Sharanya Nama, MD Michael Mangione, MD
BASICS
DESCRIPTION
• The alveolar–arterial gradient and ratio provide a useful, objective means to determine how effectively oxygen from the alveolus moves into the pulmonary circulation. It aids with:
– Identifying increases in venous admixtures, even in the presence of increased inspired oxygen concentrations
– Monitoring improvement or worsening of the venous admixture – Assessing effectiveness of treatment and interventions
– Differentiating between causes of hypoxia (impaired uptake vs. decreased alveolar oxygen availability)
PHYSIOLOGY PRINCIPLES
• Definitions:
– PAO2 = alveolar PO2. It is determined by the alveolar gas equation and is calculated as follows: PAO2 = [FiO2 × (Patm – PH2O) – (PaCO2/0.8)]; measured in units of mm Hg.
– PaO2 = arterial PO2. It is determined by direct arterial blood gas values and is measured in units of mm Hg. Small amounts of oxygen are dissolved in the plasma, which are in equilibrium with the oxygen bound to hemoglobin. Thus, a decrease in arterial oxygen content would reflect a decrease in hemoglobin binding and decreased oxygen saturation.
• A-a gradient: The difference between the alveolar and arterial partial pressure of oxygen – Normal adult values in nonsmokers are <15 mm Hg on room air (FiO2 = 0.21) (1). For
example, a patient with a PAO2 = 100 mm Hg and a PaO2 = 93 mm Hg has an A-a gradient of 7.
– Higher FIO2 values result in an increased A-a gradient. For every 10% increase in FiO2, the A-a gradient increases by 5–7 mm Hg. This effect is caused by the loss of regional hypoxic vasoconstriction in the lungs (2).
• Advancing age: Results in a steady rise in the A-a gradient (3); PaO2 predicted = 109 – (0.4
× age in years). For example, a 60-year-old breathing room air would have an average A-a gradient of 14 mm Hg. In comparison, someone below the age of 40 would have a gradient of 7 mm Hg (3).
• A-a gradient: The arterial oxygen concentration divided by the alveolar oxygen concentration. This value is useful in predicting the change in PaO2 when the FIO2 also changes since it is relatively unaffected by varying oxygen levels (4).
– The normal a/A PO2 ratio is 0.74–0.77 when breathing room air (FIO2 = 0.21). It only
increases to 0.80–0.82 when breathing 100% oxygen (5).
• Physiologic shunting and normal venous admixture
– The thebesian veins drain venous blood from all 4 walls of the myocardium (mostly right atrium) and empty into the left atrium.
– Deep bronchial veins drain venous blood from the bronchi and roots of the lungs and empty into the pulmonary veins (deoxygenated blood that returns to the left atrium).
– Venous blood from these areas does not enter the pulmonary circulation; instead, it returns to the systemic circulation without becoming oxygenated. This accounts for a total of 2–5% of cardiac output, and the mixing of oxygenated and deoxygenated blood is known as venous admixture.
– This normal venous admixture accounts for the 10–15 mm Hg A-a gradient and the 0.74–
0.77 a/A ratio that is considered normal.
• Hypoxic pulmonary vasoconstriction describes a physiologic phenomenon in which the pulmonary arterioles constrict in the presence of low oxygen tension in the alveoli (e.g., atelectasis).
– This vessel constriction results in re-directing blood flow to well-oxygenated lung units and away from poorly oxygenated lung units to ultimately improve ventilation-perfusion (V/Q) matching.
– When a patient is given supplemental oxygen, more alveoli become well-oxygenated;
however, it also, in turn, decreases hypoxic vasoconstriction.
– This increase in V/Q mismatch leads to more deoxygenated blood entering the systemic circulatory system and in turn increases the A-a gradient.
ANATOMY
• Alveolus
– Air sac that is lined with a thin membrane consisting of epithelium with collagen and elastin
– Gas exchange occurs across this membrane where gases move down a concentration gradient between alveolus and pulmonary capillary.
– Pulmonary shunt: Perfusion of the alveolar unit without ventilation, due to pathologic processes. Atelectasis describes alveolar deflation or fluid collection of the alveolar unit.
Deflation can result from airway obstruction, mucus or blood plugging, inadequate tidal volumes due to pain, or positioning changes; other causes include endobronchial intubation, pneumothorax, collapse of emphysematous blebs, and one lung ventilation (6).
Fluid collection can result from pulmonary edema, pneumonia, or adult respiratory distress syndrome (ARDS).
– Intracardiac shunt: Venous blood is diverted from the pulmonary circulation directly into the systemic circulation. Examples include atrial or septal defects, pulmonary atrioventricular (AV) malformations, and cyanotic congenital heart disease.
– Diffusion defects: Observed when the alveolar oxygen and carbon dioxide tensions are normal, but oxygen uptake by the alveolar capillaries is abnormal or impaired. Examples
– Hypoventilation: Respiratory depression from drugs, stroke in the pontine area, respiratory muscle fatigue (such as myasthenia gravis), or obesity–hypoventilation syndrome. The increase in carbon dioxide decreases the oxygen partial pressure (concentration) within the alveoli.
PERIOPERATIVE RELEVANCE
• Assessing the A-a gradient or ratio can:
– Differentiate between hypoxia secondary to low alveolar oxygen tension or due to increase in venous admixture from underlying pathology
– Provide an objective means to trend venous admixtures and, hence, assess pulmonary processes
– Assess the effectiveness of treatment and interventions such as positive end expiratory pressures (PEEP)
FiO2; his PAO2 is 350 mm Hg and his PaO2 is 120 mm Hg resulting in an A-a gradient of 230 mm Hg and SpO2 of 99%. Patient B also has ARDS and is on 50% FiO2; his PAO2 is 350 mm Hg and his PaO2 is 320 mm Hg resulting in an A-a gradient of 30 and SpO2 of 99%. Therefore, it is not possible to assess the status of the underlying pathology with higher supplemental oxygen based on oxygen saturation alone; one must obtain a blood gas and calculate the A-a gradient.
– Assessing a/A ratio: In patients receiving higher or changing FiO2, the ratio can provide a more consistent value that allows for comparison. Additionally, it has been shown to be more reliable than the A-a gradient in hemodynamically stable patients (7).
– Perioperative conditions: The functional residual capacity (FRC) is decreased by several factors that ultimately increase the venous admixture, A-a gradient, and a/A ratio.
General anesthesia
Positioning (supine, prone or steep Trendelenburg position) Surgical procedure (laparoscopy, abdominal retractors) Patient (obesity, pregnancy, ascites) (8)
• Maneuvers and techniques to improve lung oxygenation can be assessed objectively by calculating the A-a gradient or a/A ratio.
– Pulmonary edema may be treated by optimizing preload (diuresis, venodilators) and afterload (vasodilators) to increase inotropy.
– Ventilator adjustments such as PEEP, adjusting rate, volume, I:E ratios, and lung recruitment maneuvers
– Surgical maneuvers such as decreasing the insufflation pressures during laparoscopy or retractor tension
– Positioning changes: Elevating the head of the bed can shift the abdominal contents away from the diaphragm and allow for increased lung expansion.
EQUATIONS
• A-a gradient = PAO2 – PaO2
• a/A ratio = PaO2/PAO2
• PAO2 = [FiO2 × (Patm – PH2O) – (PaCO2/0.8)]
• On room air (21%) at sea level, a simplified version: A-a gradient = [(150 – 5)/4(PCO2)] – PaO2
• Normal A-a gradient ∼ (age +10)/4
REFERENCES
1. Mellemgaard K. The alveolar–arterial oxygen difference: Its size and components in normal man. Acta Physiol Scand. 1966;67(1):10–20.
2. Williams AJ. ABC of oxygen: Assessing and interpreting arterial blood gases and acid-base balance. BMJ. 1998;317(7167):1213–1216.
3. Kanber GJ, King FW, Eshchar YR, et al. The alveolar–arterial oxygen gradient in young and elderly men during air and oxygen breathing. Am Rev Respir Dis. 1968;97(3):376–381.
4. Peris LV, Boix JH, Salom JV, et al. Clinical use of the arterial/alveolar oxygen tension ratio. Crit Care Med. 1983;11(11):888–891.
5. Gilbert R, Kreighley JF. The arterial/alveolar oxygen tension ratio: An index of gas exchange applicable to varying inspired oxygen concentrations. Am Rev Respir Dis.
1974;109:142–145.
6. Thurlbeck WM, Müller NL. Emphysema: Definition, imaging, and quantification. Am J Roentgenol. 1994;163:1017–1025.
7. Gilbert R, Auchincloss JH Jr, Kuppinger M, et al. Stability of the arterial/alveolar oxygen partial pressure ratio: Effects of low ventilation/perfusion regions. Crit Care Med.
1979;7(6):267–272.
8. Woodring JH, Reed JC. Types and mechanisms of pulmonary atelectasis. J Thorac Imaging.
1996;11:92–108.
ADDITIONAL READING
• Rodríguez-Roisin R, Roca J. Mechanisms of hypoxemia. Intensive Care Med.
2005;31(8):1017–1019.
See Also (Topic, Algorithm, Electronic Media Element)
• Functional residual capacity
• Mixed venous oxygen saturation
• Oxygen carrying capacity
• Pulmonary ventilation perfusion matching
• One lung ventilation
• Hypoxia, intraoperatively
• PaO2
CLINICAL PEARLS
• Pulse oximetry in the presence of a high FIO2 may not be an adequate marker of pulmonary pathology as reflected by the A-a gradient.
• Hypoxemia caused by physiologic shunt may not be responsive to increased FiO2.
ALVEOLI
Megan Freestone-Bernd, MD Mary E. McAlevy, MD
BASICS
DESCRIPTION
Alveoli are the thin-walled, sac-like, terminal dilations of the respiratory bronchioles, alveolar ducts, and alveolar sacs. They serve as the functional unit for gas exchange with pulmonary capillaries.
• The adult lung contains approximately 300 million alveoli.
• The combined maximal volume is approximately 5–6 L.
• Each alveoli is surrounded by capillaries.
• The combined surface area ranges from 50 to 100 m2. PHYSIOLOGY PRINCIPLES
• Alveolar walls: Comprised of a thin epithelial layer that consists of alveolar type I and alveolar type II cells.
– Alveolar type I cells are squamous epithelial cells and cover approximately 80% of the alveolar surface. They are highly differentiated and very susceptible to injury. If the type I cell is damaged, the type II cells replicate and modify to form new type I cells.
– Alveolar type II cells are cuboidal epithelial cells that synthesize and secrete the fluid layer (surfactant) that lines the alveoli. The type II alveolar cells also control local electrolyte balance and lymphatic cell functions.
– Alveolar type III cells are alveolar macrophages and are an important element of lung defense. They are part of the lung inflammatory response and ingest foreign materials within the alveoli.
• Alveoli size:
– Individual alveoli range from about 75 to 300 μm.
– Surface tension: Describes the force exhibited by water molecules in the alveoli towards one another. Water has a greater attraction to each other than to air, causing the alveoli to tend towards collapse. For example, as alveoli become smaller, water molecules come closer together, and surface tension is increased. As alveoli increase in size, water molecules are further apart, and surface tension is decreased.
– Law of Laplace: The pressure required to keep an alveolus open is directly proportional to the surface tension within the alveolus and indirectly proportional to the alveolar radius.
P = 2T/r, where P = pressure, T = surface tension, and r = radius.
– Surfactant: A phospholipoprotein that contains both a hydrophilic and hydrophobic region that lines the alveoli. It adsorbs to the alveolar air–water interface and decreases surface tension by decreasing the interaction between water molecules. Thus, surfactants function to stabilize the alveoli; the tendency for small alveoli to collapse would result in emptying into larger alveoli.
– Pleural pressure: Varies throughout the lung. At the apices, the pleural pressure is the most negative; therefore, the alveoli are more expanded than at the bases of the lungs.
• Gas exchange across the alveoli is determined by the partial pressure difference across the membrane and the solubility of the gas. The alveoli epithelium and basement membrane provide minimal hindrance and are optimal for this function. Carbon dioxide diffuses 20 times as rapidly as oxygen; oxygen diffuses twice as rapidly as nitrogen.
ANATOMY
• Alveoli are the terminal branches in the pulmonary tree.
• The pulmonary tree begins with the trachea which then branches into the right and left mainstem bronchi. These bronchi then further divide into bronchioles, alveolar ducts, and alveolar sacs.
• The lungs receive blood from the pulmonary and bronchial circulation.
– Pulmonary circulation: Deoxygenated blood flows from the right ventricles into the pulmonary arteries which branch along with the bronchial tree until they reach the respiratory bronchioles. At this point, they form a dense capillary network that provides a very large area for gas exchange. Oxygenated blood returns to the left atrium via the pulmonary veins.
– Bronchial circulation: The blood is supplied from the aortic arch, the thoracic aorta, and the intercostals arteries. It feeds the trachea, bronchi, and bronchioles as well as the intrapulmonary nerves, ganglia, and interstitial lung tissue. It drains into the right atrium as deoxygenated blood.
• Zones: Blood flow through the lungs is dependent upon gravity as well as the relative pressures in each area. These pressures include the pulmonary artery pressure (Ppa), the pulmonary venous pressure (Ppv), and the alveolar pressure (PA). Three zones have been described:
– Zone 1: Located at the lung apex, the perfusion pressure is about equal to the alveolar pressure so blood flow is low (PA > Ppa > Ppv). Zone 1 therefore has ventilation without perfusion and is essentially dead space.
– Zone 2: The middle zone where the perfusion pressure is greater than the alveolar pressure so blood flows easily (Ppa > PA > Ppv). Zone 2 is the area of “best matched”
ventilation and perfusion; it also contains the most number of alveoli.
– Zone 3: Located at the lung base, where the perfusion pressure is much greater than the alveolar pressure so blood flow is high (Ppa > Ppv > PA). Zone 3 has very good perfusion, but less ventilation which results in shunting. with resultant hypoxemia, decreased compliance, and problems re-inflating the lungs.
Surfactant may be present by week 24 and is almost always present by gestational week 35.
If there are mature levels of surfactant, the amniotic fluid will have a lecithin:sphingomyelin ratio >2:1. Corticosteroids may be given to encourage formation of surfactant in cases of pre-term labor.
• Emphysema is a disease where alveoli undergo destruction and elastic recoil is decreased;
this results in increased alveolar size. It is most commonly caused by smoking, but can also result from alpha-1 antitrypsin deficiency. Bronchoalveolar lavage will demonstrate the presence of neutrophils; these cells cause damage to the lung parenchyma by secretion of proteolytic enzymes. Alveolar damage decreases gas exchange area, leading to hypoxemia, hypercarbia, and chronic dyspnea.
• Pulmonary fibrosis describes thickening of the alveolar wall; this impairs the diffusing capacity of gas through the alveoli.
• Cystic fibrosis is a genetic disease of the epithelial chloride channel to open normally in response to cyclic AMP. This defect decreases water passage across the epithelial membrane, leading to abnormally thick mucous in the airways. Mucus can obstruct small airways (plugs) and result in frequent pulmonary infections.
• Aspiration pneumonitis of acidic solutions may lead to destruction of surfactant-producing type II pneumocytes and the capillary endothelium. Damage to these cells may lead to atelectasis and leakage of fluid into the lungs. Arterial hypoxia may ensue, which leads to lung compliance, and increased work of breathing). As capillary pressures increase, fluid will eventually extravasate into the interstitial space around the alveoli. With further increases in pressure, fluid will eventually enter into the alveoli.
• Acute respiratory distress syndrome (ARDS) is defined as severe hypoxemia, diffuse shadows on CXR, low pulmonary compliance, and pulmonary edema not from left-sided heart failure.
The lung parenchyma is severely damaged due to chemical mediators and fibroblasts. There is an inflow of protein-rich fluid into the alveoli due to increased permeability of the alveolar capillary membranes. Diseases that may precipitate ARDS include: septic shock, aspiration of gastric contents, pneumonia, pulmonary contusions, near drowning, severe trauma with associated shock, and inhalation of toxic gases or smoke.
PERIOPERATIVE RELEVANCE
Positive end-expiratory pressure (PEEP) is effective in improving arterial oxygenation and should be used when indicated. PEEP helps prevent alveolar collapse at the end of expiration and in doing so may decrease the shear stress associated with the opening and closing of alveoli with mechanical ventilation. PEEP also helps ventilation-to-perfusion matching as well as decreasing right-to-left intrapulmonary shunt. Because PEEP recruits alveoli that were previously collapsed, it helps to increase lung volumes and functional residual capacity (FRC).
However, by increasing the intrathoracic pressure, it can decrease preload to the right atrium and decrease cardiac output.
EQUATIONS
Law of Laplace: P = 2T/r, where P = pressure, T = surface tension, and r = radius
REFERENCES
1. Daniels CB, Orgeig S. Pulmonary surfactant: The key to the evolution of air breathing.
News Physiol Sci. 2003;18:151–157.
2. Smetana GW. Preoperative pulmonary evaluation. N Engl J Med. 1999;340:937–944.
3. Staton GW, Ingram RH. Pulmonary edema. Sci Am Med. 1997:1–10.
4. Tobin MJ. Culmination of an era in research on the acute respiratory distress syndrome. N Engl J Med. 2000;342:1360–1361.
See Also (Topic, Algorithm, Electronic Media Element)
• Atelectasis
• Surfactant
• Pulmonary ventilation and perfusion matching
• Acute respiratory distress syndrome
• Cardiogenic pulmonary edema
• Noncardiogenic pulmonary edema
CLINICAL PEARLS
• During normal spontaneous ventilation, the alveolar-to-dead space ventilation ratio is 1:1.
During mechanical ventilation under anesthesia, dependent lung regions will have alveolar collapse, and ventilation is preferably distributed to the nondependent areas (ratio changes to 1:2). These alveoli may become over-aerated if high levels of PEEP are used.