HBAP exam 3 first part

Exam 3 pp dirst two lessons, airway b, chapter 13

Overview – What are the two meanings of respiration

(1) Internal (cellular) respiration: use of oxygen by cells in the metabolism of organic molecules. (2) Exchange of oxygen and carbon dioxide between an organism and the external environment (pulmonary physiology; 'pulmonary' = refers to the lungs). This chapter is about the second meaning.

Overview – What are the functions of the respiratory system (Table 13.1)

(1) Provides oxygen to the blood. (2) Eliminates carbon dioxide from the blood. (3) Regulates the blood's hydrogen ion concentration (pH) in coordination with the kidneys. (4) Forms speech sounds (phonation). (5) Defends against inhaled microbes. (6) Influences arterial concentrations of chemical messengers by removing some from pulmonary capillary blood and producing/adding others. (7) Traps and dissolves blood clots from systemic veins, such as those in the legs.

Overview – What does the respiratory system include

The oral and nasal cavities, the lungs, the series of tubes leading to the lungs, and the chest structures responsible for moving air into and out of the lungs during breathing.

Overview – Define: alveoli, airways, inspiration, expiration, respiratory cycle.

Alveoli: tiny air-containing sacs (about 300 million in an adult); sites of gas exchange with the blood. Airways: tubes through which air flows from the external environment to the alveoli and back. Inspiration (inhalation): air moves from the environment through the airways into the alveoli. Expiration (exhalation): air moves in the opposite direction. Respiratory cycle: one inspiration plus one expiration.

Overview – Typical resting air and blood flow in a healthy adult, and how much do they increase in heavy exercise

At rest: about 4 L of fresh air enters and leaves the alveoli per minute, while 5 L of blood (the cardiac output) flows through the pulmonary capillaries. Heavy exercise: airflow can increase 20-fold; blood flow 5- to 6-fold.

Overview – What are the 5 steps of respiration, and what is the steady state

(1) Ventilation: exchange of air between atmosphere and alveoli by bulk flow. (2) Exchange of O2 and CO2 between alveolar air and blood in lung capillaries by diffusion. (3) Transport of O2 and CO2 through pulmonary and systemic circulation by bulk flow. (4) Exchange of O2 and CO2 between blood in tissue capillaries and cells by diffusion. (5) Cellular use of O2 and production of CO2. Steady state: the net volumes of O2 and CO2 exchanged per unit time in the lungs equal the net volumes exchanged per unit time in the tissues.

Airways – What is the path of air from the outside to the alveoli

Nose/mouth → pharynx (passage common to air and food; it branches into the esophagus, for food, and the larynx, part of the airways) → larynx → trachea → two bronchi (one enters each lung) → within the lungs more than 20 generations of branching: bronchioles → terminal bronchioles → respiratory bronchioles → alveolar ducts → alveolar sacs. Each branching gives narrower, shorter and more numerous tubes.

Airways – What is the larynx, and what are the upper airways

The larynx is part of the airways and houses the vocal cords: two folds of elastic tissue stretched horizontally across its lumen. Airflow past them makes them vibrate, producing sounds. Upper airways = nose, mouth, pharynx and larynx.

Airways – Conducting zone vs respiratory zone: where do they extend and what do they do

Conducting zone: from the top of the trachea to the end of the terminal bronchioles. It contains no alveoli and does not exchange gases with the blood. Respiratory zone: from the respiratory bronchioles down. It contains alveoli and is the region of gas exchange with the blood.

Airways – Where is cartilage found, where do alveoli first appear, and what does smooth muscle do

Walls of the trachea and bronchi contain rings of cartilage (give cylindrical shape and support). The first branches without cartilage are the bronchioles. Bronchioles are surrounded by smooth muscle that contracts or relaxes to change bronchiolar radius (like arterioles). Alveoli first appear attached to the walls of the respiratory bronchioles; their number increases in the alveolar ducts; the airways end in grapelike clusters called alveolar sacs, which consist entirely of alveoli.

Airways – What are the functions of the conducting zone (Table 13.2)

(1) Low-resistance pathway for airflow (resistance is regulated by contraction of bronchiolar smooth muscle and by physical forces acting on the airways). (2) Defends against microbes, toxic chemicals and other foreign matter (cilia, mucus, macrophages). (3) Warms and moistens the air. (4) Takes part in sound production (vocal cords).

Airways – How does the mucous escalator work, and what damages it

Oral and nasal cavities trap airborne particles in nasal hairs and mucus. Airway epithelium (to the end of the respiratory bronchioles) has cilia beating upward toward the pharynx, plus glands and epithelial cells that secrete mucus, and macrophages that phagocytize inhaled pathogens. Dust sticks to the mucus, which the cilia move slowly to the pharynx, where it is swallowed. This keeps the lungs clear of particles and bacteria. The airway epithelium also secretes a watery fluid on which the mucus rides freely. Ciliary activity and number are decreased by noxious agents such as tobacco smoke (why smokers cough up mucus).

Airways – What other protective mechanisms do the airways and alveoli have

Constriction of bronchioles in response to irritation helps keep particles and irritants from entering the sites of gas exchange. Macrophages in the airways and alveoli engulf and destroy inhaled particles and bacteria that reach the alveoli. Macrophages, like the ciliated epithelium, are injured by tobacco smoke and air pollutants.

Airways – Cystic fibrosis (CF): cause, effect and treatment

Cause: autosomal recessive mutation in an epithelial chloride channel, the CF transmembrane conductance regulator (CFTR) protein. Effect: problems with ion and water movement across cell membranes, so the watery fluid is impaired and the mucous layer becomes thick and dehydrated, obstructing the airways; thick secretions and a high incidence of lung infection. Most common lethal genetic disease among Whites. Other organs are usually affected too (e.g., secretory organs of the GI tract such as the exocrine pancreas). Treatment: therapy to improve mucus clearance and aggressive antibiotic use to prevent pneumonia; lung transplantation may be needed. Median life expectancy is still only about 35 years.

Airways – What are the characteristics of the pulmonary blood vessels and circulation

Pulmonary blood vessels generally accompany the airways and branch many times into capillary networks that richly supply the alveoli. The pulmonary circulation has a very low resistance compared with the systemic circulation, so pressures in all pulmonary blood vessels are low. This minimizes accumulation of fluid in the interstitial spaces of the lungs (Starling forces).

Alveoli – What is the structure of an alveolus and its wall

Tiny, hollow sacs with open ends continuous with the lumens of the airways. A single alveolar wall typically separates the air in two adjacent alveoli. Type I alveolar cells: flat epithelial cells, one cell thick, lining most of the air-facing surface. Type II alveolar cells: thicker, specialized cells interspersed between type I cells; make a detergent-like substance called surfactant (prevents alveolar collapse). The wall contains capillaries and a very small interstitial space (interstitial fluid + loose meshwork of connective tissue).

Alveoli – Why is the alveolar-capillary barrier good for gas exchange

In many places the interstitial space is absent and the basement membranes of the alveolar epithelium and capillary endothelium fuse. The barrier between blood and alveolar air is extremely thin (0.2 μm, compared with a 7 μm red blood cell), and the total alveolar surface in contact with capillaries is roughly the size of a tennis court. This allows rapid exchange of large quantities of O2 and CO2 by diffusion (structure is a determinant of function).

Alveoli – What are the pores in the alveolar walls for

They let air flow between alveoli. This is very important when the airway leading to an alveolus is blocked by disease, because some air can still enter that alveolus through the pores from adjacent alveoli.

Thorax – What is the thorax and what forms its wall

Thorax = chest: the closed compartment between neck and abdomen that contains the lungs and heart. Bounded at the neck by muscles and connective tissue; completely separated from the abdomen by the diaphragm (large dome-shaped sheet of skeletal muscle). The wall is formed by the spinal column, ribs, sternum and the intercostal muscles (between the ribs), and contains much elastic connective tissue.

Pleura – How are the pleural sac, visceral pleura, parietal pleura and intrapleural fluid arranged

Each lung is surrounded by a completely closed pleural sac (thin sheet of cells); the sacs of the two lungs are separate (no communication between right and left intrapleural fluids). Visceral pleura: covers the outer surface of the lung, firmly attached by connective tissue. Parietal pleura: attached to and lines the inside of the thoracic wall and diaphragm. The two layers are very close but not attached to each other; they are separated by an extremely thin layer of intrapleural fluid (only a few mL) that surrounds the lungs and lubricates the surfaces so they slide over each other during breathing. Intrapleural pressure (Pip) = hydrostatic pressure of this fluid; changes in it make the lungs and thoracic wall move in and out together.

Pleura – What analogies are used to picture the pleura

Fist pushed into a fluid-filled balloon: arm = major bronchus, fist = lung, balloon = pleural sac (balloon coats the fist and is folded back on itself, its two surfaces separated by a thin fluid layer). Two glass microscope slides with a drop of water between them: they slide over each other easily but are very difficult to pull apart.

Ventilation – Define ventilation and give the airflow equation.

Ventilation = exchange of air between the atmosphere and the alveoli. Air moves by bulk flow from high to low pressure: F = ΔP/R. For airflow: F = (Palv − Patm)/R, where Palv = alveolar pressure, Patm = atmospheric pressure (at the nose and mouth), R = airway resistance. Flow is proportional to the pressure difference and inversely proportional to resistance.

Ventilation – How are pressures expressed, and what decides the direction of airflow

All respiratory pressures are given relative to atmospheric pressure (760 mmHg at sea level, lower at higher altitude). Between breaths Palv = 0 mmHg (= Patm), so with no airflow and the airway open, Palv = Patm. Palv < Patm → (Palv − Patm) negative → air flows in (inspiration). Palv > Patm → positive → air flows out (expiration). Alveolar pressure changes are caused by changes in the dimensions of the chest wall and lungs.

Ventilation – What is Boyle's law and how is it used in breathing

P1V1 = P2V2. At constant temperature, the pressure of a fixed number of gas molecules is inversely proportional to the volume of their container: volume increases → pressure decreases; volume decreases → pressure increases. In breathing, the lung volume is changed, and by Boyle's law this changes alveolar pressure, which drives airflow in or out.

Ventilation – What determines lung volume (lungs have no muscles on their surface)

The lungs are passive elastic structures, like balloons; no muscles are attached to the lung surface to pull them open or push them shut. Lung volume depends on (1) the pressure difference between inside and outside the lung (transpulmonary pressure) and (2) how stretchable the lungs are (compliance).

Ventilation – Define transmural pressure, transpulmonary pressure (Ptp) and chest wall pressure (Pcw), with resting values.

Transmural = 'across a wall'; Pin − Pout (pressure inside the structure minus pressure outside). Transpulmonary pressure: Ptp = Palv − Pip; resting value 0 − (−4) = +4 mmHg; it holds the lungs open (opposes inward elastic recoil of the lung); governs the static properties/size of the lungs. Ptp must always be positive because the lungs always contain air (Palv > Pip). Chest wall pressure: Pcw = Pip − Patm; resting value −4 − 0 = −4 mmHg; it holds the chest wall in (opposes outward elastic recoil of the chest wall).

Ventilation – Why is intrapleural pressure (Pip) negative (subatmospheric) between breaths

Elastic recoil = tendency of an elastic structure to oppose stretching or distortion. At rest the lungs (which contain air) tend to collapse, and the chest wall tends to expand. These forces are balanced by the positive Ptp and the negative Pcw, so lung volume is stable. As lungs and chest wall move very slightly away from each other, the fluid-filled intrapleural space enlarges infinitesimally; fluid cannot expand like air, so Pip falls below atmospheric (about −4 mmHg). This keeps them from moving farther apart (like the glass slides).

Ventilation – What is a pneumothorax and what happens

Air enters the intrapleural space, e.g., through a wound that pierces the chest wall, or from a hole in the lung leaking air into the pleural space (e.g., high airway pressure in artificial ventilation of a premature infant with fragile lungs). Pip rises from −4 mmHg to 0 (= Patm), so Ptp = 0: the force holding the lung open is gone and the lung collapses; the chest wall moves outward because its elastic recoil is no longer opposed. Usually unilateral, because the mediastinum divides the thorax into right and left sides.

Ventilation – Sequence of events in quiet inspiration

(1) Neurally induced contraction of the diaphragm (phrenic nerves; the most important inspiratory muscle in quiet breathing; its dome moves down into the abdomen) and the external intercostal muscles (intercostal nerves; ribs move up and out). (2) Thorax expands. (3) Pip becomes more subatmospheric. (4) Ptp increases, so the lungs expand (passively forced to enlarge). (5) Palv falls below Patm (Boyle's law). (6) Air flows into the alveoli. At the end of inspiration Palv = Patm again and flow stops; lung volume is stable whenever Ptp is balanced by the elastic recoil of the lungs (end of both inspiration and expiration).

Ventilation – Which muscles are added in maximal inspiration

Besides the diaphragm (contracts more) and external intercostals (pull ribs up and out): sternocleidomastoid and scalenes (elevate the sternum) and pectoralis minor (elevates the ribs).

Ventilation – Sequence of events in quiet expiration

(1) Motor neurons to the diaphragm and external intercostals decrease firing; the muscles relax. (2) Diaphragm and chest wall recoil inward. (3) Pip becomes less subatmospheric and Ptp decreases. (4) Ptp is now smaller than the elastic recoil of the stretched lungs, so the lungs passively recoil. (5) Alveolar air is compressed, so Palv > Patm (Boyle's law). (6) Air flows out. Expiration at rest is passive: it depends only on relaxation of the inspiratory muscles and elastic recoil of the stretched lungs.

Ventilation – How is forced (larger-volume) expiration achieved, e.g., in exercise

By contraction of the internal intercostal muscles (pull the chest wall downward and inward, decreasing thoracic volume) and the abdominal muscles (increase intra-abdominal pressure and force the relaxed diaphragm up into the thorax). Chest dimensions decrease more rapidly, Palv rises even more, and expiration is more rapid.

Ventilation – What are the typical pressures in a normal breath at rest

End of expiration (no flow): Palv = 0, Pip = −4, Ptp = +4 mmHg. During inspiration Pip becomes more negative, Ptp rises and Palv becomes negative; during expiration Palv is positive. The Palv − Patm difference during a normal breath is only about 1 mmHg, yet it moves about 500 mL of air. Pip stays negative relative to Patm throughout a normal respiratory cycle.

Compliance – Define lung compliance and what low compliance means.

CL = ΔVL/ΔPtp (change in lung volume produced by a given change in transpulmonary pressure). Greater compliance = easier to expand the lungs at a given change in Ptp; compliance is the inverse of stiffness. Low compliance (stiff lung): a greater-than-normal Ptp is needed, so Pip must become more subatmospheric, which needs more vigorous contraction of the diaphragm and inspiratory intercostals and more energy. People with low compliance due to disease breathe shallowly and at a higher frequency, which reduces the work of breathing. Increased compliance (e.g., emphysema): small decreases in Ptp allow the lung to collapse.

Compliance – What are the two major determinants of lung compliance

(1) Stretchability of the lung tissues, especially their elastic connective tissue (thickening of lung tissue decreases compliance). (2) Surface tension at the air–water interface within the alveoli (equally if not more important).

Compliance – What is surface tension and why does it matter in the alveoli

The inner surface of the alveoli is moist (air-filled sacs lined with a thin liquid layer). At an air–water interface, the attractive forces between water molecules (surface tension) make the water lining like a stretched balloon that constantly tends to shrink and resists further stretching. Expanding the lung therefore takes energy to stretch the connective tissue and to overcome the surface tension. If alveoli were lined with pure water, lung expansion would require exhausting muscular effort and the lungs would tend to collapse.

Surfactant – What is it and what does it do (Table 13.4)

Mixture of lipids and proteins (major component: a phospholipid whose hydrophilic end is inserted in the water layer, with hydrophobic ends forming a monomolecular layer between air and water); secreted by type II alveolar cells. It lowers the surface tension of the water layer, which increases lung compliance and makes the lungs easier to expand. Its effect is greater in smaller alveoli, which stabilizes alveoli. A deep breath stretches the type II cells and increases its secretion; its concentration decreases when breaths are small and constant (so patients breathing shallowly after thoracic or abdominal surgery must be urged to take occasional deep breaths). In the fetus, production occurs in late gestation, stimulated by the rise in cortisol (glucocorticoid).

Surfactant – What is the Law of Laplace and how does surfactant stabilize alveoli of different sizes

P = 2T/r (P = pressure inside the alveolus, T = surface tension, r = radius). Smaller radius → higher pressure; higher surface tension → higher pressure. Two alveoli sharing an alveolar duct, with ra > rb: if T were equal, Pb > Pa, air would flow from b into a, and small alveolus b would collapse into the large one. Surfactant prevents this: as an alveolus gets smaller, its surfactant molecules are less spread out, so surface tension is lower. This keeps pressure in small alveoli equal to that in larger ones (Pa = Pb), so there is no flow from small to large alveoli.

Surfactant – What is respiratory distress syndrome of the newborn

A leading cause of death in premature infants, whose surfactant-synthesizing (type II) cells are too immature. Surfactant deficiency → high surface tension in the alveoli → very low compliance. The infant can inspire only with the most strenuous effort, which may end in exhaustion, inability to breathe, lung collapse and death. The fetus does not need surfactant (lungs filled with amniotic fluid; oxygen comes from maternal blood via the placenta). Treatment: assisted breathing with a mechanical ventilator plus natural or synthetic surfactant given through the infant's trachea (before this, almost half of the infants died).

Airway resistance – What determines airway resistance

Same factors as vascular resistance: tube length, tube radius, and interactions between moving gas molecules. Radius is by far the most important: airway resistance is inversely proportional to the fourth power of the airway radius. Normal airway resistance is so small that tiny pressure differences (about 1 mmHg) produce large airflow (about 500 mL).

Airway resistance – What keeps the airways open and how does resistance change during breathing

(1) Transpulmonary pressure exerts a distending force on the airways (as on the alveoli); this keeps the smaller airways without cartilage from collapsing. Ptp increases in inspiration, so airway radius becomes larger and resistance lower; the opposite occurs in expiration. (2) Lateral traction: elastic connective-tissue fibers linking the outside of the airways to the surrounding alveolar tissue are pulled as the lungs expand and help pull the airways open even more. Both act in the same direction: lower airway resistance during inspiration.

Airway resistance – What happens to airway resistance in a forced expiration

The increase in intrapleural pressure compresses the small conducting airways and decreases their radii, so resistance increases. There is a limit to how much expiratory airflow can be increased no matter how intense the effort: the harder one pushes, the more the airways are compressed.

Airway resistance – Which chemicals change airway smooth muscle, and why do these factors matter

Epinephrine relaxes airway smooth muscle (acts on beta-adrenergic receptors). Leukotrienes (eicosanoids produced in the lungs during inflammation) contract it. They matter because under abnormal circumstances changes in these factors can greatly increase airway resistance, as in asthma and COPD.

Airway resistance – Asthma: what is it, what triggers it, and how is it treated

Intermittent episodes of strong airway smooth muscle contraction that markedly increase airway resistance. Basic defect: chronic inflammation of the airways (allergy, viral infections, sensitivity to environmental factors), which makes the smooth muscle hyperresponsive. Triggers: exercise (especially in cold, dry air), tobacco smoke, environmental pollutants, viruses, allergens, normally released bronchoconstrictor chemicals, others. Treatment aim 1: reduce chronic inflammation and hyperresponsiveness with anti-inflammatory drugs (leukotriene inhibitors, inhaled glucocorticoids; dexamethasone, a very potent glucocorticoid, has been used for COVID-19 lung inflammation). Aim 2: overcome acute excessive contraction with bronchodilators, which relax the airways: drugs mimicking epinephrine on beta-2 (β2) adrenergic receptors, or inhaled drugs blocking muscarinic cholinergic receptors (implicated in bronchoconstriction).

Airway resistance – What is COPD (emphysema vs chronic bronchitis)

COPD = chronic obstructive pulmonary disease: emphysema, chronic bronchitis, or both. It causes severe difficulty in ventilation and in oxygenation of the blood. Unlike asthma, the obstruction is not due to increased smooth muscle contraction. Emphysema: obstruction from damage to and collapse of the smaller airways (increased compliance). Chronic bronchitis: excessive mucus production in the bronchi plus chronic inflammation of the small airways; obstruction from mucus accumulation and thickened inflamed airways. Smoking causes both, so they often coexist. Acute bronchitis (e.g., viral infections) typically resolves within 2 to 3 weeks.

Lung volumes – Define the 4 lung volumes and give typical values (young adult male).

Tidal volume (TV/Vt): air inhaled or exhaled in one breath; ~500 mL at rest. Inspiratory reserve volume (IRV): air in excess of tidal inspiration that can be inhaled with maximum effort; ~3000 mL (6 times resting tidal volume). Expiratory reserve volume (ERV): air in excess of tidal expiration that can be exhaled with maximum effort; ~1200 mL. Residual volume (RV): air remaining in the lungs after maximum expiration; keeps alveoli inflated between breaths and mixes with fresh air on the next inspiration; ~1200 mL. The lungs are never completely emptied of air. The four volumes are the distinct components of total lung capacity.

Lung volumes – Define the 4 lung capacities, their formulas and typical values.

Capacities = sums of two or more volumes. Vital capacity (VC) = ERV + TV + IRV = maximal air exhaled with maximum effort after maximum inspiration; ~4700 mL; used to assess strength of thoracic muscles and pulmonary function. Inspiratory capacity (IC) = TV + IRV = maximal air that can be inhaled after a normal tidal expiration; ~3500 mL. Functional residual capacity (FRC) = RV + ERV = air remaining in the lungs after a normal tidal expiration; ~2400 mL; it is the resting position of lungs and chest wall with no respiratory muscle contraction (500 mL of each resting breath mixes with this larger volume). Total lung capacity (TLC) = RV + VC = maximum amount of air the lungs can contain; ~5900 mL.

Lung volumes – Which volumes/capacities cannot be measured with a spirometer

Residual volume (RV), functional residual capacity (FRC) and total lung capacity (TLC). (A spirometer records inspired and expired volumes: the pen moves up with inspiration and down with expiration.)

Lung volumes – What is FEV1 and what are pulmonary function tests

Vital capacity and FEV1 are pulmonary function tests (useful diagnostically). FEV1 = forced expiratory volume in 1 second: the person takes a maximal inspiration, then exhales maximally as fast as possible; the important value is the fraction of the total forced vital capacity expired in 1 second. Healthy individuals can expire at least 80% of the vital capacity in 1 second.

Lung volumes – Obstructive vs restrictive lung diseases: what changes in VC and FEV1

Obstructive (increased airway resistance, e.g., asthma): FEV1 is less than 80% of the vital capacity, because air cannot be expired rapidly through narrowed airways. Restrictive: normal airway resistance but impaired respiratory movements because of abnormalities in the lung tissue, pleura, chest wall or neuromuscular machinery; typically reduced vital capacity but a normal ratio of FEV1 to vital capacity.

Alveolar ventilation – What is minute ventilation

Total ventilation per minute = tidal volume × respiratory rate (VE = Vt × f; mL/min = mL/breath × breaths/min). Example: 500 mL/breath × 12 breaths/min = 6000 mL/min. Not all of this air is available for gas exchange because of dead space.

Alveolar ventilation – What is dead space and what types are there

Dead space = volume of inspired air that does not take part in gas exchange. Anatomical dead space (VD): the conducting airways, about 150 mL; no gas exchange occurs there. Alveolar dead space: fresh air that reaches alveoli with little or no blood supply (poorly or not perfused); quite small in healthy people, may be very large in lung disease; local mechanisms matching air and blood flow minimize it. Physiological dead space = anatomical + alveolar dead space (also called wasted ventilation).

Alveolar ventilation – How does anatomical dead space affect one 500 mL breath

During expiration, about 350 mL of alveolar air leaves at the nose/mouth and about 150 mL stays in the airways. During the next inspiration the first 150 mL entering the alveoli is the old air left in the airways, so only 350 mL of new atmospheric air reaches the alveoli. 150 mL of each 500 mL breath never reaches the alveoli; it just moves in and out of the airways.

Alveolar ventilation – What is alveolar ventilation and why is it important

Total volume of fresh air entering the alveoli per minute: VA = (Vt − VD) × f. Example: (500 − 150 mL) × 12 breaths/min = 4200 mL/min. Alveolar ventilation, not minute ventilation, is the important factor in the effectiveness of gas exchange.

Alveolar ventilation – Compare breathing patterns A, B and C (Table 13.5) and give the lesson. All have a minute ventilation of 6000 mL/min. A (rapid, shallow): Vt 150 mL × 40/min; dead-space ventilation 6000; alveolar ventilation 0 (would quickly become unconscious). B (normal): Vt 500 × 12/min; dead space 1800; alveolar ventilation 4200. C (slow, deep): Vt 1000 × 6/min; dead space 900; alveolar ventilation 5100.

Lessons: increased depth of breathing is far more effective for alveolar ventilation than an equivalent increase in rate; a decrease in depth can critically reduce alveolar ventilation because a fixed volume of each breath goes to dead space (any increase in Vt goes entirely to alveolar ventilation). Situations that increase ventilation, such as exercise, reflexively increase depth relatively more than rate.

Gas exchange – What is the respiratory quotient (RQ) and what are typical resting O2 and CO2 values

RQ = carbon dioxide production divided by oxygen consumption. Typical RQ = 0.8. At rest: O2 consumption ~250 mL/min and CO2 production ~200 mL/min. Resting summary (Fig 13.20): alveolar ventilation 4 L/min, cardiac output 5 L/min; arterial blood carries 1000 mL O2/min (200 mL O2/L × 5 L) and venous blood 750 mL O2/min (250 mL lost to the tissues); CO2 carried per minute: 2600 mL in arterial blood, 2800 mL in venous blood (200 mL added by the tissues). These are amounts per minute of cardiac output, not per liter of blood.

Gas exchange – State Dalton's law and how to calculate a partial pressure (include PO2 of air).

Dalton's law: the total pressure of a mixture of gases is the sum of the individual partial pressures; the pressures of individual gases are independent of each other. Partial pressure of a gas = fractional concentration of the gas × total pressure of all gases. Atmospheric (barometric) air is ~79% nitrogen and ~21% oxygen (plus very small amounts of water vapor, CO2, inert gases); atmospheric pressure is 760 mmHg at sea level (varies with weather and altitude). PO2 of air at sea level = 0.21 × 760 = 160 mmHg. Respiratory physiologists express gas concentration (in a gas mixture or dissolved in water) as partial pressure. Partial pressures determine the rate of diffusion in lungs and tissues: gases diffuse from higher to lower partial pressure.

Gas exchange – State Henry's law and explain why gas diffusion in liquids is described by partial pressures, not concentrations.

Henry's law: the amount of gas dissolved in a liquid is directly proportional to the partial pressure of that gas in the gas phase with which the liquid is in equilibrium; at equilibrium the partial pressures in the liquid and gas phases are identical. Net diffusion goes from higher to lower PO2 (into or out of the liquid) until the pressures are equal (example: bubbles of CO2 leaving a carbonated drink). This is what happens between alveolar air and pulmonary capillary blood; within a liquid, dissolved gas also diffuses from higher to lower partial pressure (cells, extracellular fluid, capillary blood). The concentration of a gas in a liquid depends on both its partial pressure and its solubility: at equal partial pressures, a more soluble gas has a higher concentration.

Gas exchange – What are the normal gas pressures (PO2 / PCO2) in atmosphere, alveoli, arterial blood, venous blood and cells (Table 13.7, Fig 13.21)

Atmosphere: 160 / 0.3 mmHg. Alveoli: 105 / 40. Systemic arterial blood (= pulmonary vein): 100 / 40. Systemic venous blood (= pulmonary artery): 40 / 46. Cells: PO2 < 40 (mitochondria < 5), PCO2 > 46. Alveolar PO2 is lower than atmospheric because O2 leaves the alveoli into the capillaries; alveolar PCO2 is higher because CO2 enters the alveoli. Arterial PO2 is about 5 mmHg less than alveolar PO2 (ventilation–perfusion inequality). Nitrogen is not considered: it is biologically inert and has no net exchange. Alveolar gas pressures set the systemic arterial values.

Gas exchange – What determines alveolar PO2 and PCO2

Give the effects in Table 13.6. Alveolar PO2 depends on: the PO2 of inspired air, the rate of alveolar ventilation, and the rate of total-body O2 consumption. The ratio of O2 consumption to alveolar ventilation determines alveolar PO2 (higher ratio → lower PO2); the ratio of CO2 production to alveolar ventilation determines alveolar PCO2 (higher ratio → higher PCO2). Effects (PO2 / PCO2): breathing air with low PO2: decreases / no change (reflex hyperventilation later lowers PCO2); ↑ alveolar ventilation: increases / decreases; ↓ alveolar ventilation: decreases / increases; ↑ metabolism: decreases / increases; ↓ metabolism: increases / decreases; proportional increases in metabolism and alveolar ventilation: no change / no change. Alveolar ventilation of ~1 L/min would bring alveolar PO2 near zero (Fig 13.22).

Gas exchange – Define hypoventilation and hyperventilation.

Hypoventilation: increased ratio of CO2 production to alveolar ventilation (alveolar ventilation cannot keep pace with CO2 production); alveolar/arterial PCO2 rises above normal. Hyperventilation: decreased ratio of CO2 production to alveolar ventilation (ventilation too great for CO2 produced); PCO2 falls below normal. Hyperventilation is NOT the same as increased ventilation: it is increased ventilation relative to metabolism. If ventilation changes in proportion to metabolic rate (e.g., moderate exercise) it is neither, because arterial PCO2 does not change.

Gas exchange – What happens in the pulmonary capillaries (alveoli ↔ blood)

Blood entering is systemic venous blood pumped by the right ventricle (PCO2 46, PO2 40 mmHg). Net diffusion of O2 from alveoli to blood and of CO2 from blood to alveoli; capillary PO2 rises and PCO2 falls until they equal the alveolar values. In a healthy person diffusion is fast enough and capillary blood flow slow enough that equilibrium is reached well before the end of the capillary, so blood leaving (to the systemic arteries) has essentially alveolar PO2 and PCO2.

Gas exchange – In what ways can diffusion between alveoli and capillaries be impaired

(1) Decreased total alveolar surface area in contact with pulmonary capillaries. (2) Pulmonary edema: alveoli filled with fluid, increasing the diffusion barrier. (3) Thickened, fibrotic alveolar walls, e.g., diffuse interstitial fibrosis (causes: infection, autoimmune disease, hypersensitivity to inspired substances, toxic airborne chemicals, etc.). In a diseased lung the blood is not fully oxygenated by the end of the capillary. Symptoms: shortness of breath and poor oxygenation. Pure diffusion problems are restricted to O2 and usually do not affect CO2 elimination, because CO2 diffuses more rapidly than O2.

Gas exchange – What is ventilation–perfusion inequality and what are its effects

Mismatch between alveolar airflow (ventilation) and capillary blood flow (perfusion); each alveolus should have the right proportion. Main effect: decreases systemic arterial PO2. Even in healthy people (gravity effects, e.g., upright posture fills lower-lung vessels with more blood) it lowers arterial PO2 about 5 mmHg (the normal alveolar–arterial O2 gradient). Extremes: (1) ventilated alveoli with no blood supply (e.g., blood clot) = dead space/wasted ventilation; (2) blood flowing through unventilated areas (e.g., collapsed alveoli) = shunt. In disease, regional changes in compliance, airway resistance and vascular resistance cause marked inequalities. CO2 elimination is also impaired, but much less (small rises in arterial PCO2 increase alveolar ventilation); severe inequality can raise arterial PCO2.

Gas exchange – What local responses minimize ventilation–perfusion mismatch (Fig 13.24)

(1) Decreased ventilation in a group of alveoli (e.g., mucus plug) → low alveolar/arteriolar PO2 → vasoconstriction of the pulmonary arterioles (unique to pulmonary arterial vessels) → blood flow diverted away from poorly ventilated areas. (2) Decreased blood flow in a region (e.g., small clot) → less CO2 delivered → local fall in PCO2 → local bronchoconstriction → airflow diverted to better-perfused areas. Net effect: blood goes to well-ventilated areas and air is redirected from diseased/damaged alveoli to healthy ones. Not perfect even in healthy lungs (small mismatch, ~5 mmHg gradient).

Gas exchange – How does gas exchange between tissues and blood work

Systemic capillary walls and cell plasma membranes are highly permeable to O2 and CO2. Cells constantly use O2 and make CO2, so intracellular PO2 is lower and PCO2 higher than in arterial blood; the lowest PO2 of all (< 5 mmHg) is in the mitochondria. Net diffusion of O2 from blood → interstitial fluid → cells → mitochondria; net diffusion of CO2 from cells → blood. Along the tissue capillary blood PO2 decreases and PCO2 increases (giving the venous values). Overall: new O2 supply to alveoli plus cellular O2 consumption create PO2 gradients; CO2 production plus its exhalation create PCO2 gradients.

O2 transport – How much O2 is in arterial blood and in what forms

~200 mL O2 per liter of arterial blood: 3 mL physically dissolved (1.5%, proportional to PO2 by Henry's law; low solubility) + 197 mL reversibly bound to hemoglobin in erythrocytes (98.5%, 'more than 98%'). Only dissolved O2 contributes to blood PO2 and drives diffusion; hemoglobin determines the total amount that diffuses. Cardiac output 5 L/min × 200 mL O2/L = 1000 mL O2 carried to tissues per minute.

O2 transport – Describe hemoglobin and define percent saturation and carrying capacity.

Hemoglobin (in erythrocytes) = protein of four subunits bound together; each subunit = heme + a polypeptide; the four polypeptides together are called globin. Each heme contains one iron atom (Fe2+) that binds one O2, so one Hb binds four O2. O2 + Hb ⇌ HbO2. Deoxyhemoglobin (Hb) vs oxyhemoglobin (HbO2). Percent Hb saturation = (O2 bound to Hb / maximal capacity of Hb to bind O2) × 100. The denominator is the oxygen-carrying capacity of the blood. Saturation = percent of Hb with O2 (or any other gas) bound to its iron, regardless of red cell concentration.

O2 transport – What is anemia and how does it affect O2 transport

Anemia = significant decrease in hemoglobin in the blood, most commonly from a low hematocrit (e.g., chronic blood loss, dietary deficiencies causing inadequate erythrocyte production). Total O2 carried depends on percent saturation AND amount of Hb per liter (half the Hb → half the O2 content at any PO2 and saturation). Hb can be 100% saturated yet carrying capacity is reduced. Anemia does not change Hb binding characteristics (curve shape unchanged, unloading per Hb unaffected), so total O2 delivered falls but it is generally less of an emergency than CO poisoning (onset is slower). Arterial PO2 is normal in anemia, so peripheral chemoreceptors are not stimulated and ventilation is not increased.

O2 transport – Describe the O2–hemoglobin dissociation curve and why it is sigmoid.

Plots percent Hb saturation against PO2 (blood at 37°C, normal H+). Sigmoid because of cooperativity: each Hb has four subunits; deoxyhemoglobin is held in a low-affinity conformation by electrostatic bonds between globin subunits; binding of O2 breaks some bonds, exposing the remaining sites, so each O2 bound increases the affinity of the others. Steep slope between 10 and 60 mmHg; plateau between 70 and 100 mmHg. Key points: ~100% saturated at arterial PO2 100 mmHg; ~90% at 60 mmHg; ~75% at normal venous PO2 40 mmHg (only ~25% of the O2 has been unloaded at rest).

O2 transport – What are the consequences of the plateau and the steep part of the curve

Plateau = safety factor: if PO2 falls from 100 to 60 mmHg (high altitude, lung disease) Hb carries only ~10% less O2, so moderate limitation of lung function still gives significant saturation. In a healthy person at sea level, hyperventilating or breathing 100% O2 raises arterial PO2 but does not appreciably raise blood O2 content (Hb already nearly saturated; only a little more dissolves). This does not apply to people with low arterial PO2 (lung disease, altitude), where more O2 would be carried. Steep portion (60 → 20 mmHg) = ideal for unloading in tissues: a small PO2 decrease releases a large quantity of O2.

O2 transport – How does hemoglobin work in the lung and tissue capillaries

Lungs: blood enters with PO2 40 (Hb 75% saturated); alveolar PO2 105 so O2 diffuses into plasma, then erythrocytes; most O2 combines with Hb rather than staying dissolved, so blood PO2 stays below alveolar PO2 until Hb is ~100% saturated, maintaining the diffusion gradient during the large O2 transfer. Tissues: reverse; cell PO2 < interstitial PO2 < plasma PO2 < erythrocyte PO2, so O2 diffuses out of the erythrocyte, Hb dissociates and releases O2 (transfer by diffusion only: Hb → plasma → interstitial fluid → mitochondria). At rest Hb is still ~75% saturated leaving the tissues (~25% extracted). In exercising muscle: lower cell PO2 → larger gradient → more dissociation, so extraction exceeds 25%, and increased blood flow (active hyperemia) adds to O2 supply. Effect of Hb (Fig 13.27): adding Hb to one compartment binds O2, lowering dissolved O2 and PO2 there, so more O2 diffuses in.

O2 transport – Which factors change hemoglobin's affinity for O2 (Table 13.9)

Affinity is DECREASED (curve shifts right; more unloading in tissues at a given PO2) by: increased H+ (acidity), increased PCO2, increased temperature, increased DPG. Decrease in these → increased affinity (curve shifts left). Mechanism: CO2 and H+ combine with the globin portion and alter conformation (allosteric modulation); temperature alters conformation. Tissue capillary blood has more CO2, H+ (CO2 plus lactic acid etc.) and heat than arterial blood; the more active the tissue, the greater these are, so Hb releases more O2 to the most active cells (local mechanism). Increased PO2 decreases Hb's affinity for H+ and CO2 (deoxyhemoglobin has greater affinity for both).

O2 transport – What is DPG (2,3-diphosphoglycerate / BPG)

Substance produced by erythrocytes during glycolysis; erythrocytes have no mitochondria and rely on glycolysis, so they contain large quantities (only trace amounts in cells with mitochondria). It reversibly binds Hb and, allosterically, lowers its affinity for O2 (right shift) → enhanced O2 unloading in tissues. DPG increases in conditions of inadequate O2 supply to tissues (e.g., high altitude), helping maintain O2 delivery.

O2 transport – What is special about fetal hemoglobin

Its subunits are coded by different genes than those expressed after birth, giving a Hb with a higher affinity for O2 (binds more O2 at any PO2). This increases O2 uptake across the placental diffusion barrier, so the fetus is adequately supplied although fetal arterial PO2 is much lower than in the air-breathing newborn.

O2 transport – What is carbon monoxide (CO) poisoning and why is it dangerous

CO: colorless, odorless gas; produced in small amounts by certain body cells (signaling molecule, e.g., in the nervous system) but toxic at higher concentrations; product of incomplete combustion of hydrocarbons (e.g., gasoline); common cause of accidental and intentional poisoning. (1) Affinity for Hb's O2-binding sites is 210 times that of O2, so it competes with O2 and reduces the O2 bound (lower plateau; y-axis expressed as mL O2 per liter blood). (2) Alters Hb's structure so facilitation between subunits is lost (sigmoid shape lost) and O2 is bound more tightly: curve shifts left, so less O2 is unloaded in tissues. Arterial PO2 is normal, so there is typically no reflex increase in ventilation. More serious than anemia (rapid onset). Hint in text: CO can be displaced if dissolved O2 (PO2) is increased enough, since CO and O2 compete for the same sites.

CO2 transport – In what forms is CO2 carried in blood

Waste product, toxic partly because it generates H+; resting metabolism produces ~200 mL CO2/min. CO2 is more soluble than O2. (1) ~10% dissolved in plasma and erythrocyte cytosol. (2) 25–30% carbaminohemoglobin: CO2 + Hb ⇌ HbCO2 (reacts with amino groups of Hb; deoxyhemoglobin has greater affinity for CO2 than oxyhemoglobin). (3) 60–65% as bicarbonate (HCO3−). Total-blood CO2 = dissolved CO2 + HCO3− + CO2 in carbaminohemoglobin (measured in routine blood chemistry).

CO2 transport – Explain the bicarbonate reaction, carbonic anhydrase and the chloride shift.

CO2 + H2O ⇌ H2CO3 (carbonic acid) ⇌ HCO3− + H+. The first step is rate-limiting and very slow unless catalyzed (both directions) by carbonic anhydrase, which is in erythrocytes but not plasma, so the reaction occurs mainly in erythrocytes. Carbonic acid dissociates rapidly without an enzyme. Most HCO3− leaves the erythrocyte into plasma through a transporter exchanging one HCO3− for one Cl− (the 'chloride shift', maintains electroneutrality), which favors the reaction going to the right. The reaction also explains why H+ concentration is higher in tissue capillary and systemic venous blood than in arterial blood, and rises with metabolic activity.

CO2 transport – What happens to CO2 in the lung capillaries

Blood PCO2 is higher than alveolar PCO2, so CO2 diffuses from blood into alveoli; the fall in blood PCO2 drives the reactions to the left: HCO3− + H+ → H2CO3 → CO2 + H2O, and HbCO2 → Hb + CO2. CO2 diffuses into the alveoli and is eliminated by expiration (bulk flow). Unloading of CO2 is facilitated by loading of O2 onto Hb: HbO2 has a lower affinity for CO2 than Hb. Path of a CO2 molecule: cell → interstitial fluid → tissue capillary blood (forms above) → venous blood → right heart → pulmonary capillaries → alveoli → exhaled.

H+ transport – How is H+ handled between tissues and lungs

In tissue capillaries, H+ generated from CO2 (via carbonic acid) is mostly bound (buffered) by deoxyhemoglobin, which has a much greater affinity for H+ than oxyhemoglobin: HbO2 + H+ ⇌ HbH + O2 (Hb and HbH both = deoxyhemoglobin). Only a little H+ stays free, so venous blood (pH 7.36) is only slightly more acidic than arterial blood (pH 7.40). In lung capillaries the reaction reverses: Hb becomes HbO2 and releases H+, which combines with HCO3− → carbonic acid → (carbonic anhydrase) CO2 + H2O; CO2 is exhaled. All H+ generated in the tissues is thus recombined in the lungs, none appears in arterial blood.

H+ transport – Define respiratory and metabolic acidosis and alkalosis.

Respiratory acidosis: increased arterial H+ from CO2 retention (hypoventilation or lung disease preventing CO2 elimination; arterial PCO2 rises). Respiratory alkalosis: decreased arterial PCO2 and H+ from hyperventilation. Metabolic acidosis: increased arterial H+ due to a cause other than a primary change in PCO2 (e.g., lactic acid). Metabolic alkalosis: decreased arterial H+ from a cause other than a change in PCO2 (e.g., loss of H+ from the stomach by vomiting).

Control – How is rhythmic breathing generated (neural)

Diaphragm and intercostals are skeletal muscles, so they only contract when motor neurons stimulate them; breathing depends entirely on cyclical excitation by their motor neurons. Destruction of these neurons or disconnection from the brainstem paralyzes the respiratory muscles and causes death unless artificial respiration is used. Inspiration starts with a burst of action potentials in spinal motor neurons to inspiratory muscles (diaphragm); then firing stops, the muscles relax, and expiration occurs by elastic recoil. When expiratory muscles are used (e.g., exercise), their neurons (silent in inspiration) fire during expiration. Control resides primarily in neurons of the medulla oblongata (same area as the major cardiovascular control centers).

Control – What are the DRG and VRG of the medullary respiratory center

Dorsal respiratory group (DRG): neurons fire mainly during inspiration; input to spinal motor neurons of the diaphragm (phrenic nerves; primary inspiratory muscle at rest) and inspiratory intercostals. Ventral respiratory group (VRG): contains the respiratory rhythm generator in the pre-Bötzinger complex (upper VRG; pacemaker cells + complex neural network that set the basal respiratory rate) and expiratory neurons, most important when large increases in ventilation are needed (e.g., strenuous activity): they activate expiratory muscles for rapid active expiration. Quiet breathing: rhythm generator activates DRG inspiratory neurons → inspiratory muscles contract; when they stop firing → passive expiration. When breathing increases, inspiratory and expiratory neurons/muscles alternate, they are not active at the same time. DRG and VRG innervate each other.

Control – What do the apneustic and pneumotaxic centers (pons) do

Medullary inspiratory neurons receive rich input from the pons, which fine-tunes their output and may help terminate inspiration by inhibiting them. Apneustic center (lower pons): likely the major source of this output (fine-tunes, helps end inspiration). Pneumotaxic center (upper pons; also called the pontine respiratory group): modulates the apneustic center; smooths the transition between inspiration and expiration, particularly with afferent input from pulmonary receptors about the degree of lung inflation. Higher brain centers also input to the medulla/pons, so respiration can be controlled voluntarily (speaking, diving) and is affected by emotions and pain.

Control – What is the Hering–Breuer reflex

Pulmonary stretch receptors in the airway smooth muscle layer are activated by large lung inflation; their afferent fibers travel to the brain and inhibit the medullary inspiratory neurons (DRG), terminating inspiration (feedback from the lungs). It is important in setting respiratory rhythm only with very large tidal volumes, as in strenuous exercise.

Control – Which drugs depress breathing

Medullary inspiratory neurons are very sensitive to inhibition by sedative-hypnotics (e.g., barbiturates) and opiates (e.g., morphine, heroin, fentanyl). Death from an overdose is often directly due to cessation of breathing.

Control – Where are the chemoreceptors and what stimulates them (Table 13.10)

Peripheral chemoreceptors = carotid bodies (at the bifurcation of the common carotid arteries, high in the neck; well placed to monitor O2 supply to the brain; the predominant peripheral receptor for respiratory control) and aortic bodies (on the aortic arch). In contact with arterial blood, near but distinct from the baroreceptors; specialized receptor cells that synapse on afferent fibers to the brainstem and excite the medullary inspiratory neurons. Stimulated by: significantly decreased PO2 (hypoxia), increased H+ (metabolic acidosis), increased PCO2 (respiratory acidosis). Central chemoreceptors = in the medulla; respond to changes in brain extracellular fluid; stimulated by increased H+ in brain ECF, mainly resulting from increased blood PCO2; also excite medullary inspiratory neurons.

Control – How does arterial PO2 control ventilation

Ventilation increases little until arterial PO2 falls to about 60 mmHg; below that, any further fall causes a marked reflex increase (via peripheral chemoreceptors: ↑ firing → ↑ action potentials → stimulate medullary inspiratory neurons → more O2 to alveoli). Insensitivity to smaller reductions fits the Hb curve: total O2 transport is not much decreased until PO2 < 60. Peripheral chemoreceptors respond to low arterial PO2 (lung disease, altitude) but NOT to a lowered O2 content with normal arterial PO2, as in mild/moderate anemia or moderate CO poisoning (no change in dissolved O2 or lung diffusion), so ventilation is not stimulated.

Control – How does arterial PCO2 control ventilation

Even a very small rise in arterial PCO2 causes a marked reflex increase in ventilation; this stabilizes arterial PCO2 near 40 mmHg (a fall removes part of the stimulus, ventilation decreases and CO2 accumulates). These mechanisms prevent small increases in PCO2 much more than equivalent decreases in PO2. The effect is largely due to H+: peripheral chemoreceptors are stimulated by the increased arterial H+; CO2 diffuses rapidly into brain ECF, raising brain ECF PCO2 and H+, which stimulates the central chemoreceptors. Central chemoreceptors account for ~70% of the increased ventilation. Low PO2 and high PCO2 potentiate each other: the response to both is much greater than the sum of the separate responses. Very high CO2 inhibits ventilation (anesthesia-like effect on the medulla; severe headache, restlessness, loss of consciousness) and can be lethal.

Control – How is ventilation controlled by H+ that is not due to CO2 (metabolic acidosis/alkalosis)

Peripheral chemoreceptors provide the major input. Example: lactic acid in strenuous exercise causes hyperventilation almost entirely via the peripheral chemoreceptors; central chemoreceptors are only minimally stimulated because H+ crosses the blood–brain barrier slowly (CO2 crosses easily). Increased ventilation lowers arterial PCO2, bringing H+ back toward normal (this regulates H+ at the expense of PCO2; enzymes work best at physiological pH). Conversely, when H+ falls by means other than reduced PCO2 (e.g., loss of stomach H+ by vomiting), peripheral chemoreceptor output decreases, ventilation is depressed, PCO2 rises and H+ is restored toward normal. Inhibited by: increased arterial PO2 (hyperoxia) and decreased PCO2 (hypocapnia).

Control – What happens to ventilation and blood gases during exercise

Alveolar ventilation can increase up to 20-fold. Moderate exercise: ventilation rises in exact proportion to O2 consumption and CO2 production (increase in ventilation = hyperpnea), so arterial PO2, PCO2 and H+ stay unchanged (venous PCO2 rises and venous PO2 falls, arterial do not). Strenuous exercise: ventilation increases relatively more than metabolism = true hyperventilation, so arterial PCO2 decreases; arterial H+ rises from lactic acid, which helps stimulate the hyperventilation. In healthy people ventilation is not the limiting factor in strenuous exercise, cardiac output is. The major stimuli in moderate exercise remain unclear.

Control – What other factors stimulate ventilation in exercise

(1) Reflex input from mechanoreceptors in joints and muscles; (2) increased body temperature; (3) central command (inputs to respiratory neurons from axons descending from the brain to motor neurons of the exercising muscles); (4) increased plasma epinephrine; (5) increased plasma K+ (K+ moves out of exercising muscles); (6) a conditioned (learned) response. Factors 1 and 3 are most likely significant: ventilation increases abruptly within seconds at the onset of exercise and decreases equally abruptly (by a larger amount) at the end, too fast for blood chemistry or temperature changes. Oscillations in arterial PO2, PCO2 or H+ (despite unchanged averages) may be an additional theoretical input.

Control – What are the protective ventilatory reflexes

Cough and sneeze reflexes originate in receptors between airway epithelial cells: sneeze receptors in nose or pharynx; cough receptors in larynx, trachea and bronchi. Cough: medullary respiratory neurons cause a deep inspiration and a violent expiration, moving particles and secretions from smaller to larger airways and preventing aspiration into the lungs. Alcohol inhibits the cough reflex (partly explains choking and pneumonia in alcoholics). Another protective reflex: immediate cessation of respiration when noxious agents are inhaled (chronic smoking may cause loss of this reflex).

Control – Voluntary control of breathing: how does it work and what are its limits

Via descending pathways from the cerebral cortex to the motor neurons of the respiratory muscles. It cannot be maintained when involuntary stimuli (increased PCO2 or H+) become intense, e.g., you cannot hold your breath for very long. Deliberate hyperventilation lowers alveolar and arterial PCO2 and raises PO2; danger: swimmers who hyperventilate before underwater swimming can hold their breath longer, but low PCO2 may still allow breath holding while exertion lowers arterial PO2 to levels causing unconsciousness and drowning. Respiration must also be controlled during speaking, singing and swallowing.

Control – What are J receptors

Sensory receptors in the lung capillary walls or interstitium; normally dormant, stimulated by increased lung interstitial pressure from fluid collection: pulmonary embolism (occlusion of a pulmonary vessel), left ventricular heart failure (vascular congestion), and strenuous exercise in healthy people. Effects: rapid breathing (tachypnea), dry cough, sensation of chest pressure and dyspnea (feeling that breathing is labored or difficult).

Control – Terms: hypoxia, hypercapnia, hypocapnia, hyperoxia, hyperpnea, tachypnea, dyspnea. \

Hypoxia (in this section): decreased arterial PO2 (formally, deficiency of O2 at tissue level). Hypercapnia: increased arterial PCO2. Hypocapnia: decreased arterial PCO2. Hyperoxia: increased arterial PO2. Hyperpnea: increased ventilation in proportion to metabolism (e.g., exercise). Tachypnea: rapid breathing. Dyspnea: feeling that breathing is labored or difficult.

Hypoxia – Define hypoxia and give its four categories.

Hypoxia = deficiency of oxygen at the tissue level. (1) Hypoxic hypoxia (hypoxemia): arterial PO2 is reduced. (2) Anemic hypoxia or carbon monoxide hypoxia: arterial PO2 normal but total O2 content of blood decreased (too few erythrocytes, deficient/abnormal Hb, or CO competing for Hb). (3) Ischemic (hypoperfusion) hypoxia: blood flow to the tissues too low. (4) Histotoxic hypoxia: normal O2 reaches tissues but cells cannot use it because a toxic agent (e.g., cyanide) interferes with cell metabolism.

Hypoxia – What are the causes of hypoxic hypoxia in disease (Table 13.11)

I. Hypoventilation: defect anywhere along the respiratory control pathway (medulla to respiratory muscles), severe thoracic cage abnormalities, major upper airway obstruction, drugs such as opiates; PCO2 is increased. II. Diffusion impairment: thickened alveolar membranes or decreased surface area (e.g., diffuse interstitial fibrosis); blood and alveolar PO2 fail to equilibrate; often apparent only in exercise; PCO2 may be normal (CO2 diffuses more readily), decreased (reflex ventilation) or increased (severe). III. Shunt: (A) anatomical: mixed venous blood bypasses ventilated alveoli (e.g., hole between right and left atria = patent foramen ovale, PFO); (B) intrapulmonary: mixed venous blood perfuses unventilated alveoli; PCO2 usually not increased (counterbalanced by reflex ventilation). IV. Ventilation–perfusion inequality: by far the most common cause (e.g., COPD); PCO2 normal or increased. Exposure to high altitude also causes hypoxic hypoxia (not a disease).

Hypoxia – Why do ventilation–perfusion abnormalities affect O2 more than CO2

O2: the Hb curve is sigmoid; raising PO2 above 100 mmHg adds little O2 to nearly saturated Hb. Poorly ventilated alveoli that are perfused add low-O2 blood to the pulmonary vein, and increased ventilation of healthy regions adds little extra O2, so mixed blood is still hypoxemic. CO2: its content curve is relatively linear because it is carried mainly as highly soluble HCO3−, which does not saturate at physiological levels. Poorly ventilated areas raise blood CO2, but compensatory increased ventilation lowers CO2 content below normal in blood from well-ventilated areas, so the mixed blood has essentially normal CO2 content and PCO2. So V/Q mismatch gives low arterial PO2 with normal PCO2.

Hypoxia – Why is giving 100% oxygen to patients with hypercapnia dangerous

Some diseases cause both hypoxia and CO2 retention (hypercapnia); treating only the O2 deficit may be inadequate because it does nothing about hypercapnia, and may be dangerous. In chronic situations the reflex ventilatory response to increased PCO2 may be lost, so the primary respiratory drive is the hypoxia; pure oxygen may make the patient stop breathing. Such patients are treated with a mixture of air and oxygen instead of 100% oxygen.