)∗frequency of breathing (breaths/min) product is called minute ventilation or minute volume (ml/min).
Measurements of lung volumes
Changes in the lung volume (VT and VC) can be measured with a spirometer. This test is simple and widely used. In order to measure the other volumes, such as the functional residual capacity FRC, different approaches have to be employed.
body plethysmograph method
In one method, the body plethysmograph method, the subject sits in an airtight chamber, breathing through a mouthpiece. FRC is estimated essentially from the change in pressure that occurs when the lung expands.
forced expirogram
There are also dynamic measurements of lung volume. The most common of these is called the forced expirogram, which is particularly effective in separating normal from obstructive and restrictive anomalies. the volumes measured by a spirometer when a subject inspires maximally and then exhales as hard and as completely as possible. The volume exhaled in the first second is called the forced expiratory volume, FEV1.0. The total volume exhaled is the forced vital capacity, FVC (or just vital capacity VC). For normal subjects, the ratio FEV1.0/FVC is about 80%. This test is particularly effective in diagnosing diseases that impact airway resistance and some diseases that increase compliance.
a restrictive disease and pulmonary function tests
such as pulmonary fibrosis. Recall from a previous lecture that this is a disease caused by the infiltration of connective tissue, which decreases lung compliance, making inspiration difficult. With this disease, we predict that there will be a change in the vital capacity, VC, since the difficulty in expanding the lung will prevent the patient from inflating his lung maximally upon a forced inspiration. A restrictive disease however may not show up as a significant reduction in the rate of air-flow during dynamic measurements of expiration (the ratio between FEV1.0/FVC). That’s because restrictive diseases do not impact airway resistance; also, the decrease in lung compliance can actually cause small increases in the FEV1.0/FVC ratio.
Obstructive diseases and pulmonary function tests
such as chronic bronchitis and asthma are associated with increases in airway resistance. Thus, there are pronounced effects on dynamic measurements of expiration; the FEV1.0/FVC ratio decreases significantly. In terms of static lung volumes, obstructive diseases are typically associated with increases in the functional residual capacity FRC and residual volume RV. One reason is air- trapping. Because of the limitation of airflow during expiration, there may be extra air trapped inside the lungs at the end of expiration. Also, patients tend to breath at higher lung volumes, both so that they can lower airway resistance and, also, so that they can increase the elastic recoil pressure. In measurements of changes in lung volume, such as vital capacity VC, these obstructive diseases cause decreases. That’s related to the increase in airway resistance and the air-trapping phenomenon, which increase RV.
Emphysema and pulmonary function tests
is also an example of an obstructive disease since it increases airway resistance, through dynamic airway collapse. Patients tend to inspire quickly and expire slowly through pursed lips. Emphysema shows up during pulmonary function tests as a reduced rate of expiration (a reduced FEV1.0/FVC ratio) and an increase in the functional residual capacity FRC, like other obstructive diseases. Unlike the other obstructive diseases, emphysema can be associated with unchanged or small increases (not decreases) in vital capacity. That’s because the increase in lung compliance allows emphysema patients to achieve higher maximal lung volumes (total lung capacity) upon forced inspiration.
Oxygen transport in the airways
O2 transport in the airways can be separated into two steps: (1) transport of O2 from the outside air into the airways; and (2) transport of O2 through the airways into alveoli. The latter depends on ventilation, or, more formally, alveolar ventilation, which was discussed in an earlier lecture. These two steps yield specific quantities of O2: PIO2, which is the partial pressure of O2 in inspired air at the point at which it has just entered the airways, and PAO2, the partial pressure of O2 in alveoli. These numbers, PIO2 and PAO2, are of obvious interest because they place upper limits on the amount of O2 that can ultimately enter blood.
barometric pressure (PB) of air
the sum of the partial pressures of the gas mixture in air: PB = PIN2 + PIO2 + PICO2 + etc.
Dalton’s Law for inspired air
For estimating PIO2 for inspired air, one cannot however simply multiply these fractions times the barometric pressure PB. These fractions were for dry air. One has to take into account the fact that when atmospheric air enters the airways, it becomes saturated with water vapor at 37 0C. At this temperature, the partial pressure of water vapor is 47 Torr. Estimating PIO2 using the fractional values of O2 for dry air thus requires that we first subtract off the water vapor pressure from the barometric pressure: PIO2 = (PB – 47 Torr) ⋅ 0.21. At sea-level, the barometric pressure is 760 Torr, which substituting into the equation, gives a value of PIO2 = 150 Torr. With increases in altitude, it is important to point out that the water vapor pressure stays constant (47 Torr). Thus, in Denver, where PB is typically 620 Torr, PIO2 is estimated to be 120 Torr.
Alveolar oxygen (PAO2)
The partial pressure of oxygen in inspired air PIO2 sets the upper limit for the partial O2 pressure in alveoli, PAO2. For understanding the degree of decrement in oxygen between inspired air and alveolar air, consider a bolus of air that is moving from the airways into an alveolus. Notice that, whereas inspired air has only two main components, oxygen and nitrogen, alveolar air also has a third component CO2, which is expelled from the blood. This presents a bit of a problem for this system, which must maintain near-constant total barometric air pressure PB throughout the airway (of course, there may be some small pressure gradients to account for air movement). In order to accommodate the extra CO2 component in alveolar air while maintaining near-constant barometric pressures, some of the oxygen and/or nitrogen in alveolar air must be replaced by CO2.
How much of the alveolar oxygen and nitrogen is replaced by CO2?
An important clue is provided by recalling that CO2 is a metabolic product of the same biochemical reactions in tissues that utilize oxygen. In fact, when those metabolic reactions produce the exact same quantity of CO2 as oxygen consumed, oxygen in the alveolus is exchanged for CO2 in a one-to- one fashion. In this situation, the additional CO2 in the alveolus is entirely accounted for by a reduction in oxygen. These considerations lead naturally to the first equation that describes the decrement in alveolar oxygen PAO2 with respect to PIO2: PAO2 = PIO2 - PACO2 (equation for R=1). Here PAO2 will simply reflect oxygen in inspired air minus the carbon dioxide. This equation is the simplest form of the alveolar gas equation. For a typical PIO2 at sea level = 150 Torr and a typical PACO2 = 40 Torr, the equation gives PAO2 = 110 Torr.
respiratory exchange ratio (R)
for many important metabolic reactions such as oxidative phosphorylation, there is less carbon dioxide produced as compared to oxygen consumed. The exact relationship between O2 consumed and CO2 produced is given by the respiratory exchange ratio (R), which is the ratio of the amount of CO2 generated ( V ̇CO 2) per amount of O2 consumed ( V ̇O 2 ): R= V ̇CO2/ V ̇ O 2. R varies for different metabolites. It is near one for carbohydrates but drops to 0.7 for fats (meaning that for every 10 molecules of O consumed, only 7 molecules of CO are produced). For a typical diet, R is about 0.8
CO2 transport in the airways
CO2 is of course transported in a direction opposite from O2: from our blood, through airways, and out into the outside air. We begin the discussion of CO2 transport in airways by also discussing the transport step that just precedes it: diffusion of CO2 from pulmonary capillaries into alveoli. The step of CO2 transport from alveoli to outside air will depend on alveolar ventilation V ̇A . There are 2 main principles that form the basis for understanding much of CO2 transport. The first is that the diffusion-step is extremely fast, meaning that, for all practical purposes, CO2 in alveoli and in pulmonary capillaries equilibrates near-perfectly. This is true even under quite severe disease conditions. A result of this near-perfect equilibration is that the partial pressures of CO2 in alveoli (PACO2) and that ultimately seen in arterial blood (PaCO2) will be very nearly equivalent: PACO2 = PaCO2. The second main principle is a corollary to the first: how efficiently the body transports CO2 out of the body is much more dependent on the step of CO2 transport between alveoli and the outside air. Accordingly, many more things can go wrong with CO2 transport due to problems with this step. Consider for example what would happen if alveolar ventilation V ̇A goes down. First, PACO2 will increase, as a result of the fact that the rate of removal of CO2 from alveoli will decrease, leading to CO2 accumulation. Then, because blood CO2 equilibrates near perfectly with alveolar CO2, PaCO2 will increase by a near-equivalent amount. This is bad, because PaCO2 is ultimately what we care about. If VA goes up, PACO2 and PaCO2 will decrease by near-equivalent amounts.
How does one relate PACO2 to alveolar ventilation V ̇A in a quantitative way?
For setting up this equation, imagine a body that is constantly producing CO2 and also getting rid of it through the ventilation process. At equilibrium, the rate of CO2 production must be matched by the rate of removal of CO2 from alveoli (or else our blood would have ever-increasing concentrations of CO2!). If we express the CO2 quantity being ventilated in terms of volumes and CO2 concentrations CACO2, this equilibrium situation can be expressed as: V ̇CO2 =V ̇A xCACO2. where V ̇CO 2 is the quantity of CO2 produced in one minute. Rearranging, we have CACO2= V ̇CO2/ V ̇A.
alveolar ventilation equation
PACO2= V ̇CO2/ ̇VA * K. where k is a constant the value of which is given according to the units and the conditions. Because PACO2 is essentially equivalent to
PaCO2
one can also substitute PaCO2 for PACO2 in the equation. This expression is useful for determining exactly what effect different ventilation rates will have on arterial PaCO2.The very tight relation between alveolar ventilation and PACO2/PaCO2, as expressed in the alveolar ventilation equation, is of crucial importance. For example, the equation shows that if the alveolar ventilation rate is doubled (and CO2 production remains unchanged), PACO2 and PaCO2 will be exactly halved.
Measurement of alveolar ventilation
Rearranging the ventilation V ̇A and PACO2 terms in the above equation yields the modified expression: VA=VCO2/PACO2*K. This equation shows how alveolar ventilation V ̇A can be estimated under practical conditions. V ̇ (CO production in one minute) can be measured by catching the air expired by a subject, and measuring the volume of expired air and concentration of CO2 (done with a CO2 analyzer). PACO2 can be estimated from arterial PCO2 (since, again, alveolar and arterial PCO2 are nearly equivalent), and k can be looked up in a book
Hypoventilation and hyperventilation
The discussion of the relationship between alveolar ventilation and PACO2 /PaCO2 brings us to some important definitions for words that you will hear repeatedly. The terms “hypoventilation” and “hyperventilation” are used to indicate that alveolar ventilation is abnormally low or abnormally high, in relation to CO2 production and elimination rate. In a subject breathing atmospheric air, a decrease in PaCO2 (and an associated increase in V ̇A ) means
hyperventilation
while an increase in PaCO2 (a decrease in V ̇A ) means hypoventilation. At sea level, a “normal” PaCO2 ranges between 35-45 Torr; if a patient deviates from this range, he is said to be hyper- or hypoventilating. In Denver, the normal PaCO2 range is 30-40 Torr (lower because of chronic hypoxia, which increases ventilation). Common causes of hyperventilation include acute hypoxemia (low arterial oxygen), metabolic acidosis, or CNS stimulation. Hypoventilation can be caused by obstructive/restrictive disease, metabolic alkalosis, or CNS depression. It is important to remember that hyperventilation and hypoventilation refer to ventilation and not frequency of breathing! A higher than normal frequency of breathing is referred to as tachypnea (Greek for fast-breathing). Also, an increase in ventilation that is not accompanied by a reduction in PaCO2 will not be called hyperventilation either. For example, during moderate exercise, the increase in V ̇A matches the increase in CO2 production V ̇CO 2 , resulting in a PaCO2 that is the same as at rest. The increase in ventilation during moderate exercise is called hyperpnea (Greek for lots-a-breathing).
Basic properties of oxygen in blood
Oxygen in blood is carried in two basic forms, reflected in the equation: CaO2 = hemoglobin-bound O2 concentration + freely-dissolved O2 concentration. CaO2 is the arterial oxygen content, which is the total concentration of O2 in blood. For a healthy person CaO2 is about 9.1 mM (expressed in millimoles) or 20.7 ml O2/100 ml blood (a more common way of expressing it in a clinical setting). Of the total arterial oxygen content, the vast majority of it (>98%) is bound to hemoglobin (called oxy-hemoglobin). The freely-dissolved concentration is much smaller, but it is the component that is reflected in partial pressure values (PO2) typically provided for arterial blood (called PaO2). In the next two subsections, we consider (1) the reasons why so little O2 is freely-dissolved, and (2) the basic properties of O2 binding to hemoglobin as reflected in the oxy-hemoglobin dissociation curve.
Oxygen solubility
One of the fundamental reasons for why so little O2 is carried in blood in freely-dissolved form is that O2 simply does not dissolve very well in blood (the other reason is that O2 binds quickly to hemoglobin). The tendency of any molecule to dissolve in a liquid is given by its solubility coefficient, which for O2 is expressed as aO2. At 37 0C, in isotonic NaCl solution (close enough to blood), the solubility coefficient for O2 is aO2 = 0.0013 mM/Torr. This value for aO2 is a small number. If one uses the expression [O2] = aO2 x PO2 to find the dissolved O2 concentration in blood ([O2]), one gets a value of only 0.13 mM (expressed in millimoles) at a typical arterial PO2 of 100 Torr. If one expresses dissolved concentrations in ml O2/100 ml blood, the solubility coefficient is aO2 = 0.003 ml O2/100 ml blood/Torr and the oxygen concentration (for PO2 = 100 Torr) is 0.3 ml O2/100 ml of blood. The small solubility coefficient for O2 compares with a moderate coefficient for CO2: aCO2 = 0.03 mM/Torr. Note that CO2 is about 20 times more soluble in blood than O2. As will be seen below, the differences in solubility between O2 and CO2 has implications for understanding how diffusion of these two molecules between alveoli and pulmonary capillaries is impacted by disease.
Oxy-hemoglobin dissociation curves
Since only about 0.13 mM of the oxygen in arterial blood is freely dissolved, this means that, of the 9.1 mM of arterial oxygen content, about 9 mM is oxy-hemoglobin. Here we consider some basic aspects of O2 binding to hemoglobin, as expressed in the oxy-hemoglobin dissociation curve. This curve relates oxygen saturation of hemoglobin, SO2, at equilibrium, to the PO2 in the blood. For PO2 = 100 Torr, which is normal arterial oxygen, SO2 = 97.5%. This means that in arterial blood, hemoglobin is very close to full saturation: a further increase in PO2 would not substantially increase the amount of O2 carried by hemoglobin. The high degree of hemoglobin saturation at arterial PO2 has important implications for understanding perfusion-effects on arterial oxygenation (see below). For PO2 = 40 Torr (mixed venous blood), SO2 = 75%, while half- saturation, SO2 = 50%, occurs for PO2 = 26 Torr. Importantly, the curve is steep at moderate PO2 between 20 to 60 Torr (recall that the steepness comes from the fact that O2 binding to hemoglobin is a “cooperative” process). The steep drop in SO2 with decreasing PO2 allows peripheral tissues that see relatively unsaturated hemoglobin to withdraw larger amounts of O2 for only small drops in capillary PO2. The standard ODC applies exactly only under the following conditions: pH = 7.40; PCO2 = 40 Torr; temperature = 370C; and [2,3-DPG] = 15 μmoles/gr Hb.
Diffusion
The rate of gas transfer across an arbitrary tissue plane is a function of the (1) the difference in partial pressure of the gas on the two sides of the membrane, (2) the tissue plane area (A), (3) the tissue thickness (d), and (4) a constant k reflecting the tissue solubility and molecular weight of the gas. If the gas transfer rate is defined as VG, then we have: VG = (P1-P2) x A/d x k (Fick’s Law) where P1 and P2 are the partial pressures of the gas on one or the other side of the membrane. This equation is commonly known as Fick’s Law for diffusion. In this equation, the terms A, d, and k are often grouped into a single constant called the diffusing capacity Dm: D m = A/dx k. Dm is thus a function of the physical properties of the tissue plane (A and d), as well as of the gas in question (reflected in the constant k). The most common way of determining diffusing capacity is the CO single breath method.
Factors that maximize O2 flux
If one considers oxygen diffusion across the alveolar membrane, it turns out that, under normal conditions, several factors conspire to maximize O2 flux. The first is the large surface area A of the alveolar membrane. One adult human lung has about 300 million alveoli, providing a surface area of 50-100 m2 (about half the size of a tennis court!). By contrast, a single sphere with a volume of 4 liters would have an area of only 1/100 m2. This difference illustrates how the lung morphology is well-adapted for diffusion. Equally important is the thin membrane width d, only about 0.3 μm. Since d is in the denominator of Fick’s Law, the thin membrane maximizes diffusion. A last factor that promotes oxygen diffusion is a mechanism that helps maintain a large oxygen pressure gradient between alveoli and capillaries (PAO2- PcapO2). Specifically, the low solubility of O2 in blood, together with the tendency for O2 to bind quickly to hemoglobin, ensures that PcapO2 remains low and the gradient (PAO2- PcapO2) large. The question is how quickly the capillary PO2 reaches the alveolar PAO2 = 100 Torr, which is the maximal value that PO2 can be in the blood. Under normal conditions, one can see that PO2 reaches 100 Torr very fast, in about 1/3 of the time it takes for blood to pass through the capillary bed. If PO2 reaches alveolar values in 1/3 of the time it spends in the pulmonary circulation, why, then, have all of that extra time for diffusion to occur? The extra time is essentially a safety net, to account for situations such as exercise, when the faster blood flow reduces the time that diffusion can occur. The extra time also accounts for pathologic conditions in which O2 and CO2 transfer slows.
Disease and oxygen diffusion
During interstitial disease, when there is thickening of the alveolar walls (increased d), the rate of diffusion is slowed, sometimes to the point where arterial oxygen levels do not reach alveolar levels. Diffusion can also go down during emphysema, when breakdown in lung tissue decreases the surface area for diffusion (decreased A). One last condition that can alter diffusion somewhat is abnormalities in the hemoglobin concentration, in situations of polycythemia (when diffusion increases) or anemia (when perfusion decreases). This can impact the pressure gradient for oxygen diffusion by altering free oxygen levels in blood. It should be pointed out, however, that changes in hemoglobin concentration generally exert much larger effects on tissue oxygenation by altering oxygen delivery to tissues (see next lecture) rather than through changes in oxygen diffusion.
Comparison of CO2 and O2 diffusion
In the case of CO2, PCO2 must go from a value of 45 Torr (the value in mixed venous blood coming via the pulmonary artery) to an alveolar PACO2 = 40 Torr. CO2, like O2, reaches the alveolar value in only about 1/3 of the time it takes for blood to pass through the capillary bed. An important difference between O2 and CO2 is that O2 diffusion is much more affected by disease. Recall from above that O2 is 20 times less soluble in blood than CO2. It turns out that this consideration impacts the diffusion process, since O2 diffusion between alveoli and blood requires that it be dissolved (since only dissolved O2 can cross the alveolar membrane and enter blood). Thus, while O2 diffusion is generally quite efficient for all of the reasons cited above (small d, large A, large pressure gradient), it is somewhat slowed by its poor solubility even under normal conditions, and, so, is susceptible to disease. In contrast, the ease at which CO2 dissolves means that CO2 diffusion is much less affected by disease. With extremely large reductions in diffusing capacities (by >75%), CO2 levels can fail to reach alveolar values by the time blood passes through the capillary bed, but this is extremely unusual.
Perfusion versus diffusion-limited transfer rates
Pulmonary physiologists use two terms to distinguish between situations in which O2 has reached its maximal value by the time it has passed through the pulmonary capillary bed and those in which it has not. If conditions do permit rapid equilibration of blood with alveolar air, and PO2 and PCO2 in blood exiting the pulmonary exchange area is similar to alveolar PO2 and PCO2, the O2 transfer rate is said to be perfusion limited. This means that for a given composition of alveolar air and of venous blood entering the lungs, the only major factor limiting the rate of oxygen uptake and CO2 excretion is pulmonary blood flow. This is the normal condition, even during moderate exercise. If these conditions do not permit the complete equilibration of alveolar air and blood, then the PO2 in the blood exiting the pulmonary exchange area will be less than alveolar PO2, and the O2 transfer rate will be diffusion limited.
Perfusion
Since blood is the carrier of O2 and CO2, the blood flow through the lung, the perfusion of the lung, is very important. Perfusion, Q ̇, is the blood flow of the pulmonary circulation available for gas exchange (in one minute). Perfusion equals the cardiac output, which for an adult at rest is Q ̇ = 5 liters/ min. At any given time, there is about 500 ml blood in the lung, comprising 40% of the lung weight. The pulmonary circulation has very low blood pressure. The reasons are the vast number of vessels and their normally dilated state. In conformity with the low pressure, the walls of the pulmonary artery and its branches are very thin and contain relatively little smooth muscle. The reason for these properties of the pulmonary vessels and circulation is related to the function of the pulmonary circulation: the lung receives all of the cardiac output and does not have to direct blood from one region to another; the low pressure keeps the work of the right heart as small as possible for efficient gas exchange.
O2 tension regulation of perfusion
The factor of overriding importance in governing minute-to-minute regulation of the pulmonary circulation is the alveolar O2 tension, PAO2. O2 diffuses through the thin alveolar walls into the smooth muscle cells of the microvessels. The response of the pulmonary vascular smooth muscle to low PO2 is opposite from that of the systemic circulation. Low alveolar PO2 constricts the nearby arterioles. This constriction, hypoxic pulmonary vasoconstriction, decreases local blood flow and shifts it to other regions of the lung.
Other chemical agents regulation of perfusion
Other agents that regulate perfusion are thromboxane and prostacyclin, two products of arachidonic acid metabolism. Thromboxane A2 is the most important vasoconstrictor, and, as with O2, its effect is mainly localized to the region of release. Prostacyclin (prostaglandin I2) is a potent vasodilator.
Capillary recruitment regulation of perfusion
In the case of moderate exercise there is passive regulation of perfusion. Cardiac output may rise 3-fold, and the increase is accommodated by the pulmonary circulation through recruitment of new capillaries and distension of previously-open microvessels. The volume of blood in the pulmonary capillaries at rest is ~75 ml. This can increase up to 200 ml through capillary recruitment.
Gravity regulation of perfusion
Because of gravity, the pulmonary blood pressure is low at the apex of the lung. At the base of the lung, the blood pressure is higher, allowing more capillaries to open and higher blood flow. Thus, perfusion increases as we go from the apex to the bottom of the lung. This change is about 6-fold. There may also be additional regional differences in perfusion due to a variety of causes, as local hypoxia, obstruction of blood vessels, etc. The significance of the variability in perfusion through the lung is related to the ratio between ventilation and perfusion (the V/Q ratio), which is a determining factor for oxygenation of blood (see below).
Perfusion problems and gas exchange
There are a number of ways in which problems in perfusion, together with ventilation, can impact gas exchange. Alveolar dead-space. Recall from a previous lecture that alveoli in unperfused regions of the lung are referred to as alveolar dead-space. Such a condition can happen if, for example, a patient has a blockage in a pulmonary capillary. These alveoli are well-ventilated, but because they do not engage in gas exchange, their ventilation is wasted.
Shunts
Alveolar dead-space corresponds to a region of the lung in which ventilation is normal but there is no perfusion. There is also shunt, which is blood perfusion where there is no ventilation. A small amount of shunt is normal because some venous blood enters the left atrium and ventricle by way of the bronchopulmonary venous anastomoses and the intracardiac Thebesian veins. This amounts to 1% to 2% of the cardiac output normally. Shunts can decrease arterial oxygenation significantly, when the well-ventilated blood mixes with the shunted blood. A shunt does not usually result in a raised arterial PCO2. The tendency for CO2 to rise is generally countered by the central chemoreceptors, which increase ventilation if PCO2 increases.
Causes of V/Q mismatch
include pulmonary disorders such as obstructive lung disease. In addition, even healthy individuals standing upright have some degree of V/Q mismatch owing to the effects of gravity. We have already discussed the decrease in ventilation and perfusion that results from gravity-effects as we go from the bottom to the apex of the lung. Because gravity has differing effects on the magnitude of ventilation and perfusion in different portions of the lung, there are resulting variations in the V/Q ratio (higher V/Q at the apex). These effects are significant enough to contribute to the 5-10 Torr difference between arterial PaO2 and alveolar PAO2 that is typically observed.
Effect of V/Q mismatch
To understand the effect of V/Q mismatch on arterial oxygenation. The key problem is that the high V/Q branch cannot add very much more oxygen as compared to the normal V/Q branch (note that the O2 content of the high V/Q branch is only slightly more than the normal branch). This is because hemoglobin is already near saturation under normal V/Q conditions. Hence, the high V/Q branch cannot make up for the deficiency in oxygenation caused by the low V/Q branch. In terms of CO2, V/Q mismatch per se generally does not reduce arterial PCO2, similar to the case of a shunt. This is because increases in PCO2 in parts of the lung with low V/Q are generally countered by increases in ventilation in other parts of the lung (these are mediated by central chemoreceptors).
Local mechanisms of V/Q mismatch regulation
There are two local mechanisms that regulate V / Q mismatch. (1) In lung areas with high V / Q ratios, the alveolar PCO2 drops, leading to an increase in local airway resistance and decreasing ventilation. Thus, V / Q tends to go down. (2) In lung areas with low V / Q ratios, the alveolar PO2 drops, leading to hypoxic vasoconstriction and decreasing local perfusion (see above). Thus, V /Q tends to go up.
Oxygen off-loading
a vast majority of O2 in arterial blood (>98%) is in a form bound to hemoglobin (called oxy-hemoglobin). This is important because it allows delivery of a significant quantity of O2 to tissues, despite the fact that O2 dissolves very poorly in blood. An equally important aspect of hemoglobin relevant to oxygen delivery is related to the dynamics of O2 unbinding from hemoglobin (called “off-loading”). The key issue here is that tissues can only use freely-dissolved oxygen, and fast unbinding makes O2 available to the tissues. Without fast unbinding, total oxygen levels might be high, but most oxygen molecules would stay bound to hemoglobin and be unavailable for use. It should be kept in mind that even though O2 unbinding rates from hemoglobin are fast, O2 binding rates are even faster, so that at any given moment in time, most O2 is bound to hemoglobin.
Bohr effect
The rates of O2 binding/unbinding to hemoglobin are also properties that can change. This is reflected in the oxy-hemoglobin dissociation curve (ODC), introduced in the last lecture. The ODC reflects the equilibrium between O2 binding and unbinding to hemoglobin. ODCs under two conditions cause rightward shifts in the curves: decreases in pH or increases in PCO2 as compared to normal (normal pH = 7.40; normal PCO2 = 40 Torr). A rightward shift in the ODC means that O2 is binding less tightly to hemoglobin. The effect of pH on the ODC is specifically called the Bohr effect.
Rightward shift in the ODC
An ODC markedly shifted to the right of normal has the disadvantage of providing arterial blood with a low saturation, but it can also have important beneficial effects. Consider that pH decreases and PCO2 increases locally within muscles during exercise, which is when muscle cells benefit from having more available free O2. The decrease in O2 affinity to hemoglobin, corresponding to the rightward shift in the ODC, means that more O2 is available through off-loading. Notably, increases in temperature, which also happens during exercise, also cause rightward shifts in the ODC. A final factor causing a rightward shift in the ODC is an increase in [2,3-DPG], as happens during chronic hypoxia at altitude.
Leftward shift of OCD
The ODC can also shift to the left, due to decreases in [H+] (increase in pH), PCO2, temperature, or [2,3-DPG]. This has the disadvantage in that O2 binds too tightly to hemoglobin and thus there is less unloading at peripheral tissues. The normal position of the ODC can be viewed as a compromise between the ability to load and to unload O2.
Quantifying O2 delivery
Such calculations are obviously important for determining effects of diseases that impact blood oxygenation. The quantity of O2 delivery happening in one minute, D ̇O2, is equal to the cardiac output Q ̇ times the concentration of oxygen in arterial blood, CaO2: D ̇ = Q ̇ x C (in ml blood per minute) O2 aO2. CaO2 is the total concentration of oxygen, including hemoglobin-bound and freely dissolved components. These can be expressed as: CaO2 = (SaO2 ⋅ [Hb] X 1.39) + (0.003 ⋅ PaO2) (in ml O2 / 100 ml blood). hemoglobin-bound O2= SaO2 ⋅ [Hb] X 1.39. freely-dissolved O2= 0.003 ⋅ PaO2. The hemoglobin-bound term is a function of the concentration of hemoglobin [Hb] and the degree of oxygen saturation of hemoglobin SaO2. The value of 1.39 is the maximum volume of O2 (in ml) that can combine with 1 gram of hemoglobin (with units of ml/gm).
oxygen carrying capacity of hemoglobin
The term ([Hb] x 1.39) is often referred to as the oxygen carrying capacity of hemoglobin, which is the maximum amount of O2 that can be combined with hemoglobin, assuming 100% saturation (SaO2 = 1.0).
concentration of O2 carried by hemoglobin in arterial blood
For a typical saturation of 98% (SaO2 = 0.98), and a typical hemoglobin concentration [Hb] = 15 gr/100 ml, the concentration of O2 carried by hemoglobin in arterial blood is 20.4 ml O2/100 ml blood (or 9.1 mM). As you do the calculation, the units work out if you remember that the value 1.39 has a ml/gram associated with it. The concentration of freely dissolved O2 in blood is small. For a typical PaO2 = 100 Torr, this term is only 0.3 ml O2/100 ml of blood (or 0.13 mM). The total arterial oxygen content under normal conditions is the sum of the hemoglobin-bound component (20.4 ml O2/100 ml) and the freely dissolved component (0.3 ml O2/100 ml), which is 20.7 ml O2/100 ml blood. For a typical cardiac output Q ̇ = 5,000 ml/minute, the oxygen delivery will be D ̇O2 = (5,000 ml blood/min) x (20.7 ml O2/100 ml blood) = ~1,000 ml O2/min. These values are for a healthy person. It is easy to see what would happen in the case of anemia, since the hemoglobin concentration [Hb] in the equation above for C will be smaller.
Effect of hypoxemia on O2 delivery
A disease that results in reduced arterial free oxygen (hypoxemia) can decrease O2 delivery in two ways: first, by reducing the percent saturation of hemoglobin SaO2 in the hemoglobin-bound component of CaO2 (this is the main way) and, second, by reducing the free oxygen component.
Oxygen consumption
In a clinical setting, one needs to know not only the quantity of oxygen being delivered to the tissue, but also how much is being consumed. Whether a patient is receiving enough oxygen will depend on whether delivery is matching consumption. Oxygen consumption can be calculated, quite simply, from the difference between the total amount of oxygen in venous blood versus arterial blood. This makes sense since it is the capillary beds between the arterial and venous circulation where oxygen is utilized. Defining oxygen consumption as V ̇O 2 , we have: V ̇ O 2 = ( Q ̇ x C a O 2 ) – ( Q ̇ x C v O 2 ) which simplifies to: V ̇ O 2 = Q ̇ x ( C a O 2 – C v O 2 ). In this expression Q ̇ is the cardiac output and CaO2 and CvO2 are, respectively, the arterial and venous oxygen contents.
Estimating the difference in oxygen saturation of hemoglobin in arterial versus venous blood
In practice, oxygen consumption is often estimated from the difference in oxygen saturation of hemoglobin in arterial versus venous blood. Consider the expressions for arterial and venous oxygen contents: CaO2 = (SaO2 ⋅ [Hb] x 1.39) + (0.003 ⋅ PaO2). CvO2 = (SvO2 x [Hb] x 1.39) + (0.003 ⋅ PvO2). The freely-dissolved components (the second terms) are very small and essentially can be ignored. For the hemoglobin-bound components, the only factor that will vary between arterial and venous blood will be the percent saturation SaO2 and SvO2. This gives: V ̇O2 = Q ̇ x (SaO2 – SvO2) x [Hb] x 1.39 as a useful expression to estimate oxygen consumption. Hemoglobin saturation of venous blood is ~75% (SvO2 = 0.75), which is 23% less than for arterial blood (SaO2 = 0.98). Using values of [Hb] = 15 g/100 ml and Q ̇ = 5000 ml/minute, we obtain an oxygen consumption V ̇O 2 = ~240 ml O2/minute (for these calculations, again remember that the value 1.39 has a ml/gram associated with it). This value for consumption V ̇O 2 compares with an oxygen delivery of 1000 ml oxygen/minute, which indicates that in a healthy individual at rest oxygen delivery far exceeds use.
PO2 change at the level of inspired air
At the level of inspired air, PO2 depends on the barometric pressure, as well as on the fraction of oxygen present (which can be artificially increased or decreased). After oxygen is brought into the system, its partial pressure is sequentially reduced. First, the inspired oxygen is diluted by water vapor. Subsequently, oxygen in the alveoli is further diluted through gas exchange with blood and the introduction of CO2. The oxygen tension in the alveoli will depend on the alveolar ventilation, V ̇A , as well as on oxygen uptake (which is the same as oxygen consumption, V ̇O2).
PO2 change at the level of alveolar
There is also an additional drop in tension between alveolar and arterial blood, due to venous admixture. The admixture consists of two components: (a) shunted venous blood and (b) a component due to ventilation/perfusion mismatch. Impaired diffusion across the alveolar/capillary membrane is usually not a significant factor influencing the alveolar/arterial PO2 difference, except during exercise at high altitude or during severe disease.
PO2 change at the level of capillaries
At the level of capillaries within the tissues, PO2 will depend on the hemoglobin concentration, which sets how much O2 can be carried to the capillaries, blood flow (Q), and the dynamics of oxygen-hemoglobin binding. Between the capillaries and the mitochondria in the cells where O2 is being utilized, there is a significant drop in PO2, which is a result of the limits of O2 diffusion and utilization of O2 in mitochondria. The gradient is of course important for maintenance of O2 delivery to mitochondria. PO2 reaches its lowest level at mitochondria, where it is within the range of 4 to 23 Torr, varying from one tissue to another, from one cell to another, and from one part of a cell to another.
Oxidative phosphorylation in mitochondria
continues normally down to a level of about PO2 = 1-2 Torr, below which oxidative phosphorylation and oxygen consumption drops. The critical point at which oxidative phosphorylation drops significantly is called the Pasteur point and varies between organs. Above the Pasteur point, oxidative phosphorylation and oxygen consumption are independent of PO2.
Assessment of arterial oxygenation from blood gas measurements
Complete assessment of arterial oxygenation requires measurement (or calculation) of the: 1) arterial oxygen tension (PaO2) 2) oxy-hemoglobin saturation (SaO2) 3) The alveolar-arterial (A-a) pressure gradient for oxygen 4) blood oxygen content (CaO2). The oxy-hemoglobin saturation provides the single best reflection of oxygen content because nearly all the oxygen in the blood exists as oxy-hemoglobin. Note that this is directly measured in a blood gas machine. An unusually low oxy-hemoglobin saturation in someone with normal PaO2 can indicate the presence of something competing with oxygen for hemoglobin (e.g., carbon monoxide). Note that this is a measured saturation of hemoglobin on an arterial blood gas and not estimated as is the case in a pulse oximeter measured non-invasively on a finger.
hypoxemia vs desaturation
it should be pointed out that hypoxemia and desaturation are not the same thing. You can, under some conditions, be hypoxemic without being desaturated (if PaO2 90%). You can also be desaturated without being hypoxemic (if SaO2 saturation is 65 mmHg). Use language correctly to avoid sloppy thinking. If you only know the saturation of a patient (based on pulse oximeter for example) you don’t know about the PaO2 or about potential gas-exchange abnormalities (A-a gradient). An arterial blood gas is required to make the diagnosis of hypoxemia.
The special case of carbon monoxide
Carbon monoxide (CO) presents a particular challenge to oxygen delivery because of its effect on hemoglobin. CO, the byproduct of partial combustion of heaters and engines, binds to hemoglobin with 210 times greater affinity than oxygen. This means that breathing 0.1% carbon monoxide for a period of time (overnight in a house with a malfunctioning heater) can lead to 50% oxy-hemoglobin and 50% carboxy-hemoglobin (0.1% CO in the alveoli is about 0.5 torr compared with 100 torr for oxygen at sea level). This can be a lethal reduction of oxygen content. Remember the equation for oxygen content (CaO2 = (SaO2 ⋅ [Hb] x 1.39 ml O2/gm Hb) + (0.003 x PaO2)). Carbon monoxide reduces content by competing with oxygen for sites on hemoglobin. In the above case, the oxygen content is severely reduced because of the decreased saturation of hemoglobin with oxygen bound to hemoglobin. Carbon monoxide does not decrease the PaO2 only the SaO2. The amount of carboxy-hemoglobin can be measured directly with a blood gas. Some heavy smokers can have 8 to 10% carboxy-hemoglobin. In addition to reducing arterial oxygen content, CO shifts the oxygen-hemoglobin dissociation curve to the left, which decreases the off-loading of oxygen from hemoglobin at the tissue level. Therefore carbon monoxide not only reduces oxygen content (and therefore delivery) but also prevents the oxygen that is delivered to tissues from leaving hemoglobin and diffusing into tissues. Additionally, CO can also poison the electron transport chain resulting in cellular anaerobic metabolism as well. CO is therefore a “triple threat”. This is why carbon monoxide poisoning is so deadly. It is odorless, does not cause dyspnea (it does not stimulate the carotid and aortic bodies) and does not cause cyanosis. Signs range from mild confusion and headache to obtundation and death.
Carriage of CO2 in blood
CO2 is a product of the oxidation of metabolites in tissues. At rest, there is production of 150-200 ml carbon dioxide/min. This CO2 is removed by the blood and excreted by the lungs. CO2 is transported by the blood in three main forms: (1) Carbon dioxide (CO2). Dissolved gas. CO2 is much more soluble in blood than O2, having a solubility coefficient of aCO2 = 0.03 mM / Torr (as compared to aO2 = 0.0013 mM/Torr). For a typical arterial PCO2 (PaCO2) of 40 Torr, the concentration of free CO2 will be 1.2 mM. (2) Bicarbonate ion (HCO -). It is produced by the hydration of CO2. The first, hydration reaction to produce carbonic acid (H2CO3) is catalyzed by an enzyme, carbonic anhydrase, which is present inside red blood cells and the endothelium. Carbon dioxide produced in tissues freely diffuses across cell membranes, including the membrane of the red blood cell. The dissociation of carbonic acid into protons and bicarbonate ions is very rapid (microseconds). Bicarbonate is highly soluble and it is the major form in which the produced carbon dioxide is transported by the blood. A typical bicarbonate concentration at sea-level is ~24 mM. Most of the bicarbonate is produced from CO2 inside the red blood cells. Bicarbonate cannot diffuse freely across the red blood cell membrane. Instead, there is a HCO -/Cl- exchanger, which allows for the transport of HCO - across the cell membrane. The contribution of carbonic acid (H2CO3) to CO2 carriage is negligible, owing to the very fast rate at which H2CO3 dissociates into protons and bicarbonate. (3) Carbamino compounds. CO2 can also be transported bound to proteins, as carbamino compounds. Almost all carbamino carriage is by hemoglobin. About 1.2 mM of CO2 in arterial blood is carried in the form of carbamino compounds.
The arterial-venous difference
Obviously, venous blood carries more CO2 than arterial blood. One reason is that venous blood has a higher PCO2. There is an additional minor reason, the enhanced contribution of carbamino compounds, specifically hemoglobin, to CO2 carriage. It turns out that de-oxygenated hemoglobin, much more abundant in venous blood, binds CO2 better than oxygenated hemoglobin (this is an indirect result of the fact that de-oxygenated blood is in a reduced form). This enhanced CO2 carriage by hemoglobin in venous blood, about 50% greater than in arterial blood, is known as the Haldane effect.
Normal pH in humans
In humans, our normal pH is 7.4 (7.38-7.43, perhaps a bit higher here in Denver) and the range compatible with life is approximately 6.8-7.8, a fairly narrow range that must be maintained by the buffering systems in the body. There are 2 main types of buffers: intracellular and extracellular. There are other mechanisms of dealing the acid load produced by the body, primarily renal mechanisms of acid excretion that involves ammonium production and bicarbonate retention. Additionally, the cells can swap potassium ions for protons to help buffer acid.
Intracellular buffers
organic phosphates, proteins. The most important intracellular protein is hemoglobin, which will be discussed a bit later.
Extracellular buffers
phosphate, bicarbonate and plasma proteins (mostly albumin). Bicarbonate is the most important buffer here, and the one that we will focus on.
Henderson-Hasselbalch equation
pH=pK+ log[A-]/[HA]. pK is a characteristic of a specific buffer and is the pH at which the concentration HA equals A- (see figure to right). Buffering is best when the pH of
the solution is closest to the pK of the buffering pair.
Thus, for humans, the best buffer ought to be close to normal pH (7.4). Let’s look closer at the most important extracellular buffer, HCO3-.
Bicarbonate acid-base balance
pH = 6.1 + log [HCO3-]/ (0.03*Pco2). For a normal bicarbonate concentration of 24 mM (at sea-level) and an arterial PCO2 of 40 Torr, the Henderson-Hasselbalch equation gives arterial blood pH of 7.40. Thus, bicarbonate is the most important buffer in the body for several reasons: 1. It is present in relatively high concentration (higher than phosphate)
2. The pK is relatively close to arterial pH and 3. The conjugate acid, CO2, is readily controlled via ventilation by the lungs. Indeed, the lungs excrete more than 10,000 mEq of acid per day in the form of CO2. By contrast, the kidneys excrete less than 100 mEq of acid per day. Before turning to the issue of acid/base disturbances, let’s revisit the most important intracellular buffer, hemoglobin. Hemoglobin is abundant in red blood cells and as they enter the capillaries, oxygen dissociates from hemoglobin and diffuses into the tissues. Deoxyhemoglobin has a pK of 7.9, so is a very good buffer. Carbon dioxide can then diffuse into red blood cells, where it is rapidly converted to bicarbonate and the protons are buffered by deoxyhemoglobin. Thus, venous pH is only slightly lower than arterial blood, about 7.37, despite all of the CO2 it transports.
Disturbances of acid/base balance
The acid/base status of normal arterial blood can be altered in two general ways: (a) by altering PCO2 resulting in a respiratory disorder or (b) by too much or too little acid, resulting in a metabolic disturbance. Too much acid in the blood is referred to as acidemia, and conversely too much base in the blood is referred to as alkalemia. Because CO2 can be regulated by the lungs and bicarbonate can be regulated by the kidneys, the body will attempt to compensate for any acid-base disturbance to try and correct the pH back towards normal. However, compensation will never completely correct the initial acid-base disorder. There are four types of acid-base disturbances and compensation for each: respiratory acidosis, respiratory alkalosis, metabolic acidosis, and metabolic alkalosis.
Respiratory acidosis
This is caused by an increase in arterial PCO2, leading to a decrease in pH (see the Henderson-Hasselbalch equation). Hypoventilation (reduced ) leading to increased PCO2 can be either acute or more chronic. For example, emphysema/chronic bronchitis (COPD) and bronchiectasis can lead to chronic hypercapneic respiratory failure. Central hypoventilation disorders (obesity hypoventilation is a classic example) and neuromuscular diseases (e.g. ALS, AKA Lou Gehrig’s disease) can also lead to chronic respiratory failure. The most common cause of acute respiratory failure is drugs that suppress the breathing centers in the brainstem. Opiates, benzodiazepines and alcohol are the most common, but the list of CNS depressants is long. Another cause of acute respiratory failure is simply muscle fatigue. It is not an inherent problem with the respiratory muscles, but they cannot continue to perform the required work. For example, if you have a bad pneumonia and you are breathing really fast because your brain senses you are hypoxemic, eventually your respiratory muscles may fatigue, then your minute ventilation falls and you start to retain CO2 resulting in an acute respiratory acidosis. Compensation of respiratory acidosis takes place through conservation of bicarbonate by the kidneys. The kidneys excrete protons in the form of NH4Cl, while retaining bicarbonate. This compensatory mechanism is relatively slow, taking two to three days to complete.
Respiratory alkalosis
This is caused by a decrease in arterial PCO2, leading to an increase in pH. The decrease in PCO2 can result only from ventilation that is excessive in relation to carbon dioxide production. Again, there are acute and chronic forms. The most common causes of chronic alveolar hyperventilation include residence at high altitude (due to excessive respiratory drive resulting from hypoxia), and neurological disorders that decrease inhibitory input to the respiratory center in the brain. Chronic salicylate (aspirin) toxicity can cause a respiratory alkalosis (as well as a metabolic acidosis, see below). Acute alveolar hyperventilation, resulting in alkalemia, is more commonly seen and is generally due to pain or anxiety. Additionally it can occur during mechanical ventilation with a minute volume set on the machine that is too high. Compensation of respiratory alkalosis takes place through the kidneys, which increase the excretion of bicarbonate and lower the pH toward its normal value. Renal compensation for respiratory alkalosis is slow, taking hours or days.
Metabolic acidosis
This is caused by a primary addition of an acid other than CO2 leading to a reduction in bicarbonate. There are two major classes of metabolic acidosis, but first we must discuss the anion gap.
The Anion Gap
The blood is electrochemically neutral, meaning that the concentration of cations is balanced by the concentration of anions. The major cation in serum is sodium and the major anions are chloride and bicarbonate. These values are easily measured as part of a basic metabolic panel on patients’ serum. There are other cations and anions, which are generally at lower concentrations and/or less commonly measured (potassium, plasma proteins, phosphate, sulfate, etc). These unmeasured substances lead to a difference between sodium concentration and the two major anions, and that difference is called the anion gap (AG). AG = Na+ - (Cl- + HCO3-) = 12 ± 2 under normal circumstances. Thus, if the anion gap is larger than normal, there are additional unmeasured acids in the blood and the resulting metabolic acidosis is referred to as an anion gap metabolic acidosis. If the anion gap is not elevated but the pH is low, then a non-gap metabolic acidosis exists. It occurs either because of GI losses (i.e. diarrhea which has a high bicarbonate concentration) OR Renal losses (failure to reabsorb bicarbonate or retention of H+). This will be covered more completely in your Renal block. Another common cause is giving large quantities of normal saline (0.9% NaCl) to patients, who retain more chloride than normal and bicarbonate drops resulting in a metabolic acidosis. It is seen commonly in the ICU but is generally corrected by the kidneys over hours to a day.
mnemonic for the most common causes of an anion gap acidosis
MUDPILES = Methanol, Uremia, Diabetic ketoacidosis (and other causes of ketoacidosis such as starvation and alcoholism), Propylene glycol, Isoniazid, Lactate, Ethylene glycol and Salicylates.
Winter’s formula
Compensation for a metabolic acidosis is increased ventilation, resulting in the removal of more CO2 and compensating for the initial pH change. This compensation takes place quickly. Winter’s formula is used to calculate the expected pCO2: Expected pCO2 = 1.5[HCO3-] + 8 ± 2. If the pCO2 measured on the blood gas is in the range of the expected value then the compensation is considered complete. If the pCO2 is higher than expected then it is incomplete (or you could say there is a primary metabolic acidosis with a respiratory acidosis; both are correct ways of describing the acid-base problem).
Metabolic alkalosis
This is caused by a primary increase in a base such as bicarbonate or decrease in acid other than CO2. Examples of base-additions include ingestion of antacid tablets or sodium bicarbonate (AKA baking soda). Acid-loss can occur during vomiting, which causes loss of gastric acid. The final cause of a metabolic alkalosis is hypovolemia, which causes re-absorption of bicarbonate by the kidney. This contraction alkalosis will be discussed further in your renal block. Compensation for the increase in pH leads to a decrease in ventilation and an increase in PCO2. This would tend to bring the pH back towards its normal value. However, the respiratory compensation in metabolic alkalosis is often small or absent, because this respiratory compensation reduces the alveolar and arterial PO2. Generally speaking your brain does not allow you to hypoventilate to the point of hypoxemia, so alkalemia tends to have a smaller effect on ventilation than does acidemia.
The Davenport Diagram
One useful tool for summarizing acid-base disturbances is the Davenport Diagram. This is a plot that shows the relationship between 3 variables: pH on the x-axis, plasma bicarbonate on the y-axis, and PCO2, which is represented as a series of curves of iso-PCO2. A quick glance of the PCO2 curves in the figure (20, 40, and 60 Torr) shows what you would expect: PCO2 generally increases as pH decreases; PCO2 also increases as bicarbonate increases. These relationships fall naturally out of the dissociation of carbon dioxide to protons and bicarbonate. Each iso-PCO2 curve on the diagram is quantitatively described by the Henderson-Hasselbalch equation.
Interpreting acid/base status
If a patient comes in with abnormal arterial pH (out of the range of 7.38-7.43), there are numerous questions that you will need to ask: 1) What is the primary acid-base abnormality? Is it acidosis or alkalosis? Is the cause respiratory or metabolic? Is it an acute or chronic problem?
2) Is there compensation (secondary) for the primary abnormality? Is it adequate? 3) Might there be more than one acid-base abnormality? Answers to these questions can be obtained by appropriately interpreting blood gas measurements. The key ones here include pH, PaCO2, PaO2, and [HCO3–]. PaCO2 and PaO2 are especially useful for giving information about the respiratory status. [HCO3–] is especially useful for discriminating whether the primary acid/base abnormality is metabolic in origin and also gives information about renal compensation for respiratory disturbances.
important numerical relationships that fall out of the Henderson-Hasselbalch equation
1) For respiratory disturbances, an acute change in PaCO2 of 10 Torr yields a pH change of about 0.08 (increased PaCO2 leads to decreased pH). By “acute”, we mean a situation in which there has not been enough time for renal compensation. 2) For chronic respiratory disturbances, a change in PaCO2 of 1 Torr should lead to compensatory change in [HCO3–] of 0.4 meq/L in the same direction (e.g., increases in [HCO3–] for increases in pCO2) to bring the pH back to normal. 3) For metabolic disturbances, a decrease in [HCO3–] of 1 meq/L should result in a decrease in PaCO2 of 1.3 Torr and an increase in [HCO3-] of 1mEq/L should result in an increase in PaCO2 of 0.7 Torr to bring the pH back to normal. Generally we will use Winter’s formula to calculate the expected PaCO2 in metabolic acidosis.
The respiratory center
The respiratory rhythm is generated in the medulla, which is in the lower portion of the brain-stem just below the pons and above the spinal cord. The medulla can generate a rhythm spontaneously, without input from the lungs or anywhere else in the body. A likely candidate for the rhythm generator is the rostral ventrolateral medulla, and specifically an area called the pre- Botzinger complex. The breathing rhythm drives the respiratory motoneurons and interneurons in the spinal cord, which then drive the respiratory muscles, both inspiratory and expiratory. Recall from an earlier lecture that, during quiet breathing, expiratory muscles are silent; inspiration and expiration are caused by the contraction and relaxation of inspiratory muscles. Expiratory muscles are stimulated by the medullary inputs under conditions of exercise or forced breathing. While the medulla generates the breathing rhythm without input from other areas, the frequency of breathing can be markedly modulated by these inputs.
Peripheral chemoreceptors
These are divided into two groups, the carotid and aortic chemoreceptors. The carotid group is located in the carotid bodies, which are small nodules of tissue found bilaterally at the bifurcation of the common carotid arteries into the internal and external carotids. The aortic group is located in the aortic bodies, found around the arch of the aorta and between the arch of the aorta and the pulmonary artery. Both groups are stimulated by decreases in arterial PO2 or increases in PCO2. The carotid group is also stimulated by decreases in arterial pH. Both groups of peripheral chemoreceptors are involved in cardiovascular and respiratory regulation, but the carotid group exerts the dominant effect on respiration. The most important function of the carotid bodies is to sense the level of O2. In general, the carotid body- mediated response increases for decreasing PO2, with significant steepening of the relationship occurring around 60 Torr. At sea-level O2 receptors are basically not activated at all, and are only modestly activated in Denver, where arterial PO2 is 70-80 Torr. Carotid bodies also respond to changes in CO2, but they are generally not as important as the central chemoreceptors in this regard. When a subject is given CO2 to breathe, the peripheral chemoreceptors are responsible for only about 20% of the total ventilatory response. A key feature of the responses of carotid bodies to changes in CO2 and pH, however, is that they are very rapid. This is important during sudden physical exertion, when the respiratory system must quickly match ventilation to metabolic rate. The carotid bodies are also important during metabolic acid-base disturbances, as they are the sole detectors of arterial pH in the body that can mediate ventilatory changes.
Central chemoreceptors
The central chemoreceptors are situated close to the ventral surface of the medulla. They bind to protons in the brain, but, somewhat paradoxically, they are not sensitive to the level of protons in arterial blood, but instead arterial PCO2. This can be understood by recalling that the brain and its surrounding cerebrospinal fluid CSF are separated from the blood stream by the blood-brain barrier. The blood-brain barrier membrane greatly restricts diffusion of ions such as H+ between blood and CSF, while it allows free diffusion of fat-soluble substances like CO2. CO2 first crosses the blood-brain barrier into the CSF, where it combines with water and dissociates into protons and bicarbonate. The chemoreceptors then bind the protons and stimulate breathing (increase ventilation V ̇A ). There are no central chemoreceptors for oxygen. Since the CSF contains much less protein than blood, it has a much lower buffering capacity. As a result, the change in CSF pH for a given change in P is greater than in blood. This is part of the reason why the central chemoreceptors provide such a strong response to changes in blood PCO2. It is important to note that the response of the central chemoreceptors to changes in blood PCO2 takes a relatively long time to develop (CSF has to equilibrate with the blood PCO2, and this takes minutes). If arterial PCO2 is maintained at an abnormal level, the blood pH gradually returns towards normal over the time-course of several hours-to-days as a result of renal control of blood bicarbonate levels. The time-course of pH recovery in the CSF in response to abnormal PCO2 is rather slower, taking a few days. The reason for this is the additional time it takes for passive redistribution of bicarbonate ions across the blood barrier. The recovery of the CSF pH through the compensatory change in bicarbonate is of primary importance for the initial acclimatization to high altitude.
Cortex inputs into the respiratory center
Inputs from the cortex are important for voluntary control of breathing and essential for speaking, singing, sniffing, coughing and expulsive efforts. There are also inputs from the limbic system and the hypothalamus, which can influence the pattern of breathing in emotional states.
Pons inputs into the respiratory center
This structure has historically been considered to play a primary role in the control of breathing. The pons is not essential for the generation of the respiratory rhythm. Nevertheless, its input is important in the modification and the fine control of the respiratory rhythm, for example, in setting the lung volume at which inspiration is terminated.
Pulmonary stretch receptors inputs into the respiratory center
They lie in airway smooth muscle, are activated by lung distension, are slowly adapting, and are innervated by large, myelinated vagal fibers. These receptors provide the basis for the inflation reflex. This consists of inhibition of inspiration in response to sustained inflation of the lung. In adults, this reflex is usually inactive, unless the tidal volume exceeds 1 liter, as in exercise.
Pulmonary irritant receptors inputs into the respiratory center
They lie between airway epithelial cells, are activated by irritants like smoke, noxious gases, cold air, are rapidly adapting, and are innervated by myelinated vagal fibers. The reflex effects of their stimulation include hyperpnea (increase in ventilation without a decrease in alveolar PCO2) and bronchoconstriction.
Juxtapulmonary capillary (Type J) receptors inputs into the respiratory center
They lie in or near the walls of the pulmonary capillaries and are activated by an increase in pulmonary interstitial fluid, which occurs, for example, in pulmonary congestion and edema. They are rapidly adapting and are innervated by slowly conducting nonmyelinated vagal fibers. The reflex effects caused by these receptors include apnea, hypotension, and bradycardia. Their physiological role is unclear.
Nose and upper airway receptors inputs into the respiratory center
The nose, pharynx, larynx and trachea contain receptors that are an extension of the irritant receptor system described above. These receptors respond to chemical and mechanical stimulation. Irritants can initiate sneezing. Presence of solids or liquids in the pharynx may initiate the swallowing reflex, which involves laryngeal closure. Chemical and mechanical stimulation of the larynx cause cough, laryngeal closure, and brochoconstriction.
Joint and muscle receptors inputs into the respiratory center
A variety of mechanical stimuli applied to muscle can produce a reflex increase in ventilation. Afferents from the musculoskeletal system probably have an important role in the stimulation of ventilation during exercise.
Gamma system inputs into the respiratory center
Muscle spindles are abundant in the intercostal and abdominal wall muscles, but scarce in the diaphragm. The spindles sense the elongation of the muscle and they control the strength of contraction. Spindle afferents provide information to the cortex that allows respiratory movements to be perceived consciously.
Arterial baroreceptors inputs into the respiratory center
The most important arterial baroreceptors are in the carotid sinus and the aortic arch. These receptors are primarily concerned with regulation of circulation, but a decrease in blood pressure stimulates breathing, while a rise in pressure causes respiratory depression and, ultimately, apnea.
Pain and temperature inputs into the respiratory center
Pain stimulates breathing, as do changes in temperature. A cold shower stimulates breathing as does an increase in skin temperature.
Integrated responses under special conditions, like high altitude
Exposure to high altitude entails a lower inspired PO2. The resulting hypoxia stimulates breathing through the peripheral chemoreceptors. The increase in ventilation leads to a reduction in blood PCO2 and an increase in blood and CSF pH, which opposes the initial stimulation of breathing. After a few days, the pH of the CSF recovers through compensatory changes in CSF bicarbonate and the major opposition to the hypoxic stimulation of breathing is eliminated. The blood pH also recovers through the excretion of bicarbonate by the kidneys, eliminating the suppression of peripheral chemoreceptor activity. These changes allow ventilation to increase above the initial value, allowing blood O2 to rise above initial levels. Long periods of residence at high altitude result in adaptation, involving an increase in the number of red blood cells (polycythemia) and increased vascularity of heart and striated muscles. Polycythemia increases the oxygen capacity of the blood (hemoglobin concentrations up to 22.9 gr/dl have been observed in Andean miners) but at the same time it increases blood viscosity. Long-term exposure to high altitude can also result in increased vascularity in muscle. The increased vascularity allows for increased perfusion, which compensates very effectively for the reduced oxygen content of the arterial blood.
Integrated responses under special conditions: Exercise
Exercise increases metabolism and the demands on the respiratory system for oxygen delivery and carbon dioxide elimination. The central and peripheral chemoreceptors for PCO2 and pH (discussed in this lecture) play the most important role for ensuring that CO2 removal keeps up with production. Specifically, the increase in arterial PCO2 and the resulting decrease in pH lead to activation of chemoreceptors, which in turn send signals to the respiratory center in the brain to increase ventilation. The increase in ventilation is accomplished by both increases in breathing frequency and tidal volume. During moderate exercise, alveolar ventilation goes up by as much as a factor of 10. If one plots the relationship between oxygen consumption or CO2 production and ventilation, there is generally a linear relationship for moderate exercise. However, with very intense exercise, ventilation increases more steeply. This is shown in Fig. 4, which plots the relationship between oxygen consumption V ̇O 2 and minute ventilation (a similar relationship would be seen between CO2 production and ventilation). The steeper increase at high V ̇O 2 occurs because lactic acid is liberated, which increases the proton-mediated ventilatory stimulus. Sometimes there is a clear break in the slope, which has been called the anaerobic threshold, although the term is somewhat controversial.
Bronchial Circulation
Human bronchial arteries normally arise directly from the aorta or upper intercostal arteries and usually number from two to four (average = 2.8). Since they arise from the aorta they are considered systemic arteries with systemic pressures. They supply the trachea, the airways down to the terminal bronchioles as well as other structures such as parts of the esophagus and the vaso-vasorum of the aorta. The bronchial circulation is important in fetal lung development and also protects the lung against the infarcting effects of pulmonary emboli. Although pulmonary emboli are rather common, pulmonary infarction is not, primarily due to the collateral blood supply via the bronchial circulation. In chronic pulmonary inflammatory states (like chronic bronchitis and bronchiectasis) the bronchial arteries enlarge and provide increased blood flow. The source of most bleeding in the lung (hemoptysis) is the bronchial circulation not the pulmonary circulation. When patients have severe persistent hemoptysis (frequently as a complication of bronchiectasis or cystic fibrosis) the offending bronchial artery can be identified by radiography and embolized to stop the bleeding (via interventional radiology).
The Pulmonary Circulation
The pulmonary circulation sits between the right and left ventricles. Its main function is to facilitate the delivery of blood under low pressure to the micro- circulation which allows for adequate exchange of carbon dioxide and oxygen. The pulmonary circulation begins at the pulmonary valve (the exit from the right ventricle) and extends to the orifices of the pulmonary veins in the walls of the left atrium. The pulmonary circulation includes the pulmonary trunk, the right and left main pulmonary arteries and their lobar branches, intra-pulmonary arteries, arterioles (pre-capillary vessels), capillaries, venules (post-capillary vessels), and large pulmonary veins. Pathologic changes in any of these vessels can cause problems.
Types of arterial vessels apart of pulmonary circulation
large elastic pulmonary arteries, muscular pulmonary arteries, and pulmonary arterioles. The large elastic arteries include the pulmonary trunk, the main pulmonary arteries, all extra-alveolar arteries, and arteries within the lung that have elastic fibers encoded in a bed of muscle (down to about 500um). These vessels are not constrictors, but like the elastic aorta absorb the pulsatile pressure of the flowing blood. The muscular pulmonary arteries (70-500um diameter range) have a thin medial (muscular) layer and are probably responsible for regulation of blood flow in response to hypoxia and other stimuli. As these vessels divide they gradually lose their muscle and become pulmonary arterioles (8-70um diameter)- the terminal branches of the pulmonary arterial system. Arterioles supply alveolar ducts and alveoli. The diameter of capillaries is about 8um.
Pulmonary veins
have thinner walls than arteries because the muscular layer is less developed. Small intrapulmonary venules combine to form increasingly larger veins and finally a single lobar vein emerges from each lobe.
The pulmonary vascular bed
a highly distensible circulation. The pulmonary vessels are about seven times more compliant than systemic vessels primarily due to less smooth muscle and elastic fiber content. All these factors combine to create a low resistance, high volume vascular bed ideal for gas exchange. The pulmonary artery pressure is about 25/10 with a mean of approximately 15 mmHg- about one sixth that of the systemic circulation. Because the right ventricle propels blood through such a low resistance system it requires less wall tension to be generated in the ventricle and thus has a much thinner wall than the left ventricle. Unfortunately when the pulmonary resistance increases pathologically (pulmonary hypertension) the right heart is put under significant stress, which it is not able to handle, and can result in right heart failure (cor pulmonale).
Ohm’s law applied towards blood circulation
Since the pulmonary circulation is a resistance bed it can be viewed in terms of Ohm’s law (V = IR). V in this case is the drop in pressure across the pulmonary circulation [mean pulmonary artery pressure (PPA) minus the pressure at the end of the pulmonary circulation, the left atrial pressure (PLA) or pulmonary capillary wedge pressure (PCWP)]. Restating Ohm’s law in these terms yields the following equation, which represents the pulmonary circulation: PPA- PLA = CO x PVR where
PPA = mean pulmonary artery pressure PLA = left atrial pressure (wedge pressure) CO = cardiac output
PVR = pulmonary vascular resistance The lung is not like a fixed pipe, however. As flow (cardiac output) increases, the pulmonary artery pressure does not increase linearly. For example when you exercise, although your cardiac output may increase from 5 to 20 L/minute your mean pulmonary pressure does not increase 4 times (i.e. from 15 to 60 mmHg), but probably closer to 1.5 or 2 times (i.e. from 15 to 25 mmHg).
Pulmonary circulation in response to an increase in cardiac output
in response to an increase in cardiac output the pulmonary circulation has a decrease in its intrinsic resistance. There are two key ways this is done: 1) high distensibility of the perfused vessels. 2) recruiting previously unperfused vessels (this also decreases alveolar deadspace). For example, when standing upright at rest, most of the cardiac output goes to the bases of the lung due to gravity. With exercise, cardiac output increases and the increased flow goes to the upper lobe vessels. Therefore pulmonary pressures increase only slightly.
Echocardiography
Echocardiograph is a non-invasive method to determine an estimated pulmonary artery pressure. This is done using the Modified Bernoulli equation, which states Δ pressure = 4 x velocity2. We can apply this equation to the tricuspid valve, with the velocity being the peak Doppler-measured velocity of the regurgitant jet through the tricuspid valve. The equation then becomes (Right ventricular systolic pressure) – (Right atrial pressure) = 4 x (Maximum tricuspid regurgitant jet velocity)2. There are several assumptions required to apply this equation:
The tricuspid valve is actually leaky and has a regurgitant jet. The Doppler signal of the tricuspid valve regurgitant jet can be well
measured. The right atrial pressure is known or can be estimated. There is no significant pulmonary valve disease, which will result in a
difference between the right ventricle systolic pressure and the pulmonary artery systolic pressure. Given these assumptions and general inaccuracies about doing the measurement (when you perform the square of an inaccurate number, things get very inaccurate quickly), +/- 5mmHg is extremely common and +/- 10mmHg or more is definitely seen.
Right heart catheterization
Using the “flow directed” pulmonary artery catheterization method developed by Drs. Swan and Ganz (“Swan-Ganz catheterization”), a flexible pulmonary artery catheter is inserted in a central vein with an air-filled balloon at the tip. The balloon is advanced and the blood flow carries the catheter through the right heart and into the pulmonary artery. The pressure is measured through the tip of the catheter, and this is a true measurement: no equations or approximations needed. The catheter can then be advanced a little extra far until the balloon occludes a small branch of a pulmonary artery, measuring the pulmonary artery (or capillary) occusion (or wedge) pressure (PAOP/PCWP). As the flow of blood distal to the catheter is zero, there is no pressure drop, and this measurement is thus approximately equal to the left atrial pressure, and (assuming no mitral valve disease) the left ventricle end-diastolic pressure. The right ventricle diastolic pressure is about equal to the right atrial pressure (if there is no tricuspid valve stenosis: very uncommon).
The right ventricle systolic pressure is about equal to the pulmonary artery systolic pressure (if there is no pulmonary valve stenosis: fairly uncommon). There may or may not be a decrease from the PA diastolic pressure to the pulmonary artery wedge pressure, depending on whether or not there is intrinsic pulmonary vascular disease (i.e. pulmonary arterial hypertension). A difference of more than 5 mmHg between the PA diastolic pressure and the PCWP suggests pulmonary vascular disease.
Matching of perfusion to ventilation
An important factor controlling the pulmonary circulation (and therefore ventilation-perfusion, or V/Q, matching) is gravity. The height of the lung is about 30 cm from apex to base. The pulmonary artery enters the lung at midway (about 15 cm). (Note that 15 cm H20 pressure is equal to 11 mmHg pressure: the density of mercury is 13.6 g/cm3). Therefore, if the mean pressure measured at the pulmonary hilum is taken as 13 mmHg then the pressure at the base will be 24 while at the apex it will be 2 mmHg. Clearly at rest, blood flow follows gravity and is greater at the base of the lung.
Regional distribution of pulmonary perfusion
Three pressures are important in determining pulmonary blood flow: 1) alveolar pressure (PA), 2) pulmonary arterial pressure (Pa), and 3) pulmonary venous pressure (Pv). The relative magnitude of these pressures passively regulates pulmonary blood flow and has traditionally been classified into three different physiologic zones, also known as the West zones of the lung. Alveolar pressure is constant throughout the lung (from apex to base), because the density of air is negligible when considering the 30cm of lung height. Because of gravity and the density of blood, however, pulmonary artery pressure increases from apex to base. Therefore, the closer to the base in the upright person, the greater the driving force (Pa) for blood flow.
Zone 1
the region where PA exceeds Pa which in turn exceeds Pv (PA> Pa> Pv). In this zone the pulmonary microvasculature is compressed because the (positive) alveolar pressure exceeds the arterial driving pressure. Blood flow in zone 1 is minimal. In an upright person this can be found in the apices of the lung, but is minimal in a healthy individual.
Zone 2
that part of the lung in which pulmonary arterial pressure exceeds alveolar pressure, but alveolar pressure exceeds venous pressure (Pa> PA> Pv). The driving pressure in this zone therefore is the difference between arterial and alveolar pressure. Flow is greater than in zone 1, but less than in zone 3.
Zone 3
that part of the lung in which pulmonary arterial and venous pressure exceeds alveolar pressure (Pa> Pv> PA). The driving pressure is the difference between arterial and venous pressure without contribution from alveolar pressure. The greatest blood flow occurs in this region of the lung. In zone 3 there is a solid uninterrupted column of fluid (blood) from the arterial side across the gas exchange units and into the venous side. In this way the use of a pulmonary artery (Swan-Ganz) catheter can measure pulmonary venous pressure and estimate left atrial pressure, by wedging/occluding a small artery, and measuring the pressure at the distal tip. In zone 1 or 2 a catheter would be measuring alveolar not venous pressure. Note that these are physiologic zones, not anatomic zones. That is if position changes (lying prone or supine, or standing on your head) the location of the zones will change.
Active Regulation of the pulmonary circulation
Pulmonary blood can also be actively regulated. One example of active regulation is hypoxic pulmonary vasoconstriction (HPV). This consists of contraction of smooth muscle in the small arteries in a region of lung with alveolar hypoxia. The precise mechanism of this response is the subject of extensive research, but likely involves activation or inactivation of ion channels in the smooth muscle cells of the small muscular arteries, with hypoxia potentially being sensed by the mitochondria. HPV has the effect of directing blood flow away from hypoxic areas of the lung. In general this will optimize ventilation- perfusion matching, by shunting blood away from diseased parts of the lung. This matching of ventilation to perfusion is a crucial function of the lung, although HPV is probably not necessary in a healthy lung. Note that vasoconstriction of pulmonary vessels in response to hypoxia is in complete contrast to the systemic circulation where hypoxia leads to arterial vasodilation. Other active regulators include nitric oxide, endothelin, and prostaglandin, products released by the pulmonary endothelial cells constitutively and in response to increases in shear forces on the vessel.
Matching of Ventilation and Perfusion
In a perfect world ventilation and perfusion would be totally matched (that is, each acinus (gas exchange unit) would receive just the right amount of ventilation to oxygenate the hemoglobin completely and remove the carbon dioxide). The figure below shows the theoretical distribution of V/Q ratios in the lung using five compartments. The unit in the middle corresponds to the ‘ideal’ unit with a V/Q ratio of 0.9. In this acinus ventilation is sufficient to achieve an alveolar oxygen tension (PAO2) of approximately 100 mmHg (80 mmHg at Denver’s altitude) which is adequate to attain almost 95% saturation of hemoglobin leaving this acinus. Note that the PCO2 of this ideal acinus is about 40 mmHg (35 mmHg at Denver’s altitude). Any deviation from this ideal acinus will alter the ventilation-perfusion matching and can lead to clinical problems. Since ventilation and perfusion are not uniform throughout the lung, the actual PaO2 and PaCO2 measured represent a mixture of blood draining from lung units (like the 5 compartments below). The degree of mixing can be determined by the Alveolar- arterial oxygen gradient (more in upcoming lecture).
Ventilation and perfusion mismatching with lung disease
With the development of lung disease, ventilation and perfusion mismatching increase. Any pathologic process in which alveolar air spaces are filled with transudate (heart failure) or exudate (pneumonia, ARDS) and thus do not ventilate and in which perfusion persists results in a true shunt. Airway diseases that affect regional airway resistance (bronchitis, asthma) affect ventilation distribution (the V) and thus alter V/Q matching (decreased ventilation relative to perfusion). Abnormalities of the pulmonary vasculature such as destruction of the capillary bed (as in emphysema) or obstruction of vessels (pulmonary hypertension) alter regional vascular perfusion and thus affect the Q in V/Q (decreased perfusion relative to ventilation). Complete vascular obstruction (thromboembolism) converts affected regions of lung to dead space (ventilated but not perfused). Therefore you can see that abnormalities in the pulmonary circulation can lead to abnormal gas-exchange- through either abnormal increases in dead space (high V/Q - left in figure below) or through the presence of shunt and/or V/Q mismatching (low V/Q - right in figure below).
Water and solute balance
The lung is about 80% water at baseline and is actively involved in water and solute exchange across the pulmonary circulation. Too much water, or water in the wrong places, can significantly impair the lungs’ ability to perform gas- exchange. Pulmonary edema represents a failure of the protective mechanisms that keep fluid exchange under control. Pulmonary edema is a pathologic event that results in the accumulation of excess water in the interstitial space and the alveoli. The sequence of pulmonary edema involves the initial accumulation of fluid in the interstitial spaces followed by flooding into the alveolar space. The rate of fluid movement across the microvascular endothelium into the interstitium is determined by the net hydrostatic and oncotic pressures acting along the microvascular wall. This is described by Starling’s Law
Decrease in interstitial oncotic pressure (∏i)
edema safety factor
Because the vascular endothelium is semi-permeable (i.e. allows some fluid transport), an increase in microvascular hydrostatic pressure (such as occurs in left heart failure) leads to increase fluid leaving the vascular space into the surrounding interstitial space. This fluid decreases interstitial oncotic pressure essentially by dilution (i.e. it dilutes out the oncotic protein concentration). As a result the net increase in hydrostatic force (Pmv-Pi) is partly counterbalanced by an increase in the oncotic resorptive force (∏mv- ∏i) to pull fluid back into the vessels, and net filtration (Qf) is minimized.
Increase in interstitial hydrostatic pressure ( Pi) edema safety factor
As edema fluid begins to accumulate within the interstitium surrounding the pulmonary microcirculation, there is an increase in interstitial pressure (Pi) which opposes fluid flow out of the vessels. The peri-microvascular interstitium is relatively noncompliant, therefore small increases in interstitial fluid increase Pi by 5 mmHg or more (which is a lot). Increased interstitial pressure opposes flow from the microcirculation and promotes flow into the lymphatics.
Increase in plasma oncotic pressure (∏mv)
edema safety factor
This protective mechanism is only important under extreme circumstances such as severe left ventricular failure in which 1 or 2 liters of protein poor fluid can enter the lung over a short time. The sudden loss of fluid from the microvessel increases vessel oncotic pressure (the albumin is concentrated in the vessel) and this opposes further movement of fluid into the lung.
Lymphatic Reserve System edema safety factor
The fourth edema safety factor is the reserve capacity of the lymphatic system. Lung lymph flow is a function of interstitial pressure (Pi), the pumping capacity of the smooth muscle in the collecting lymphatics, and the hydrostatic pressure in the central vein into which the thoracic lymphatics drain. As edema fluid accumulates around the terminal lymphatic vessels, pulmonary lymph flow may increase up to 15 fold to maintain a balance between the fluid that enters and that which leaves the lung. Edema accumulates in the lungs only when the reserve capacity of the lymphatics is overwhelmed.
clinically significant pulmonary edema
only two factors are known to cause this disorder: 1) an increase in microvascular hydrostatic pressure sufficient to overwhelm the protective mechanisms of the lung, resulting in hemodynamic (hydrostatic, or cardiogenic) pulmonary edema.
2) an increase in the permeability of the pulmonary microvascular walls resulting in permeability (nonhydrostatic, or noncardiogenic) pulmonary edema.
Hemodynamic pulmonary edema
This is also called hydrostatic or cardiogenic pulmonary edema. The lung is protected from modest increases in pulmonary vascular pressure by the edema safety factors discussed above. Hemodynamic edema develops when these physiologic compensatory mechanisms are overwhelmed. This can require microvascular pressures exceeding 25 to 30 mmHg (the normal range is 5-10 mmHg).
Causes of hemodynamic pulmonary edema
The most common cause of hemodynamic pulmonary edema is acute or chronic left heart failure. Other causes include severe mitral valve disease (stenosis or regurgitation) and congenital heart disease. If you recall the anatomy of the pulmonary circulation you can see that anything that increases the vessel pressure downstream from the capillaries (i.e. from the capillaries to the heart) can also cause an increase in hydrostatic pressure and lead to pulmonary edema. For example, if the pulmonary veins were compressed due to a tumor or mediastinal fibrosis, this would increase the back pressure and could lead to pulmonary edema. Renal failure can result in hemodynamic pulmonary edema if the ability of the kidneys to excrete urine is reduced (oliguric renal failure). As the intravascular plasma volume increases in a patient with oliguric renal failure, pulmonary microvascular pressure may rise and exceed the threshold for edema formation in the lung.
Diagnosis of hemodynamic pulmonary edema
Hemodynamic pulmonary edema is usually diagnosed by a correlation of clinical findings with characteristic chest radiographic abnormalities. The patient complains of dyspnea on exertion and dyspnea when lying down (orthopnea). The dyspnea frequently precedes any detectable abnormalities in gas exchange (i.e. hypoxemia). Chest radiographic findings in hemodynamic pulmonary edema reflect the physiologic basis of this disorder. The heart shadow is often enlarged reflecting dilation of the cardiac chambers. Pulmonary vessels in the upper zones appear prominent because the increase in pulmonary vascular pressure increases perfusion to these areas (cephalization of flow). Bronchial and vascular markings are blurred because of the accumulation of edema fluid in the surrounding interstitium (peribronchovascular interstitial spaces). Fluid can thicken the major and minor fissures. Also because the lymphatics and veins are engorged trying to handle the increase fluid load these can be visible in the lung periphery. These small straight lines in the subpleural region are called Kerly B lines and represent engorged lymphatics usually as a consequence of increase in vascular congestion.
Treatment of hemodynamic pulmonary edema
Importantly, the treatment for cardiogenic pulmonary edema is diuretic therapy. This will decrease the intravascular pressure and allow the fluid to leave the alveolar space.
Permeability Pulmonary Edema
This is also called non-cardiogenic or non-hydrostatic pulmonary edema. Pulmonary edema due to increased permeability is caused by acute widespread injury to the pulmonary microvascular endothelium. In the Starling equation it equates to a change of σ from near 1 (total reflection) to near zero (no reflection) of plasma proteins. Water and proteins leak from the pulmonary microcirculation into the adjacent interstitium and alveoli via the damaged vessel endothelium and alveolar epithelium. In permeability edema, acute injury to the pulmonary microcirculation increases the filtration coefficient (Kf) and decreases the osmotic reflection coefficient (σ) so that fluid leaks into the lungs at a rate that is disproportionately high relative to the net driving / hydrostatic pressure (figure at left). When the permeability of the alveolar-capillary membrane increases, edema forms even at normal microvascular hydrostatic pressures (8-12 mmHg). Severe edema develops at elevated pressures (concurrent hydrostatic and non-hydrostatic edema).
Non-cardiogenic vs. cardiogenic pulmonary edema
Permeability (non-hydrostatic, non-cardiogenic) pulmonary edema differs from hydrostatic pulmonary edema with regard to time course. Hydrostatic edema is manifest within minutes of an acute elevation of microvascular pressure and rapidly responds to therapy (i.e. diuretics to decrease vascular volume or improvement in cardiac function). In contrast, non-hydrostatic pulmonary edema presents more slowly (6-24 hours after acute lung injury). Similarly the resolution of non-cardiogenic pulmonary edema is slower as the microvascular endothelium must repair itself which takes time. Another key distinction between the two etiologies is that diuretics are not effective in treating permeability pulmonary edema.
Causes of non-cardiogenic pulmonary edema
include trauma, sepsis, inhalation of toxic gases, aspiration, amniotic fluid embolism, fat embolism, and multiple blood transfusions–to name a few. Although the causes of increased permeability are many and the mechanism by which they injure the endothelium varies, the end result is the same: microvascular endothelial cell injury leading to alveolar flooding. This leads to an increase in lung water with a resultant decrease in compliance (stiffer lungs). Gas exchange is impaired and patients develop hypoxemia. As you might suspect these patients are difficult to oxygenate and require high pressures to inflate the lung (because of low compliance). This clinical syndrome is referred to as the adult respiratory distress syndrome (ARDS), which was originally described at the University of Colorado in 1968.
Hemodynamic vs. Permeability Pulmonary Edema
Both hydrostatic and nonhydrostatic pulmonary edema present with dyspnea, hypoxemia and bilateral dense radiographic infiltrates. How can you distinguish between the two? The first clue is usually provided by history and exam. Someone with a history and symptoms suggestive of heart failure, or presenting with EKG changes and chest pain likely has hydrostatic (cardiogenic) pulmonary edema. Someone who presents with an exposure known to cause non-cardiogenic pulmonary edema, such as inhalation of toxic gas, trauma, fever and cough suggestive of pneumonia, or aspiration of gastric contents likely has non-cardiogenic pulmonary edema. The second (and most reliable) clue is provided by the left atrial pressure (as reflected by the pulmonary capillary wedge pressure). The presence of a wedge pressure less than 15 mmHg with coexistent pulmonary edema is consistent with non-cardiogenic pulmonary edema. This differentiation is important because outcome and therapy are very different. Unfortunately measurement of the wedge pressure requires placement of a pulmonary artery catheter with its associated risks, and in practice is not commonly done. In hydrostatic pulmonary edema the focus of treatment involves lowering the microcirculation hydrostatic pressure. This is commonly done by giving diuretics to reduce plasma volume or by improving cardiac function by giving inotropic drugs that enhance cardiac output. Therapy for non-cardiogenic pulmonary edema is mostly supportive. Patients frequently require prolonged mechanical ventilation with high oxygen concentrations to maintain acceptable oxygenation. They are difficult to ventilate because their lungs are stiff (noncompliant) and require high pressures from the ventilator, which can lead to barotrauma, pneumothorax and other complications. In contrast to cardiogenic edema, diuretics generally will not help decrease the alveolar fluid content in patients with non-cardiogenic pulmonary edema.
Increases in Pulmonary Vascular Resistance
the pulmonary circulation is a low resistance, high capacitance vascular bed. Marked increases in cardiac output are handled by the pulmonary circulation with only mild increases in pressure. In contrast, pulmonary hypertension is a pathologic state characterized by an increase in pulmonary arterial pressure as a consequence of an increased resistance to blood flow through the lungs. The severity of pulmonary hypertension is generally defined by the elevation of the mean PA pressure. Normal pulmonary arterial pressure is 25/10 mmHg with a mean of 15 mmHg. Elevation of mean pulmonary pressure above 25mmHg is diagnostic of pulmonary hypertension, (although not strictly defined, general ranges for severity are 25-35 mmHg is mild PH, 35-44 is moderate PH and ≥ 45 mmHg is severe PH). Pulmonary hypertension is a state, not a specific disease, and there are many causes. Pulmonary hypertension can lead to V/Q mismatch and increases the work of the right ventricle (RV). Normally the walls of the right ventricle are much thinner than the left ventricle (as the pulmonary circulation pressures are much lower, and the force and work required of the RV is less than the LV in health). The RV pumps blood through a low resistance bed and is much less capable of dealing with sudden increases in arterial pressures than the LV, leading to right heart failure. It is important to understand how pulmonary artery pressure can become pathologically elevated.
Ohm’s law and pulmonary pressure
pulmonary pressure can be described mathematically via the equivalent to Ohm’s law as: ∆Pressure = cardiac output x pulmonary vascular resistance or
∆P = CO x PVR. The change in pressure (∆P) represents the drop in pressure across the pulmonary vascular bed, that is, mean pulmonary artery pressure (Ppa) minus left atrial pressure (PLA). Rearranging the equation leads to: Ppa -PLA =CO x PVR and therefore: Ppa =Co x PVR + PLA. In this form you can see that mean pulmonary arterial pressure can be elevated by three mechanisms (assuming that the other factors stay constant which is not always true). It can be increased by an increase in: 1) PLA (such as in heart failure or mitral stenosis) 2) PVR
3) cardiac output. However, an increase in cardiac output in a normal pulmonary bed generally does not significantly increase pulmonary artery pressure because of vessel recruitment and dilation. Therefore, clinically the causes of pulmonary hypertension are either an increase in the PLA (the wedge pressure) or an increase in pulmonary vascular resistance. A concurrent increase in cardiac output (such as can occur in patients with liver failure) can worsen the situation.
Primary vascular disorders
Remember that the pulmonary circulation is a low resistance bed. This occurs because of vessel recruitment and distensibility. The obliteration of vessels or the loss of distensibility of those vessels will lead to an increase in pulmonary resistance- initially with exercise and later at rest. The key feature of this classification of pulmonary hypertension is that the lung parenchyma (i.e. the bronchi and alveoli) is normal. This represents a disease of the blood vessels only. On chest radiograph there is no pulmonary edema (as opposed to post capillary pulmonary hypertension) and there is no evidence of parenchymal lung disease (COPD, ILD etc).
Diseases that affect the pulmonary vessels only
PAH (as listed above in the WHO classification) Embolic disease (leads to vessel obliteration) thromboembolic - acute and chronic, tumor emboli, or injected emboli (i.e. a drug abuser crushing up tablets and injecting talc, etc.)
Chronic exposure to low ambient O2 (chronic global hypoxic vasoconstriction)
Mechanisms of vessel injury
Note that although the mechanisms of vessel injury are different (increase blood flow vs. embolic obliteration of vessels vs. remodeling of vascular walls) they do not involve the pulmonary parenchyma. A test that is helpful in identifying this group of patients with pulmonary hypertension is an abnormally low DLCO in the presence of normal lung function on pulmonary function tests. Remember that one of the things that decreases gas transfer is pulmonary vascular disease: poor perfusion through blood vessels or absence of effective blood vessels for gas exchange. This occurs because there is decreased blood flowing past the alveoli for the carbon monoxide to bind with. The presence of a low DLCO with normal pulmonary function (lung volumes and spirometry) should lead you to suspect the presence of pulmonary vascular disease.
PH associated with lung diseases and/or hypoxia (Group 3)
In this classification pulmonary hypertension is associated with either parenchymal or pleural disease. Such diseases include: emphysema (combined effect of chronic hypoxia and obliteration of capillaries). Remember that emphysema destroys the alveolar/capillary membrane so it destroys capillaries along with alveolar spaces. interstitial lung disease (effect of hypoxia and destruction of alveolar/capillary interface): idiopathic pulmonary fibrosis (IPF), sarcoidosis, asbestosis, silicosis, pleural disease (fibrothorax), and
chest wall deformities - thoracoplasty, kyphoscoliosis. In these diseases, pulmonary hypertension results from impaired ventilation (and resultant hypoxemia causing chronic hypoxic vasoconstriction and remodeling - see below) and/or destruction of the lung (i.e. emphysema, fibrosis). In these cases DLCO will be decreased proportionally with FEV1 and FVC.
Alveolar hypoventilation disorders
are a group of diseases are characterized by chronic elevations of PCO2 without identifiable parenchymal lung disease. The diagnostic test is an arterial blood gas. If someone has a chronically elevated daytime carbon dioxide level (greater than 40 mmHg in Denver, 45 mmHg at sea level) without parenchymal lung disease then he/she has chronic alveolar hypoventilation. In the absence of supplemental oxygen, hypoventilation leads to hypoxemia.
Causes of alveolar hypoventilation
neuromuscular disorders, obesity hypoventilation syndrome (Pickwickian syndrome), Ondine’s curse (central hypoventilation), and idiopathic
Hypoxic vasoconstriction
The combination of elevated PCO2 and low PO2 (but particularly the chronic hypoxia) leads to hypoxic vasoconstriction (HPV), which over time is thought to lead to fixed vessel wall remodeling (less distensibility), smooth muscle cell proliferation in the wall of the pulmonary arteries and some obliteration of small vessels. This fixed remodeling does not resolve with normalization of oxygen concentration. Polycythemia may also result due to the chronic hypoxemia stimulating erythropoeisis with a subsequent increase in blood viscosity (further increasing resistance through the blood vessels of the lung). Polycythemia can of course occur due to any cause of chronic hypoxia but it tends to be more profound in the hypoventilation syndromes.
Classifying pulmonary arterial hypertension
(pre-capillary vs. post capillary pulmonary hypertension) in this way allows one to narrow the site of disease with some common non-invasive tests: history and physical exam, chest radiograph, arterial blood gas, pulmonary function tests, cardiac echo
evaluation for thromboembolic disease (VQ, CTA). Since it is such a diverse group, individuals with pulmonary hypertension present in varied ways frequently related to the underlying disease. Dyspnea on exertion, chest pressure, syncope, and occasionally peripheral edema due to right heart failure are perhaps the most consistent signs and symptoms, but unfortunately are relatively non-specific and many are shared with more common causes of these same signs and symptoms (congestive heart failure, asthma, etc.). Additional testing can reveal a pulmonic heart sound that is accentuated (loud P2) and the ECG is often abnormal (showing right heart strain or right axis deviation).
Cor Pulmonale
Cor pulmonale refers to right heart failure due to pulmonary hypertension in the presence of a normal left ventricle and left atrium. However, the most common cause of right heart failure is left heart failure, (which would not be Cor Pulmonale: this would be post capillary PH, with an elevated wedge pressure). Peripheral edema and elevated neck veins are prominent in cor pulmonale. In reality, cor pulmonale is a historic term that has fallen out of favor. I mention it here as you will likely see it in older literature but it is not used in the current WHO classification scheme.
Idiopathic Pulmonary Arterial Hypertension (IPAH)
IPAH is the “classic” form of WHO Group 1 disease. It is a disease that targets the pulmonary vasculature while sparing the lung parenchyma. It represents a form of pre-capillary pulmonary hypertension due to vascular causes. The pulmonary function tests of affected individuals usually demonstrate normal lung physiology with a selective decrease in diffusing capacity (decreased DLCO). Unlike other forms of pre-capillary pulmonary hypertension due to vascular involvement, however, this disease has no clear cause (hence idiopathic). It primarily affects (younger) women (3:1 ♀:♂) Individuals usually present with dyspnea on exertion and occasionally chest pain (due to increased strain on the right ventricle). Since the right ventricle is pumping against an elevated pulmonary pressure the RV first dilates and the hypertrophies leading to right heart failure. Death usually occurs from ventricular arrhythmias or from a progressive drop in cardiac output as the right ventricle fails. The average time from symptom onset to diagnosis is 2 years as the complaint of dyspnea is non specific and the affected individual is usually young. Often they are told they have asthma. Unfortunately, due to the late diagnosis patients often present with severe disease. Without medical therapy, the median survival is 2.5 years from the time of diagnosis. With current medical therapy, the median survival is approximately 7 years, but IPAH remains a fatal disease.
Cause of IPAH
The cause of IPAH is not known. In September 2000, two research groups working independently (one from Columbia and the other from Vanderbilt) identified a gene mutation that contributes to the development of IPAH. Mutations in the bone morphogenic protein receptor type 2 (BMPR2) were identified in family members who had PAH (familial form now called “heritable” PAH). Different investigators have since shown that this mutation is present in some ‘sporadic’ (i.e. no family history) cases of PAH as well. This receptor is part of the TGF-beta super-family of receptors. How mutations in this receptor lead to PAH is unclear, and despite this knowledge there have been no effective treatments developed that target this pathway in PAH. Also unclear is why individuals with similar BMPR2 mutations demonstrate a variable severity of disease even within an affected family. It has been shown that patients with BMPR2 mutations develop a more severe form of the disease and it occurs at a younger age then IPAH patients without the mutations. Further studies will likely demonstrate that mutations in this gene provide one risk factor for developing PAH, but other environmental and genetic factors are required to cause disease. At present the identification of BMPR2 mutations has not changed the treatment of this disease clinically. Affected individuals are treated with vasodilators such as calcium channel blockers, endothelin-1 blockers, phosphodiesterase-5 inhibitors and prostanoids. However, identification of this mutation will likely lead to innovations in treatment for what for now remains a progressive and fatal disease.
Medical Management of Pulmonary Arterial Hypertension
There are currently 3 classes of FDA-approved medications for the treatment of PAH (4 if you include calcium channel blockers). All are pulmonary artery vasodilators, thus decreasing right ventricular afterload and improving right heart function. There may be some direct action of these medications on the right ventricle, but this has not been clearly established. The 3 targeted pathways are: 1) endothelin pathway, 2) the nitric oxide pathway and 3) the prostacyclin pathway. See figure below. Avoid treating left heart disease with vasodilators as this can cause pulmonary edema.
Endothelin pathway
Endothelin is a potent endogenous pulmonary arterial vasoconstrictor. The endothelin receptor antagonists (bosentan, ambrisentan, and macitentan) block the endothelin receptors thus resulting in pulmonary artery vasodilatation. There are 2 endothelin receptors (ER-a and ER-b). Bosentan and macitentan blocks both receptors (ER-a and ER-b) while ambrisentan blocks only ER-a. There is some theoretic advantage to selectively blocking only ER-a as ER-b stimulation may inhibit vascular proliferation (which is thought to be pathologic in PAH), but blocking only ER-a is also associated with the occasional development of peripheral edema. Thus far selective ERA inhibition has not proven to be clinically superior to blocking both receptors.
Nitric oxide pathway
Nitric oxide is a potent endogenous vasodilator thus stimulation of this pathway can result in a direct decrease in right ventricular (RV) afterload and improved RV function. The pulmonary vasodilating effects of nitric oxide are mediated through its second messenger, cyclic guanosine monophosphate (cGMP), which is rapidly degraded by phosphodiesterases. Phosphodiesterase type 5 is the predominant phosphodiesterase isoform in the lung that metabolizes cGMP, and it has been shown to be up-regulated in conditions associated with pulmonary hypertension. The class of medications approved for the treatment of PAH in this pathway are the phosphodiesterase-5 (PDE5) inhibitors (PDE5i). Selectively inhibiting phosphodiesterase type 5 promotes the accumulation of intracellular cGMP and thereby enhances nitric oxide–mediated vasodilatation. It may also have antiproliferative effects on pulmonary vascular smooth-muscle cells. There are currently 2 FDA approved PDE5i for the treatment of PAH in the United States (sildenafil and tadalafil). Another mechanism for targeting this pathway is increasing the production of cyclic GMP by stimulating the enzyme that makes cGMP, soluble guanalyl cyclase, and another FDA approved medication, riociguat, is a stimulator of this enzyme. It is important to not use a soluble guanylyl cyclase stimulator, a PDE5 inhibitor, or a NO-donor (such as nitroglycerin or isosorbide dinitrate) in the same patient at the same time, as it will likely cause an extreme increase in vasodilation, leading to systemic hypotension. Similarly, Inhaled nitric oxide (iNO) can also be used as a direct pulmonary vasodilator but the current delivery system is too cumbersome for long term use (there are clinical trials of more portably systems currently ongoing). iNO is FDA approved for the treatment of pulmonary hypertension in the newborn and I use it frequently to perform acute vasodilator testing in patients with suspected PAH during right heart catheterization. More on this below in the discussion of calcium channel blockers.
Prostacyclin pathway
The prostaglandins are potent endogenous vasodilators with antiproliferative and cytoprotective properties. They upregulate cAMP which results in pulmonary artery vasodilatation and decreased RV afterload. They also have an anti-thrombotic effect which may be beneficial in the treatment of PAH. There are 3 formulations of prostacyclins currently FDA approved for the treatment of PAH in the U.S. (epoprostenol, iloprost and trepostinil). Epoprostenol is administered intravenously only. Iloprost is administered via inhalation only. Treprostinil can be given intravenously, sub cutaneously, via inhalation, and orally. When given intravenously the medications are administered by continuous infusion. As you can imagine, this is a big deal. The patient is given a permanent intravenous catheter which is usually placed in the internal jugular vein and positioned over the right atrium. He or she is given a small pump and taught how to mix the medication and administer it through the pump via continuous, slow drip (ng/kg/min). It is a life changing event to go on such a difficult to administer medication but it can also be a life saving event. This option is reserved for the sickest patients with PAH.
Calcium channel blockers (Ca++ blockers)
As you may have learned from your CV lectures, the calcium channel blockers are a class of medications frequently used to treat systemic hypertension and slow the heart rate. Briefly, they block voltage gated calcium channels and in arterial beds which results in vaso-relaxation and thus decreased systemic blood pressure. A landmark study by Rich et al published in the New England Journal of Medicine in 1992 demonstrated that a small percentage of patients with IPAH also have significant pulmonary artery pressure decrease with the administration of Ca++ blockers. The patients who have this response are identified by having an “acute response” to the administration of a pulmonary vasodilator during right heart catheterization. To qualify as an acute vasoresponder, (1) the mean PA pressure must drop below 40 mmHg, (2) it must drop by at least 10 mmHg, and (3) the cardiac output can not decrease. If that response is noted, the patient is placed on an oral Ca++ blocker. A positive test occurs about 5% of the time. Most patients do not have an acute response and they go on one of the other therapies listed above. This next part frequently confuses people. We use either inhaled NO (iNO) or IV prostacyclin to elicit the acute response during the heart cath. So once again, if you have an acute response to either iNO or IV prostacyclin during the right heart cath for evaluation of pulmonary arterial hypertension, you go on an oral Ca++ blocker. If you do not have this response you go on one of the other PAH therapies (ERA antagonist, PDE5-i or a prostacyclin). Which one depends on how sick you are among other considerations. So even though you do not meet criteria for an “acute response” to IV prostacyclin, you may be placed on IV prostacyclin chronically. Though the pulmonary artery pressures may not drop a lot initially to the medication, there is long term benefit to the chronic use of these medications including increased survival.
Risk Factors for PE - Deep Venous Thrombosis
Most PE’s occur due to embolism of thrombosis formed in the lower extremity or the pelvis (deep venous thrombosis - DVT). Any situation in which venous flow is decreased or obstructed may lead to in situ thrombosis. This results in lower extremity swelling and pain (due to venous congestion). Over 2 million cases of DVT are diagnosed in the US each year resulting in significant morbidity. Even with adequate treatment of DVT, chronic complications of persistent venous abnormalities (especially chronic inflammation of the vein - phlebitis) are common. Most DVTs occur in the lower extremities but the upper extremity can also develop DVT (especially with the use of intravascular catheters). The major risk factors for the development of VTE are mechanical alterations in venous blood flow and biochemical factors that promote thrombosis. Examples of mechanical factors include: 1. immobilization (bedrest is a common risk factor, or just having had surgery on a limb) with decreased venous return due to decreased muscle contraction of the lower extremity (important in promoting flow of venous blood in the lower extremity), 2. sitting for prolonged periods (i.e. travel) with compression of the venous return from the lower extremity, 3. compression of the veins due to adenopathy, tumors, and enlarged uterus (i.e. pregnancy). Biochemical factors which promote thrombosis in the lower extremities include hormones (i.e. pregnancy), hypercoaguable states associated with malignancy, and inherited deficiencies of endogenous anticoagulants (i.e Factor V Leiden, Prothombin gene mutation, Proteins C and S, etc). These risk factors are often referred to as Virchow’s triad.
Diagnosis of DVT
is made on visualization of thrombus in the vessel. Most commonly this is made using duplex ultrasound of the extremity in question. This will demonstrate decreased flow in the vessels as well as decreased compressibility of the vessel (usually venous pressure is easily overcome by the sonographer pressing down on the vessel). In other situations, venography (injection of contrast dye in the veins) may be necessary to define the clot (this is rarely done anymore for diagnosis of DVT). CT is less useful in imaging the peripheral vessels (due to problems with adequate visualization with contrast medium). In some cases, nuclear imaging (using labeled fibrin) can identify clots.
Pulmonary Embolism
PE occurs when the clot (or a portion of the clot) breaks free and travels to the pulmonary circulation and acutely obstructs the pulmonary blood flow. This results in an immediate increase in pulmonary vascular resistance which in turn can cause acute hypoxemia and, with a large enough clot, right ventricular failure and sudden death. In patients with massive PE who survive to the hospital, the mortality rates remain high (in some series as high as 10-30%) even with treatment. The key way to diagnose a PE is to first, and foremost, consider it in the differential diagnosis for a patient’s presentation. On history, the presence of shortness of breath, chest pain, and hypoxemia is unfortunately non-specific. Hemoptysis, when present, may be helpful but is also non-specific (hemoptysis occurs due to infarct of some of the affected lung parenchyma). A history of immobilization, hormonal manipulations, cancer, recent orthopaedic surgery etc. may be helpful. In the ICU, PE may present with the only sign being increased dead-space ventilation in a patient on mechanical ventilation. Thus, the diagnosis of PE must first be considered.
CXR of PE
In PE, the CXR is most often normal. Areas of atelectasis or a pleural effusion (usually small) may be seen. Occasionally a wedge shaped infiltrate (representing an infarct) can be demonstrated. This is referred to as “hampton’s hump”. One may observe a relative decrease in perfusion to a portion of the lung (the Westermark sign). The EKG may be helpful in suggesting RV strain (SIQIIITIII seen below, with a deep S wave in lead I, Q wave in lead III and inverted T wave in lead III) but is in fact rarely seen, with most often tachycardia is the only EKG abnormality.
Laboratory tests with PE
include an increased A-a gradient (on arterial blood gas) suggesting alterations in V/Q ratio. The measurement of the d-dimer has become an important laboratory test in the evaluation of suspected DVT. D-dimers represent circulating breakdown products of fibrin. It is elevated in situations of intravascular clotting (as in DVT) and in disseminated intravascular coagulation. It is also elevated in conditions associated with inflammation (as in sepsis) as well as malignancies. Elevated levels are also seen in trauma, pregnancy, pre- eclampsia, etc. so on the whole it may not be too specific. It can be negative as well in patients with a PE (i.e. is not 100% sensitive, but is probably >95%).
pulmonary angiography and PE
The next step in evaluating PE is to attempt to identify clot in the lung. The “Gold standard” is pulmonary angiography in which the detailed anatomy of the pulmonary circulation is evaluated. However, this test is invasive and is used to diagnose PE in the situation with high clinical suspicion and other tests that are non- diagnostic. Pulmonary angiography is rarely performed anymore as new generation multi- detector CT scans have a similar sensitivity and specificity in the diagnosis of PE. Pulmonary angiography is still done in the evaluation of chronic thromboembolic disease as this is less well diagnosed by CT scan. CT pulmonary angiography has become the most frequently used modality in the diagnosis of acute pulmonary embolism (see figure). A rapid injection of dye with rapid sequence imaging of the pulmonary circulation can identify abnormalities in the pulmonary vessels consistent with PE. Interpretation of these images is complicated and requires significant experience of the radiologist. In general, CT PE studies, if performed correctly (i.e. the timing of the CT scan captures the bolus of dye just as it is going through the lungs) have excellent sensitivity and specificity (>98%).
Nuclear ventilation and perfusion (VQ) imaging
is another option in the diagnosis of PE but again as been predominately supplanted by CT angiography. Patients are administered a radioactive tracer intravenously (macroaggregated albumin) which is distributed in the lung. They then receive a different radioactive gas for inhalation which distributes to the ventilated sections of the lung. Areas with no perfusion but normal ventilation are suggestive of PE (blockage of the circulation). Areas with both absent ventilation and perfusion (matched defects) are less diagnostic (can still be PE - lung can become infarcted due to decreased perfusion which radiographically looks like pneumonia). Variations of mis- matched and matched defects result in an interpretation of a V/Q scan as negative, low, intermediate or high probability of PE and must be combined with clinical suspicion to ultimately determine the likelihood of a PE. V/Q scanning requires a specialized nuclear technician. An advantage of VQ scanning over CT angiography and pulmonary angiography is that contrast dye is not used in VQ scans. Therefore, if the patient has a contraindication to contrast dye, (such as renal failure) then VQ may be the better option. VQ may also be better in the evaluation of chronic thromboembolic disease the CT scan but this is debatable. The total radiation dose administered in a V/Q scan is lower than a CT-scan, so this can be a safer test in a pregnant patient. An image of VQ scan is shown above.
Echocardiography and PE
it is an important adjunctive tool to assess the severity of the impairment caused by a PE. A dilated, poorly functioning right ventricle may be consistent with acute right heart strain and suggestive of significant hemodynamic compromise.
Treatment of PE
None of the imaging should be considered in the absence of a clinical suspicion of PE to limit the number of false positives. Treatment of acute PE does carry some risk (especially the consideration of the use of thrombolytics: severe and potentially fatal hemorrhage can occur) and should be reserved for patients with a high clinical suspicion and confirmatory imaging. The most important consideration in treatment of PE is in prevention. For those of us with long travel opportunities, frequent positional changes and walking is key (at least every hour). For hospitalized patients, appropriate prophylaxis with either anticoagulants and/or mechanical devices (to increase venous blood flow) is fundamental. For patients diagnosed with DVT, anticoagulation initially with heparin and then chronically (at least 6 months for the first episode) with warfarin is needed. For patients with PE, heparin and warfarin as above are indicated for all patients (in the absence of contraindications). Thrombolytic therapy is generally considered for patients with significant hemodynamic compromise and/or evidence of acute right heart strain. In patients with very high risk, the additional use of an inferior vena caval filter (presumably to decrease the possibility of clot migrating from the lower extremity to the lung) is also useful. In some situations, acute surgical thrombectomy may also be required but carries very significant morbidity and mortality.
PE and chronic pulmonary hypertension
PE can also result in chronic pulmonary hypertension (WHO Group 4 disease) in about 3% of patients. PE is considered in all patients presenting for evaluation of pulmonary hypertension. V/Q scanning is the most frequently used and validated method to assess the presence of chronic thromboembolic disease. Many of the patients eventually diagnosed with chronic thromboembolic disease have not had a clinically apparent episode of acute PE. Treatment is aimed at lifelong anticoagulation and, when clinically appropriate pulmonary thromboendarterectomy. This surgical procedure removes the fibrotic material (persistent clot becomes fibrotic after about 3-6 months) but is a major operation, requiring median sternotomy and cardiopulmonary bypass; the operative mortality rate is 1-5%. However, in patients with successful outcomes, the procedure is considered “curative” of their chronic thromboembolic disease, although they require again lifelong anticoagulation.
Post-capillary (Pulmonary Venous) Hypertension
If you review the equation for pulmonary pressure (Ppa = CO x PVR + PLA) you see that if PLA (wedge pressure) is increased while the cardiac output and the PVR stay the same then pulmonary pressure will rise. Basically anything that obstructs flow from the pulmonary capillaries to the aorta (post capillary) will increase pulmonary pressure. Therefore post-capillary pulmonary hypertension can be divided into cardiac causes (left heart) and pulmonary venous causes (a problem in the pulmonary vein itself or extrinsic compression of the pulmonary vein). Cardiac causes include left ventricular failure, mitral valve disease, or other atrial obstruction. Pulmonary venous causes include obstruction of the lobar pulmonary veins (fibrosing mediastinitis, pulmonary vein stenosis), obliteration of the small veins and venules (veno-occlussive disease), or anything else that is post-capillary, but does not affect the heart. Since this increase in resistance occurs distal to the capillaries, the microvascular hydrostatic pressure (Pmv) in the lungs is increased. This frequently leads to the development of hydrostatic pulmonary edema. This can be detected on a chest radiograph as Kerley B lines (engorged lymphatics) and vascular redistribution. In contrast, since pre-capillary causes of pulmonary hypertension do not increase pressure in the microcirculation (i.e. pulmonary capillary bed), pulmonary edema does not develop. Thus the chest radiograph can help distinguish pre- from post- capillary pulmonary hypertension.
Post-capillary / pulmonary venous causes of pulmonary hypertension
Cardiac (WHO Group 2) such as Left ventricular failure, Mitral valve disease, Myxoma (or thrombus) of the left atrium. Pulmonary Venous (WHO Group 1’ and some of Group 5) such as Congenital stenosis of the pulmonary veins, Chronic sclerosing mediastinitis, Pulmonary Veno-occlusive disease, Pulmonary capillary hemangiomatosis, Anomalous pulmonary venous return, and Neoplasms
Treatment of post-capillary pulmonary hypertension
Use of pulmonary arterial vasodilators (i.e. the three classes of medications discussed above) is generally contraindicated in post-capillary pulmonary hypertension. The reason is that these medications act primarily on the pre- capillary vessels, so if the PCWP is elevated and the amount of blood that is entering the capillaries is allowed to increase further, that results in a further increase in intravascular hydrostatic pressure and pulmonary edema can result.
Pulmonary function tests (PFTs)
serve to quantify lung function and can assess progression of disease and response to therapy. There are many types of PFTs that measure different aspects of pulmonary physiology, but they are most commonly used to assess six aspects of the respiratory system: 1. Airflow (also called Spirometry)
- Lung V olumes
- Gas Exchange (Diffusing Capacity) 4. Respiratory System Compliance
- Airway Responsiveness
- Respiratory Muscle Strength
Volumes and Capacities
The figure at right shows the different ways to characterize lung volumes–the spirogram. Traditionally, to do this, subjects breathe through their mouths into a floating drum that would either float or sink depending on what the patient is doing–exhaling (float) or inhaling (sink). The amount of displacement of the drum would be the volume of air that had moved. Both volumes and capacities are measured on a spirogram. Note that volumes are single entities while capacities are composed of two or more volumes (e.g. functional residual capacity = residual volume + expiratory reserve volume). Clearly technology has advanced but the old style spirogram is still useful to help understand the terminology.
TV, tidal volume.
This is the amount of gas volume moved during a normal inspiration. The subject is told to sit quietly and breathe and the tidal volume is measured. Note that at the end of a normal tidal breath, the lung and chest wall are in equilibrium. This is the functional residual capacity. Note, measuring the tidal volume does require some effort of the patient but every attempt is made to have the patient relaxed and not breathing too deeply or shallowly.
IRV, Inspiratory reserve volume.
This is the volume of gas that a subject can inhale above what they would normally inhale during a tidal breath. This requires maximum effort of the respiratory muscles.
ERV, Expiratory reserve volume.
This is the volume of gas from the end of a tidal breath that can be expelled by the subject. Remember that exhalation to FRC is usually passive while exhalation of the ERV requires active work of the respiratory muscles.
RV, Residual volume.
This is the volume of gas retained in the lung even after a maximal exhalation. This volume cannot be measured directly (see below) but can be estimated.
FRC, Functional residual capacity.
This capacity represents the sum of the RV and ERV and represents the amount of gas in the lung at the end of a normal exhalation. It is also the point at which the respiratory system is in equilibrium. It is the point at which the respiratory system is at rest, where the desire of the lung to recoil is equally opposed by the desire of the chest wall to expand. If you try to breathe at a higher or lower FRC (either voluntarily or due to disease), this will increase the work of breathing and be very uncomfortable. Normally FRC is a comfortable position because the forces are equally opposed and requires no work to maintain.
IC, Inspiratory capacity.
This is the sum of the TV and IRV and represents the amount of gas that can be inhaled from FRC. This requires maximum effort of the respiratory muscles to perform.
VC, Vital capacity.
This represents the sum of ERV, TV, and IRV and is the amount of gas that can be inhaled from the end of a maximum expiration (starting at RV) to the maximum inflation.
TLC, Total lung capacity.
This represents the total of all 4 volumes of the lung. It is VC plus RV. Note that since you can’t measure RV directly, neither can you measure TLC directly. It is therefore measured by adding the VC (which can be directly measured) to your estimated RV.
Spirometry
Spirometry is an important test of pulmonary function. During spirometry, the patient inhales and exhales with great effort and measurements are made of airflow. Airflow is defined as the change in volume over time. Some key values obtained with spirometry include: FVC, FEV1, FEV1/FVC
FVC (forced vital capacity)
The FVC represents the total volume of gas (in liters) exhaled from total lung capacity down as far as possible (i.e. from TLC to RV). Note that this is the same as VC. FVC just means that it was done with maximum effort. Usually there is a tight correlation between VC (measured more slowly) and FVC. When VC and FVC differ significantly, it may be due to dynamic collapse of the airways.
FEV1 (forced expiratory volume in the first second)
The FEV1 denotes the volume of gas (in liters) exhaled in the first second from total lung capacity. Most people exhale 70-80% of the VC in the first second.
FEV1/FVC
This ratio compares the volume of gas expelled in the first second in relation to the total amount of gas exhaled. It normalizes lung mechanics for people with different lung volumes. Most people exhale 70 to 80% of air in the first second, making a normal ratio 0.7-0.8. A reduced ratio defines an obstructive pattern of lung disease. People with obstructive disease have FEV1/FVC’s of less than 0.7 because their disease affects their ability to expire (takes longer to expire). Another pattern of abnormal pulmonary physiology is a restrictive pattern. People with restrictive disease may have FEV1/FVC’s greater than 0.8 but airflows are not diagnostic of restrictive lung disease—more on this later. Note that FEV1/FVC is a ratio and is best given as a fraction (i.e. FEV1/FVC = 0.7 not 70%) although in practice most clinicians refer to percent.
Expiratory -Inspiratory Flow loops
Flow volume loops represent airflow (velocity in L/s)
versus lung volume (rather than volume vs. time as shown above). By convention, expiratory flows are expressed above the origin on the y-axis, while inspiratory flows are below the origin on the y-axis. Volume is expressed on the x-axis. In obstructive lung disease, lung volumes are increased and the curve is shifted to the left (above the predicted total lung capacity, TLC). Note that the airflow is decreased in obstruction with coving of the expiratory flow loop, a hallmark sign of obstructive lung disease. With restrictive disease the curve is shifted right to a lower TLC and once again, the maximum airflow is decreased. In the case of airflow obstruction, the maximal airflow is reduced due to increased resistance to flow while in the case of restrictive diseases, the maximal airflow is reduced because the total volume of gas in the lung is reduced. Another important use of the flow-volume loop is the clinical assessment of suspected airway obstruction. To assess the presence and the site of airway obstruction, two physiologic principles are worth considering. First dynamic factors (i.e. expiration or inspiration) affect airways differently depending on whether the airway is intra-thoracic or extra-thoracic. Within the thorax, the airway is held open during inspiration by negative pleural pressure. During forced expiration, however, positive pleural pressure surrounding the airway compresses it, reducing airway diameter. Consequently, intra- thoracic airway resistance is increased during expiration. In contrast, the extra-thoracic airways (namely the trachea above the clavicles) are subjected to atmospheric pressure that is transduced through the tissues of the neck to the exterior walls of the trachea. Thus, negative intraluminal pressure is generated in extra-thoracic airways during inspiration resulting in airway narrowing. During expiration, the intraluminal pressure becomes positive, making the airway diameter larger.
Three functional categories of upper airway obstruction defined on the basis of the flow- volume loop
1) fixed obstruction, 2) variable intra-thoracic obstruction, and 3) variable extra- thoracic obstruction. These disorders may present with noises during respiration that may be confused with wheezing (more accurately called stridor). However, the shape of the flow-volume curve is markedly different in these disorders and can help locate the location of obstruction.
Fixed obstruction
the curve is flattened in both inspiration and expiration. This can occur as a result of circumferential lesions such as tracheal stenosis from prior intubation or a circumferential airway neoplasm.
Variable intra-thoracic obstruction
airway compression during expiration, but inspiratory loop is normal. This can be seen with a non-circumferential tracheal tumor (ball-valve effect).
Variable extra-thoracic obstruction
causes airflow limitation primarily during inspiration leaving the expiratory curve relatively normal. Examples include vocal cord paralysis, laryngeal edema, vocal cord dysfunction (VCD) or upper airway tumor.
Measuring Lung Volumes
Lung volumes can be increased, decreased, or normal. Increased lung volumes are associated with obstructive diseases such as asthma and emphysema where gas can be trapped in the lung due to decreased ability to exhale. Decreased lung volumes are diagnostic of restrictive processes. Restriction can only be diagnosed by lung volumes; airflows can be suggestive but not diagnostic of restriction. Patients can have both obstructive and restrictive processes, in which case the term “mixed” lung disease may be used. This “pattern” of lung disease may be seen where airflows show evidence of obstruction (reduced FEV1/FVC) and lung volumes are reduced indicating restriction. Below are the methods of how lung volumes are measured.
Helium Dilution
Helium dilution is based on the principle of the conservation of mass. Gas in the lung contains no helium and since helium is an inert gas, it is not taken up by the blood. As the patient breathes spontaneously, a known volume and concentration of helium is turned into the system when the patient is at FRC (the end of a normal tidal volume). After an appropriate time to allow for the equilibration of gases throughout the system (the lung and tubing), the final helium concentration is determined. C1V1 = C2(V1+V2). C1 = fraction of helium present initially (present in tubing only)
V1 = initial volume of gas in tubing
C2 = fraction of helium after equilibration with lung
V2 = volume of gas in which helium has been diluted (this is volume in tube + volume in lung (i.e. FRC)). Note that this method requires uniform diffusion of gas in the lungs. If there is gas trapping or inhomogeneity of ventilation as occurs in asthma, emphysema, or chronic bronchitis this value may be inaccurate (underestimate FRC).
Body Plethysmography
Plethysmography is a faster and more reliable method of measuring lung volume than the helium dilution method, but requires more sophisticated technology. The principle of body plethysmography is based on Boyle’s law, which describes the constant relationship between pressure and volume: P1V1= P2V2. The subject, seated in an airtight body box pants against a closed shutter. The gas contained within the lungs is alternately compressed (during expiration) and decompressed (during inspiration). Changes in pressure (PA) measured at the subject’s mouth (equivalent to alveolar pressure) and changes in the airtight body box (PB) during the panting maneuvers are displayed continuously on an oscilloscope. Note that PA and PB are inversely related as expected. The body box is so sensitive that it can detect very small changes in volume and pressure. By determining three of the variables (initial and final pressure and the change in volume in the box) you can solve for the unknown volume (FRC). (The concept is important, not the specific formula required to determine lung volume). Note that the term FRC is used when volumes are determined with helium dilution and the term TGV (thoracic gas volume) is used when volumes are determined with the body box. In general, consider that FRC and TGV indicate the same thing (the volume of gas in the lungs when the respiratory system is at equilibrium). Once FRC (or TGV) is determined, one can calculate TLC and RV since other volumes/capacities can be directly measured (e.g. FRC + IC = TLC). The important difference between measuring lung volumes with helium dilution and with the body box is that helium requires uniform diffusion of gas to get an accurate measure of FRC while the body box does not require diffusion, but relies on changes in pressure. Therefore the body box is more accurate in patients with significant air trapping such as in asthma, emphysema, or chronic bronchitis.
Measuring Gas-Exchange
Gas must not only get to the gas-exchange units, it must traverse across the alveolar- capillary membrane and into the blood. Oxygen diffuses across this membrane to combine with hemoglobin in the pulmonary capillaries while carbon dioxide diffuses from the capillary blood into the alveoli for excretion during expiration. The alveolar- capillary membrane is ideally suited for gas transfer because it is fused to form one (thin) membrane, which allows for efficient gas exchange.
Gas movement across the alveolar-capillary membrane
occurs by diffusion. The rate of gas transfer across a tissue plane or membrane is directly proportional to: 1) the difference in partial pressure of the gas on the two sides of the membrane and 2) a constant for the membrane known as the diffusing capacity (Dm): VG = Dm (P1-P2).
VG = rate of gas movement across a tissue plane
P1 = partial pressure of gas on one side of tissue plane P2 = partial pressure of gas on other side of tissue plane. Dm comprises several components including tissue solubility of the gas (α), tissue surface area (A), tissue plane thickness (d), and molecular weight of the gas (MW): Dm = k x A/d where k = constant comprising the above variables (α and MW). Combining the equations yields: VG =k x A/d x (P1-P2). This equation isn’t for general use but it points out some important clinical facts: gas exchange is decreased if surface membrane area (A) is decreased (as in emphysema) or if the membrane (d) is thickened (as in some interstitial lung diseases).
How is gas transfer measured?
Carbon monoxide is the gas of choice to quantify gas exchange–or the diffusing capacity (DLCO)–of the lung. Carbon monoxide (CO) binds readily to hemoglobin (210 times more effectively than oxygen), so the partial pressure of CO in the blood remains low. Thus the transfer of CO from the alveoli into the blood is diffusion limited. That is, it is limited by surface area (A) and membrane thickness (d). Anything that alters these can impair the transfer of CO across the membrane. In addition, the more hemoglobin CO encounters in the alveoli, the more CO will be transferred across the membrane into the capillary blood. Therefore anything that increases blood in the lung (polycythemia, interstitial pulmonary edema, alveolar hemorrhage) will increase CO transfer thereby increasing diffusing capacity. Diseases that decrease blood in the lung (anemia, pulmonary vascular disease) will decrease CO transfer and result in a low diffusing capacity. Note that too much or too little blood in the lung can alter DLCO but doesn’t accurately represent gas exchange in the lung, it is a limitation of the test. The most common way of determining diffusing capacity of the lung is the CO single breath method. The subject inhales a gas mixture containing a low concentration of CO and a tiny amount of the inert tracer gas, helium. At end-inspiration the subject holds his or her breath for 10 seconds. During exhalation the expired gas is analyzed for CO and helium concentrations. During the breath holding some CO diffuses from alveoli into blood; the amount can be calculated from measurements of the CO concentration in alveolar gas at the beginning and at the end of the 10-second interval. Diffusing capacity is inversely proportional to the concentration of CO at the end of the breath hold. The more efficient the gas exchange, the more CO will be taken up and hence a lower ending concentration of CO.
Things that increase the diffusing capacity of carbon monoxide
polycythemia, early congestive heart failure, asthma, alveolar hemorrhage. Mostly these things increase the amount of blood in lung
Things that decrease the diffusing capacity of carbon monoxide
emphysema, pulmonary vascular disease, interstitial lung disease, anemia.
Measuring diffusing capacity
The diffusing capacity can be adjusted for the alveolar volume (VA) the CO distributes in. This volume is determined by measuring the dilution of inspired helium (see section on helium dilution measurement of lung volumes). This is expressed as DLCO/VA. Remember that the purpose of this test is to determine whether there is an abnormality in the alveolar-capillary interface. If you have one lung removed due to an accident, your DLCO will be reduced by half (because the surface area for gas-exchange has been halved). However, the gas exchange units in the remaining lung are normal. By using the helium tracer to assess the volume of alveolar space that the CO diffuses into, you can correct for people who have smaller lungs or other processes that affect the amount of surface area but not the gas exchange units themselves. Another more typical example is chest wall processes that cause restriction (i.e. reduced lung volumes) but there is no actual defect in the alveolar gas exchange units. Also, it should be noted that DLCO is typically corrected for Hb concentration. In summary, the three things that affect the DLCO are: 1) Surface area 2) Membrane thickness and 3) Hemoglobin.
Measuring Respiratory Muscle Strength
The most important muscle of the respiratory system is the diaphragm. The accessory muscles of inspiration include the intercostals, the sternocleidomastoid, and the scalene muscles. Loss of muscle function can occur due to neuropathies or because of myopathies. Examples of neurologic diseases which can reduce respiratory muscle strength (aside from trauma) include: 1) diseases of the motor-neuron endplate (myasthenia gravis, botulism, anti-cholinergic poisoning, tick paralysis), 2) diseases of the neuronal axon (Guillan-Barre, critical care neuropathy), or 3) diseases of the nerve root in the anterior horn of the spinal cord (polio, amyotrophic lateral sclerosis). Muscle abnormalities can occur due to drugs (steroid myopathy), collagen vascular diseases (polymyositis, dermatomyositis), or paraneoplastic syndromes (Lambert-Eaton myasthenic syndrome) among others. Two simple tests are commonly performed to assess function: Pimax and Pemax. These measurements can be very dependent on the patient’s effort.
Pimax
The maximum intra-thoracic pressure is measured when the patient attempts to inspire as forcefully as possible against an occluded airway (Mueller maneuver) while at residual volume. This test results in measurement of maximum inspiratory pressure.
Pemax
This is measured while the patient attempts to expire as forcefully as possible against an occluded airway (Valsalva maneuver) while at TLC.
Measuring Pulmonary Compliance
Occasionally, measurement of lung compliance is important. Remember, compliance is a measure of how easily the lung inflates. A more compliant lung means that it takes less pressure to increase the volume in the lung. Emphysema is a good example (see more later). Elastance is the reciprocal of compliance. Increased elastance means that it takes more pressure to get the same change in lung volume. Interstitial fibrosis is a good example of a disease with decreased compliance and increased elastance. Compliance is a more commonly used term than elastance. It is defined as: Compliance = ∆V/∆P. Remember that lung inflation requires generation of a pressure across the lung’s surface. In an isolated lung, the inflation pressure is the pressure exerted across the wall of the alveolus, that is, the difference between alveolar pressure and surrounding pleural pressure (trans-pulmonary pressure). Alveolar pressure can be measured in the body box, while pleural pressure can be measured with catheters placed in the pleural space, or more humanely, by placement of a manometer in the esophagus (which provides a reliable measure of pleural pressure). With this technique the effects of the chest wall are eliminated and a pure lung pressure-volume curve can be generated. The additional benefit to this measurement is that there is no flow so the effect of airways resistance is not present. Thus, a P-V curve measures the compliance of the lung tissue itself. As we will discuss later, some chest wall diseases can affect the TLC, but the compliance (the relationship of the volume changes to pressure changes) remains normal. The normal pressure volume relationship of the lung is curvilinear. In the mid-portion of the vital capacity the curve is steep but as the lung nears full inflation progressively higher pressures are observed. Pulmonary fibrosis, a restrictive disease, is characterized by stiff lungs and a flat pressure-volume (P-V) curve. Relatively small changes in volume are associated with large changes in pressure. In contrast, emphysema an obstructive disease resulting from a loss of elastic recoil, is characterized by a steep pressure-volume curve. In other words, large changes in lung volume are accompanied by small changes in inflation pressure. In the figure to the right, static recoil pressure is equivalent to transpulmonary pressure at no flow.
Bronchoprovocation
Asthma is a common disease characterized
by episodic reversible airflow obstruction.
Commonly this disease is diagnosed on
spirometry by an obstructive pattern that
improves with the administration of a
bronchodilator, the β agonist albuterol. A
significant response to bronchodilator is
defined as >12% improvement in FEV1 or FVC and > 200cc increase in volume of FEV1 or FVC.
However, in order for a bronchodilator challenge to be positive, the patient must have some degree of bronchoconstriction at the start of the test. Because asthma is defined as intermittent and reversible airflow obstruction, this may not always be true. Thus, bronchoprovocation tests are of potential value in patients in whom the diagnosis of asthma is suspected but not definitively established.
Methacholine challenge
The patient inhales progressively higher concentrations of nebulized methacholine (or histamine), which stimulates bronchoconstriction in both healthy and asthmatic subjects. In asthmatics, the concentration required to reduce airflow by 20% (PC20) is several orders of magnitude lower than in healthy subjects. Therefore measurement of the PC20 can help diagnose asthma in patients with normal spirometry and no response to bronchodilator. Sometimes asthma caused by specific substances can be tested by substituting the suspected substance in place of methacholine, but this is typically only performed at very specialized centers.
EIB
Some patients have asthma only with exercise. An exercise induced bronchoprovocation (EIB) test can assess for exercise-induced asthma. The patient performs spirometry before the test, and then exercises on a treadmill breathing cold air. Spirometry is performed at intervals post exercise to see if there is >20% decrease in FEV1.
Matching of Ventilation and Perfusion
The lungs are an aggregate of gas exchange units each with a particular ratio for the amount of ventilation versus perfusion ( V / Q ). One condition that decreases arterial oxygenation is unevenness of V / Q ratios for differing units, even in a situation in which the total ventilation and total perfusion in the lung are about normal. We have already discussed the decrease in ventilation and perfusion as we go from the bottom to the apex of the lung. These differences in ventilation and perfusion will give us a variation in V / Q of about 2.4-fold going from bottom to apex (higher V / Q at the apex). V / Q can also vary locally if there are regions of low V / Q due to disease. Indeed, mild to moderate forms of most obstructive disorders (e.g., asthma, chronic bronchitis, emphysema) manifest their effects on arterial oxygenation mainly by increasing V/Q scatter. In these cases, the total ventilation can be unchanged because the tendency for CO2 to rise with reduced ventilation is generally countered by central chemoreceptor-mediated increases in ventilation (as was the case with shunts). Thus, in terms of ventilation, the low ventilation in low V / Q units is counterbalanced by increases in ventilation in normal-to-high V / Q units. Regional variations in Q can also contribute to V / Q scatter if there is destruction of capillary beds or obstructions of vessels.
what is required for appropriate oxygenation of blood
For a given blood flow, Q, there should be adequate ventilation, V, to ensure a high arterial oxygenation. A V / Q ratio of 0.8 - 1.0 is generally thought to be sufficient. At a given overall V / Q ratio, gas exchange would be the most efficient if all the lung units had the same V / Q. The scatter of the V / Q ratios through the lung results in lower arterial oxygenation for two reasons: (1) there is more blood coming from regions with low V / Q ratios, by definition (since low V / Q implies large Q). This biases the final blood mixture towards lower oxygenation levels. (2) the high V / Q ratios do not increase oxygenation (oxygen content) by a significant amount because hemoglobin is already near saturation at normal levels of ventilation (see figure above). This happens even though high ventilation can reduce alveolar CO2 and thereby create abnormally high local levels of both alveolar O2 and free O2 in blood. In contrast, low V / Q ratios lower oxygenation significantly. Thus, high V / Q cannot compensate for the low V / Q.
mild to moderate obstructive diseases that involve V/Q mismatch
In terms of CO2, mild to moderate forms of obstructive diseases that involve V / Q mismatch generally do not reduce arterial PCO2, owing, again, to the fact that increases in PCO2 are generally countered by increases in ventilation mediated by central chemoreceptors. There are limits, however, to how much ventilation can be increased because increasing ventilation involves added work. Also, increasing ventilation in very high V / Q units can reduce the efficiency of breathing because very high V / Q units are essentially alveolar dead-space.
Two local mechanisms that regulate V / Q mismatch
(1) In lung areas with high V / Q ratios, the alveolar PCO2 drops, leading to an increase in local airway resistance and decreasing ventilation. Thus, V / Q tends to go down. (2) In lung areas with low V / Q ratios, the alveolar PO2 drops, leading to hypoxic vasoconstriction and decreasing local perfusion. Thus, V / Q tends to go up. In a perfect world ventilation and perfusion would be totally matched (that is, each acinus, or gas exchange unit, would receive just the right amount of ventilation to oxygenate the hemoglobin completely and remove the carbon dioxide).
Mechanisms of V/Q mismatch
With the development of lung disease, ventilation and perfusion mismatching increase. Any pathologic process in which alveolar air spaces are filled with transudate (heart failure) or exudate (pneumonia, ARDS) and thus do not ventilate and in which perfusion persists results in a true shunt. Airway diseases that affect regional resistance (bronchitis, asthma) affect ventilation distribution (the V) and thus alter V/Q matching (decreased ventilation relative to perfusion). Abnormalities of the pulmonary vasculature such as destruction of the capillary bed (as in emphysema) or obstruction of vessels (as in pulmonary hypertension) alter regional perfusion and thus affect the Q in V/Q (increased ventilation relative to perfusion). Complete vascular obstruction (thromboembolism) converts affected regions of lung to dead space (ventilated but not perfused). Therefore you can see that abnormalities in the pulmonary circulation can lead to abnormal gas-exchange- through either abnormal increases in dead space (high V/Q) or through the presence of shunt and/or V/Q mismatching (low V/Q).
Dead Space
Calculation of the physiologic dead space provides a
useful estimation of over-ventilated lung units
(wasted ventilation). Dead space represents work
without benefit. Most people can handle the increase
in respiratory effort to compensate for this waste, but
people with limited lung function do not do well with
any extra useless work. Unlike shunt or low V/Q
units, dead space does not directly alter gas-exchange
and does not lead to arterial gas abnormalities unless
severe. Nonetheless the increase in work does pose a clinical problem.
Anatomic dead space
Remember that for any tidal volume there is some amount of gas that does not come into contact with blood. This is dead space. Anatomic dead space is normal and refers to the gas that remains in the conducting airways. This is the gas in the trachea, bronchi, and bronchioles that does not come into contact with blood. This is about 1 cc per pound in normal people.
physiologic dead space
Ventilation of totally unperfused alveoli and the excess portion of ventilation of high V/Q units, represents alveolar dead space. Such a condition can happen if, for example, a patient has a blockage in a pulmonary capillary. These alveoli are well-ventilated, but because they do not engage in gas exchange, their ventilation is wasted. Under severe disease conditions, the resulting reduced efficiency of breathing can decrease both arterial oxygenation and CO2 removal. This can be quite variable in normal situations and is referred to as physiologic dead space. PE can cause an increase in the physiologic deadspace.
Minute ventilation
(the total ventilation in one minute -VE) includes both alveolar ventilation (VA) and dead space ventilation (VD) as below: VE =VA +VD.
VE = minute ventilation (respiratory rate x tidal volume)
VA = alveolar ventilation (gas in the respiratory exchange units) VD = anatomic dead space + alveolar dead space. Together anatomic and alveolar dead space represent wasted ventilation. The ratio of dead space (VD) to tidal volume (VT) can be calculated by knowing arterial PC02 (PaCO2) and mixed expired PCO2 (PECO2): VD/VT= (arterial PCO2 – mixed expired PCO2)/arterial PCO2. In this equation, as mentioned previously, arterial PCO2 is assumed to reflect mean alveolar PCO2. Expired PCO2 is determined from a sample of expired air.
Breathing patterns and dead space
Since the anatomic deadspace is relatively fixed at about 1cc per lb body weight the larger the tidal volume the less significant is the effect of anatomic deadspace on alveolar gas tension. For the same minute ventilation, different respiratory patterns result in tremendous differences in the effective (alveolar) ventilation (VA). This shows that the most effective way to ventilate is with steady deep tidal volumes. Rapid shallow breathing is a waste of energy (in terms of ventilation anyway). When you see patients with severe metabolic acidosis on the wards you will note that they have deep steady respirations (Kussmaul breathing). This minimizes the percent of anatomic deadspace and leads to more alveolar ventilation and thus more exchange of CO2 (ultimately leading to a compensatory increase in pH). Conversely, if someone breathes rapidly and shallowly, the alveolar ventilation of the total minute ventilation is lower and the PaCO2 can increase and pH decreases (remember that PaCO2 is determined by CO2 production and alveolar ventilation).
Shunt or low V/Q
Shunt, which is blood perfusion where there is no ventilation. A small amount of shunt is normal because some venous blood enters the left atrium and ventricle by way of the bronchopulmonary venous anastomoses and the intracardiac Thebesian veins. This amounts to 1% to 2% of the cardiac output normally. Disease conditions that cause shunt include congenital heart ailments involving atrial or ventricular septal defects, as well as pulmonary disorders such as arterial-venous fistulas and pneumonia. Shunts can decrease arterial oxygenation significantly, when the well-ventilated blood mixes with the shunted blood. The figures on the next page illustrate the mixing effect on total O2 content when a shunt accounts for half of the pulmonary blood flow. Note that the shunt’s effect is exactly what one would expect: O2 content of arterial blood is exactly half-way between that of the well- ventilated and shunted branches. A shunt does not usually result in a raised arterial PCO2. The tendency for CO2 to rise is generally countered by the central chemoreceptors, which increase ventilation if PCO2 increases. Indeed, often the arterial PCO2 is lower than normal because of the additional hypoxemic stimulus to ventilation.
Calculating amount of shunt flow
When the shunt is caused by blood that has the same PO2 as mixed venous blood (which we know), we can calculate the amount of shunt flow. The total amount of O2 in the arterial blood is the total cardiac output, defined here as QT, times the concentration of O2 in the arterial blood, CaO2: QT × CaO2. The amount of O2 in the venous admixture will be the shunt, QS, times the concentration of O2 in mixed venous blood, CVO2: QS × CVO2. The amount of O2 at the end of the ventilated pulmonary capillaries will be the blood flow through those capillaries, (QT - QS), times the concentration of O2 in the blood at the end of these capillaries (the end-capillary blood), CcapO2: (QT - QS)× CcapO2. Since (due to the conservation of mass): QT ×CaO2 =QS ×CVO2 + (QT -QS)×CcapO2.
we can obtain the shunt as a fraction of the total cardiac output (the shunt equation): Qs/Qt=(CcapO2-CaO2)/(CcapO2-CvO2). The O2 concentrations CaO2 and CVO2 can each be obtained by sampling arterial and mixed venous blood. The O2 concentration of end-capillary blood CcapO2 is calculated from alveolar PO2 (using the alveolar gas equation) assuming complete equilibration between alveolar gas and the blood. There is a simple clinical method for estimating small shunt fractions, if the person is breathing 100% O2: the shunt is 1% of the cardiac output for each 20 Torr difference between alveolar and arterial PO2.
Distinguishing shunts from V/Q mismatch
Shunts and V / Q mismatch can both result in reduced oxygenation of arterial blood, but they can be distinguished by monitoring arterial PO2 (free O2) during the breathing of 100% O2. In the case of shunt, administration of 100% O2 does not substantially increase arterial PO2. This is because the O2 in a shunt is at a level (PO2 = 40 Torr) where the oxy-hemoglobin dissociation curve (ODC) is steep, meaning that there are relatively large changes in % hemoglobin saturation for small changes in P02. Thus, most of the free O2 added by well- ventilated branches of the pulmonary circulation goes toward increasing hemoglobin saturation rather than increasing PO2. In the case of V / Q mismatch, administration of 100% O2 will increase arterial PO2 significantly. This is because some ventilation exists even in low V / Q regions, which is likely to be sufficient to bring PO2 in blood vessels within these regions to a high enough level to saturate most hemoglobin. Thus, when high V /Q blood mixes with low V /Q blood, the vast majority of its free O2 goes toward increasing PO2.
The alveolar- arterial gradient for oxygen, the P(A-a)O2
The most commonly used and easily calculated estimate of V/Q mismatch is the alveolar- arterial gradient for oxygen, the P(A-a)O2. Remember that low V/Q and shunt units represent areas where there is excess perfusion relative to ventilation. This is usually caused by airway diseases (i.e. inadequate VA).
Complete assessment of the arterial oxygenation status
requires measurement (or calculation) of: 1) arterial oxygen tension (PaO2)
2) oxy-hemoglobin saturation (SaO2) 3) P(A-a)O2 gradient,
4) blood oxygen content (CaO2). The oxy-hemoglobin saturation provides the single best reflection of oxygen content because nearly all the oxygen in the blood exists as oxy- hemoglobin. Note that this is directly measured in the blood gas machine. An unusually low oxy-hemoglobin saturation in someone with a normal PaO2 can indicate the presence of something competing with oxygen for hemoglobin (usually carbon monoxide).
alveolar gas equation
The alveolar-arterial oxygen gradient (A-a gradient) is a quick and easy calculation and can suggest possible causes of hypoxemia in patients. Calculation of the P(A-a) O2 gradient requires knowledge of the alveolar oxygen pressure and the arterial oxygen pressure. The arterial PO2 (PaO2) can be directly measured by obtaining an arterial blood gas. The alveolar oxygen pressure (PAO2) must be calculated using the alveolar gas equation: PAO2 = (Pb -PH2O) x FIO2 - PaCO2 /R. Pb is barometric pressure (760 mmHg at sea level, 630 mmHg in Denver)
PH2O is the partial pressure of water vapor at 37 C (considered constant at 47 mmHg regardless of altitude)
FIO2 is the fraction of inspired oxygen (0.21 on room air, 1.00 on 100% oxygen, 0.5 on 50% oxygen, etc.)
PaCO2 is obtained via an arterial blood gas
R is the respiratory quotient (VCO2/VO2) and is considered to be 0.8 in most situations. The term (Pb- PH2O) x FIO2 represents the partial pressure of inspired oxygen (PIO2).
If you do the math you will see that at Denver’s altitude the PIO2 under normal conditions is: (630 mmHg - 47 mmHg) x 0.21 = 122 mmHg. So now you can calculate PAO2 for a healthy citizen of Denver (assuming PaCO2 is 35 mmHg): PAO2 = PIO2 - PaCO2 /R. PAO2 = 122 - 35/0.8 = 122 - 44 = 78 mmHg (this is what the O in the alveolus should be). If every acinus were perfectly perfused and ventilated, the arterial PO2 (PaO2) would be 78 mmHg, but this is not so. There are some areas of low V/Q matching. Most of the A-a gradient in normal people however, represents the degree of anatomic right to left shunt that occurs through arteries and veins that empty directly into the left atrium and do not undergo gas-exchange (thebesian and bronchial veins). This represents a small portion of blood flow usually less than 5%. Once the PAO2 is calculated, the A-a gradient can be obtained by comparing PAO2 with PaO2: P(A-a)O2 = PAO2 - PaO2
Intrapulmonary shunts and V/Q mismatch
are the major contributors to the P(A-a)O2. The P(A-a)O2 can give an estimate of the degree
of shunt or (low) V/Q mismatch in a lung, but it
has some limitations. It is affected by things such as the oxygen concentration in the mixed venous blood as well as the FiO2. Shunt can be determined more accurately if mixed venous PO2 is measured, but this requires a pulmonary artery catheter.
the five causes of hypoxemia
1) Low ambient PO2 (altitude) 2) Hypoventilation (Ondine’s curse). 3) V /Q mismatch (Pneumonia, COPD, asthma, etc) 4) Shunt (intracardiac or intrapulmonary). 5) Diffusion limitations (ARDS, RDS, ILD, etc..). Recall the alveolar gas equation: PAO2 = (Pb- PH20) FIO2 - PaCO2 /R.
analyzing hypoxemia with a normal A-a gradient
A normal A-a gradient tells you that hypoxemia is not due to abnormal gas exchange in the lung. Climbers ascending Mt Everest without oxygen have been estimated to have an alveolar PO2 of 35 mmHg at the summit (based on the low barometric pressure). This degree of hypoxemia can be very dangerous, but it is through no fault of the lung since gas exchange is normal (as measured by the A-a gradient). The treatment is oxygen or descent to lower altitude. The arterial PO2 in Denver is lower than sea level, but the A-a gradient is not different. The second cause of hypoxemia with a normal A-a gradient is hypoventilation. If you look at the alveolar gas equation you can see that if the PCO2 goes up then the PAO2 goes down, as does PaO2. Excessive sedation, neuromuscular disease, or blunted central chemoreceptors can all lead to hypoventilation and elevated PCO2. This will cause the PO2 to decrease, but the A-a gradient is normal since there is no defect at the gas exchange area. The hypoventilation is global and therefore you would expect blood from all capillary beds to have the same low PO2 and elevated PCO2. This is a problem with ventilation not gas exchange.
analyzing hypoxemia with a widened A-a gradient
A widened A-a gradient occurs in V/Q mismatch, shunt, and diffusion abnormalities. V/Q mismatch and shunt are similar in pathology. Blood flows past poorly ventilated (low V/Q) or unventilated (shunt) alveoli. The blood comes into complete equilibrium with those alveoli, but the PO2 is lower than normal. Remember that the PAO2 is calculated based on the ideal alveoli. The PaO2 is obtained from a blood gas. A wide A-a gradient tells you that there is blood coming from poorly or unventilated areas. The more blood that encounters poorly ventilated alveoli the farther the arterial blood is from the ‘ideal’ and the wider the A-a gradient is. (Right to left flow through intracardiac defects (i.e. ASD and VSD) are shunts and contribute to the A-a gradient).
Hypoxemia due to diffusion limitations
Hypoxemia due to diffusion limitations is less common clinically and occurs primarily at extreme altitude or extreme exercise at sea level. Diffusion limitation occurs when the blood travels through the alveoli so quickly that it does not have time to equilibrate with the alveoli. Normally a red cell takes about 0.75 seconds to traverse the capillary and is completely equilibrated with the alveoli in about 0.25 seconds. With exercise at altitude the alveolar PO2 is so low that the red cell does not equilibrate with the alveoli so the blood leaves with an oxygen tension lower than the alveoli. This does not happen in any of the other causes of hypoxemia (that blood leaves the capillary with a different oxygen tension than the alveoli it just encountered). This is not a clinically relevant cause of hypoxemia in most cases but is important at altitude and is likely important in limiting exertion at extreme altitudes. Remember that hypoxemia can be due to one or a combination of the above 5 reasons. Someone who hypoventilates due to excessive sedation can develop an aspiration pneumonia and have hypoxemia due to both hypoventilation and V/Q mismatch. An A-a gradient greater than 10 is abnormal.
Decreased fremitus
may be caused by: excess air in the lungs (emphysema, pneumothorax), fluid in the pleural space (pleural effusion), and atelectasis due to an obstructed bronchus.
Increased fremitus
occurs with consolidation in the lung (replacement of air with water, blood, pus, or other fluid) as occurs in pneumonia or pulmonary edema.
Trachea
Note if the trachea is deviated from the midline. Deviation can be due to it being pushed away from one side (large pleural effusion, tension pneumothorax) or pulled toward one side (volume loss due to focal scarring/fibrosis, or atelectasis).
Dullness
occurs when fluid or solid tissue replaces air-containing lung or occupies the pleural space beneath your percussing fingers. Causes include large pleural effusions, lobar pneumonia, and areas of atelectasis
Resonant
occurs with anything that increases air in the lung such as pneumothorax, emphysema, and large air-filled bullae in the lung
crackles (also known as rales)
discontinuous and heard more frequently during inspiration. Caused by disruptive airflow through the small airways although the specific cause is not clear. Depending on the scenario these are associated with pulmonary edema, pneumonia, and interstitial lung disease.
Rhonchi
rumbling (or snoring) sounds that are more continuous. They are caused by passage of air through an airway partially obstructed by mucous or secretions.
Wheezes
continuous high-pitched, musical sound heard during inspiration or expiration. Caused by high airflow through a narrowed airway. Diffuse wheezes suggest widespread airway narrowing such as asthma or bronchiolitis whereas localized wheezing suggests a focal obstruction that needs to be evaluated.
Egophony
a change in timbre but not pitch or volume. Have the patient say “Eeee” as you ascultate (E to A change). It occurs over areas or compressed or fluid filled areas of the lung (i.e. pneumonia).
Stridor
musical sounds typically audible without a stethoscope and can be either inspiratory or expiratory. It is loudest when ascultating the trachea. Stridor represents pathology in the upper airway (trachea, larynx, subglottis). Inspiratory stridor typically occurs due to laryngeal pathology such as laryngospasm or laryngeal edema, subglottic stenosis, or vocal cord dysfunction. Expiratory stridor typically represents central airway obstruction within the thorax, such as a tumor obstructing the trachea. Stridor almost always needs urgent evaluation, especially expiratory stridor.
