Respiratory function is fundamental in the practice of anesthesia. Knowledge of basic physiologic principles of respiration assists in the proper implementation of daily actions of induction and maintenance of general anesthesia, delivery of mechanical ventilation, discontinuation of mechanical and pharmacologic support, and return to the preoperative state. The current work provides a review of classic physiology and emphasizes features important to the anesthesiologist. The material is divided in two main sections, gas exchange and respiratory mechanics; each section presents the physiology as the basis of abnormal states. We review the path of oxygen from air to the artery and of carbon dioxide the opposite way, and we have the causes of hypoxemia and of hypercarbia based on these very footpaths. We present the actions of pressure, flow, and volume as the normal determinants of ventilation, and we review the resulting abnormalities in terms of changes of resistance and compliance.
Anesthesiologists take control of the respiratory function of millions of patients throughout the world each day. We learn to maintain gas exchange and use respiration to administer anesthetic gases through the completion of surgery, when we return this vital function to its legitimate owners, ideally with a seamless transition to a healthy postoperative course. With this being the nature of our trade, it is no surprise that a number of anesthesiologists have provided major contributions to the advancement of respiratory physiology, from early pioneers of the measurement of respiratory mechanics and gas exchange during anesthesia, to investigators of acute respiratory failure and extracorporeal gas exchange. Yet this article is for the clinical anesthesiologist: residents, educators, and those who fly solo, assisting them in perfecting their practice so that they can rouse every day healthy and happy individuals improved by their surgery. Aware that we cannot review every facet of this physiology, we focused our work on gas exchange and respiratory mechanics, developing four main themes (fig. 1): hypoxemia, hypercarbia, respiratory mechanics, and the mechanics of the lung and chest wall. To start, we recommend reading from classic textbooks of physiology.1–3
Hypoxemia deprives cells of their main source of energy—oxygen. When the Pao2 decreases below normal levels, the gradient that drives oxygen from the blood into the interstitium and finally to the cell narrows, and may eventually compromise oxygen uptake. It is important in this context to differentiate the unique danger of a low Pao2versus a decreased oxygen content; increasing oxygen content through, e.g., additional transfusions of red cells, will provide little help to the crucial lack of sufficient partial pressure. In situations of acute severe hypoxemia, swift treatment is often simple: administer oxygen! In less immediate but often complex situations such severe acute respiratory failure or intraoperative one-lung ventilation, understanding the physiology leading to hypoxemia is essential for choosing effective therapy.
What Determines Pao2: How Oxygen Gets from Air to Arteries (fig. 2).
Oxygen constitutes 21% of the air that we breathe and exerts 21% of the atmospheric pressure. At sea level (atmospheric pressure, 760 mmHg) once fully saturated by water vapor (47 mmHg), Po2 in the inspired air (Pio2) can then be calculated:
In the alveoli, oxygen is exchanged for carbon dioxide at a ratio of approximately 1.25:1, because a little more oxygen is used than carbon dioxide is produced. This phenomenon reflects the physiologic respiratory quotient (RQ), the ratio between carbon dioxide production (co2) and oxygen consumption (o2), normally approximately 0.8 when using a balanced diet. With a normal Paco2 of 40 mmHg, Pao2 at steady state will be
This is a simplified version of the alveolar air equation suitable for clinical use. Further development includes o2 and co2:
where co2 is alveolar ventilation (A) × its carbon dioxide concentration, with K = 1/760 mmHg; hence:
Under normal conditions, past the pulmonary capillaries, arterialized blood receives a small fraction of venous blood from minimal alveolar shunt (2 to 3%, increasing with age) and anatomic sources like bronchial, Thebesian, and some diaphragmatic veins, so that Pao2 decreases just under 100 mmHg. Equation 2 also explains how hyperventilation may increase Pao2 above 100 mmHg. The following paragraphs differentiate the main causes of hypoxemia based on the above schematic.
The most common cause of low Pio2 is breathing at high altitude4 ; in La Paz, Bolivia, and in Lhasa, Tibet (both approximately 12,000 feet/3,600 meters), Pio2 ≈ 100 mmHg, versus 150 mmHg at sea level (fig. 2). At high altitudes, the main concern for the anesthesiologist who treats native populations or transient workforces is hypoxemia; supplemental oxygen will be necessary for most patients and may be beneficial for the medical staff to maintain full physical and mental performance. Hypoxemia stimulates VA mainly through carotid chemoreceptors4 ; hyperventilation may be profound, and the consequent decrease in Paco2 will limit the reduction of Pao2 according to equation 2. Near the summit of Mount Everest, at approximately 27,000 feet/8,200 meters and a barometric pressure of 284 mmHg, Pao2 and Paco2 measured in climbers breathing air were 25 and 13 mmHg, respectively.5,6
A low Pio2 at sea level may be related to the accidental administration of a hypoxic mixture. The remarkable level of safety of anesthesia machines and portable field devices makes accidental delivery of a hypoxic mixture an exceptional event.
In addition to causes of low Po2 upstream from the alveoli (low Pio2), Pao2 decreases mainly in relation to an increase in Paco2. As per equation 2, Pao2 falls when VA decreases, at any given o2 and any starting Paco2. Table 1 applies the alveolar air equation to representative physiologic situations. Also, from equation 2, we appreciate the effect of fraction of inspired oxygen (Fio2): a simple increase from 21 to 30% Fio2 raises Pio2 by 64 mmHg, which may restore Pao2 to a value around 100 mmHg even in the presence of extreme hypoventilation.
In modern intensive care, we learn to take into account the possible contribution of extracorporeal carbon dioxide removal and carbon dioxide dialysis.7,8 The lung of a patient undergoing low-flow, high-efficiency carbon dioxide removal for severe acute respiratory failure will maintain a comparatively high natural lung o2 while achieving a very low VA (low natural lung co2) thanks to the high rate of carbon dioxide removal by the artificial lung. Very low respiratory quotient values, well below 0.5, are thus possible, requiring increased Fio2 to maintain a constant Pao2 despite an artificially normal or low Paco2.
Oxygen transfer from the alveolus to the circulating hemoglobin is very rapid and seldom the cause of hypoxemia.9 The high partial pressure gradient and the thinness of the alveolo-capillary membrane allow ample time for oxygen transfer to reach steady state within the normal capillary blood transit time. Hence, transfer of oxygen is limited by pulmonary blood flow rather than diffusing capacity. However, regional capillary blood flow can vary substantially due to factors such as posture, alveolar pressure, and disease. Lung regions with short capillary transit time will then yield desaturated blood, which will not be compensated by areas with prolonged transit time, because hemoglobin will not saturate above 100%. Hence, any measurement of diffusion capacity, such as carbon monoxide diffusion, will be affected primarily by regional flow abnormalities rather than diffusion. Just like for oxygen, abnormal transfer of carbon monoxide is mostly due to ventilation/perfusion ratio (/) inequality, and carbon monoxide diffusion may be used as a generic index of abnormal pulmonary function, typically in the preoperative evaluation of patients scheduled to undergo pulmonary resections.10
Shunt (or Venous Admixture) and V̇/Q̇ Inequality.
The basic principle for alveoli to work as gas exchangers is to match ventilation (provides inflow and outflow for gases from and to the air) with perfusion (provides inflow and outflow of gases to and from the tissues). The two systems cross paths in the alveoli, where blood enters with different Po2 and Pco2 from the alveolar gas and exits with near equal concentrations. Normal VA is approximately 4 l/min, and normal pulmonary blood flow (cardiac output) approximately 5 l/min, giving a / of 0.8. In reality, each individual alveolus’s / may differ substantially, from 0, that is shunt, to ∞, that is dead space and infinite combinations in between.
The most practical approach to / distribution is still the three compartments model proposed by Riley and Cournand11,12 more than half a century ago: an ideal compartment, a nonventilated compartment, and a nonperfused compartment. In the nonventilated compartment, capillary blood reaches the pulmonary venous side (oxygenated blood) without participating at all in gas exchange. The proportion of nonoxygenated blood mixing into the arterialized side is defined as shunt or venous admixture and represents the amount of blood that would justify the deficit in arterial oxygenation if it were to cross the lung without participating to gas exchange. The degree of shunt is computed when mixed venous blood gases are available:
where VA is the fraction of pulmonary blood flow exposed to ventilation, TOT is the total pulmonary blood flow, Cco2 is the oxygen content of ideal capillary blood computed from Pao2 of the ideal compartment (equation 2), Cao2 is the oxygen content of arterial blood, and Cvo2 is the oxygen content of venous blood.
In reality, hypoxemia and hypercarbia in lung disease result from infinite combinations of / relationships that lie somewhere between shunt and dead space. The structure of the lung tends to predispose to / inequality, with both perfusion and ventilation being more efficient at the bases of the lungs, but the gradient of perfusion being steeper than ventilation, creating a situation prone to mismatch.13,14 It is important to appreciate that although / inequality affects both oxygen and carbon dioxide exchange, the end result of is primarily hypoxemia, for two main reasons:
Increased Paco2 Stimulates Ventilation.
When low / develops in a portion of the lung, it decreases Po2 and increases Pco2 of arterialized blood. In spontaneously breathing patients, the higher Paco2 stimulates ventilation, and Paco2—but not Pao2—will return toward baseline. If hypoxemia is severe, as at high altitudes, an additional stimulus to hyperventilation will further decrease Paco2. In fully ventilated patients, who cannot increase their minute ventilation, Paco2 will indeed increase, but the gradient between venous and arterial Pco2 (46 to 40 = 6 mmHg) is very small, and the change is difficult to detect.
Opposite Changes in V̇/Q̇ Do Not Cancel Each Other Out.
At first glance, it would seem that comparable but opposite changes of / would cancel each other out and yield normal gas exchange. This does not occur, and hypoxemia is the main result; this phenomenon is explained in terms of blood oxygen content and the hemoglobin–oxygen dissociation curve:
In an alveolo-capillary unit with normal /, Cao2 is = 14 g/dl × 1.34 × 1 + 0.3 ≈ 19 ml of oxygen per dl, also expressed as 19 ml %. In a unit with low / and, e.g., arterial oxygen saturation (Sao2) of 0.85, Cao2 will be 16 ml %, close to a normal venous oxygen content (Cvo2) of 14 ml %. In a unit with high / and a Pao2 of, e.g., 400 mmHg, Cao2 is almost 20 ml %, only slightly above normal. The high / unit cannot carry much more than 19 ml % of oxygen because once full saturation of hemoglobin is reached, a higher Pao2 only increases dissolved oxygen, which contributes minimally to Cao2.
Clinical Evaluation of V̇/Q̇ Distribution.
Measuring regional / distribution is a complex task. The accepted standard has been the Multiple Inert Gas Elimination Technique, based on the infusion of a mixture of six dissolved inert gases with a known range of solubility, then measuring their concentrations in arterial blood and expired gas.15,16 This technique has never been simplified enough for clinical use, nor does it provide spatial information of the areas of / inequality. Recently, the evolution of lung imaging with high-definition computerized tomography scan, positron emission tomography, and electrical impedance tomography17 is taking the visualization of / distribution closer to the clinical arena, although not yet to a quantitative evaluation of the precision provided by the Multiple Inert Gas Elimination Technique.
Clinical Indices of Oxygenation and the Effect of Fio2.
Pao2 and Sao2 are precise measurements of their respective physiologic entity, but alone do not provide adequate description of an ongoing respiratory impairment, nor allow accurate comparison among patients. It is important to know partial pressure (mmHg) or fraction (%) of oxygen upstream from the artery at which a certain Pao2 is obtained18 : a Pao2 of 100 mmHg has different physiologic implications whether obtained at a Pio2 of 600 mmHg (Fio2 100%) versus a Pio2 of 150 mmHg (Fio2 21%). The alveolo-arterial oxygen gradient is the most time-honored index of oxygenation, where Pao2 is estimated from equation 2; the wider the alveolo-arterial oxygen gradient, the worse the performance of the lung as an exchanger. The most accurate application for this index is in patients intubated and breathing high Fio2, where the linearity between this index and the level of venous admixture is best.18 More recently, the ratio between Pao2and Fio2 (Pao2/Fio2 or “P/F”) has largely substituted alveolo-arterial oxygen gradient because it does not require equation 2 and its relationship with venous admixture is less affected by Fio2.19,20
Low Mixed Venous Oxygen Tension (Pvo2).
Normally, transfer of oxygen from air to blood reaches full equilibrium within the alveolo-capillary unit, and Pao2 ≈ Pao2. Such degree of efficiency allows for even a low Pvo2 to yield a normal Pao2. However, in patients with intrapulmonary shunt, blood with low Pvo2 enters the arterial stream without being saturated by alveolar oxygen and will decrease Pao2 to a degree depending on the magnitude of the shunt fraction: the higher the shunt, the more the Pao2 becomes dependent on the Pvo2.
The Physiology of Mixed Venous Po2.
The next logical question is what causes a low Pvo2. The following equation (Fick’s equation) illustrates the relationship between oxygen delivery to the tissues (Cao2 × cardiac output) and oxygen utilization, oro2:
Pvo2 and mixed venous oxygen saturation (Svo2) contribute to Cvo2 (equation 4) and are used interchangeably as indices of tissue oxygen utilization.21 Unless indicated otherwise, Pvo2 and Svo2 refer to mixed venous blood, which is blood distal to the right atrium, where full mixing has occurred. Mixed venous blood can be sampled only via a pulmonary artery catheter. Central venous blood Po2 obtained via a standard central venous catheter has been used as a surrogate, but it is not consistently accurate because is affected by separate currents of blood coming from venous districts with different Po2.22
Pvo2 may decrease for a defined number of factors: a low Pao2, low hemoglobin concentration, low cardiac output, or a high o2. With a low Pao2, the lower Pvo2 will further decrease Pao2 until a new equilibrium of lower Pvo2 and Pao2 is reached. Normally, a Cao2 of ~ 19 ml/100 ml of blood × cardiac output of 5 l/min yields a delivery of oxygen of ~ 1,000 ml/min; with a resting o2 of ~ 250 ml/min, the (Cao2 – Cvo2) × cardiac output term is 750 ml/min, meaning that under normal circumstances, approximately 25% of the available oxygen is taken up by tissues. With a lower cardiac output or hemoglobin concentration and constant o2, the term Cao2 – Cvo2 widens and Pvo2 decreases, indicating an increased extraction of oxygen by the tissues. Note that increased extraction does not automatically indicate insufficient perfusion; hence, monitoring Pvo2 or Svo222 provides information on the status of oxygen tissue delivery but does not necessarily indicate a need to normalize oxygen delivery. It is important to note that the mathematical effect of the same change of each component of oxygen delivery on Pvo2 may differ greatly from the clinical effect. This is shown in table 2, where halving any of the terms of the equation will equally half oxygen delivery and decrease Pvo2. However, while halving hemoglobin concentration may be a relatively minor event in many critically ill patients, halving Sao2 may be deadly. Furthermore, the physiologic relationship among the variables in discussion is complex and cannot be evaluated simply by the Fick’s equation. For example, accurate measurement of o2 is elusive in the clinical setting,23 and it is often referred to from tables; also, an increase in cardiac output in the presence of moderate shunt will generally increase shunt itself, negating the assumption that the other variables are constant.24,25
General Anesthesia and Hypoxemia.
A succession of physiologic events decreases Pao2 during general anesthesia.26 Shortly after induction of anesthesia, the resting volume of the lung (functional residual capacity [FRC]), which is a reserve of oxygen, decreases by an average of 500 ml in adults; added to the volume lost by going from the erect to the supine position,27 FRC is reduced from approximately of 3,000 ml to just more than 2,000, i.e., close to residual volume. The main cause is a loss of muscle tone with consequent cephalad displacement of the diaphragm; it is largely independent of the type of anesthesia and unrelated to neuromuscular blockade,28 and is aggravated by pregnancy, obesity, and abdominal distention.29 The decrease in resting lung volume causes a decrease in lung compliance, promotes cyclic airway closure at end-expiration and gas reabsorption, rapidly leading to atelectasis. Persistent blood flow during cyclic airway closure and through atelectasis causes areas of low / and shunt, contributing to hypoxemia. In the supine position, atelectases are prevalently located in the dorsal areas of the lung; normally limited to less than 10% of the lung volume, they may extend to 15 to 30% of it and be associated with persistent hypoxemia and respiratory complications.30 Almost paradoxically, a high Fio2 may add to lung collapse (absorption atelectasis) by substituting alveolar nitrogen with oxygen, the former not taking part in gas exchange. An Fio2 of 80% may limit the degree of absorption atelectasis compared to100%. The combination of an Fio2 not higher than 60%, and positive end-expiratory pressure (PEEP) during awakening from general anesthesia, may limit the degree of atelectasis and the incidence and duration of hypoxemia in the postoperative period.31,32
Different from hypoxemia, hypercarbia is generally well tolerated unless severe enough (above 80 to 100 mmHg) to cause obtundation and respiratory arrest. In susceptible patients, hypercarbia may be perilous through various mechanisms, by increasing intracranial pressure in patients with cerebral edema or exacerbating pulmonary hypertension in adults with right ventricular dysfunction and in children with congenital heart disease. On the other hand, moderate hypercarbia may be a favorable condition in a number of pathologic situations, such as in circulatory shock by improving local blood flow, and in acute respiratory distress syndrome (ARDS) as an accepted consequence of a ventilatory strategy of limited tidal volume.33
What Determines Hypercarbia: How Carbon Dioxide Gets from Cells to Air.
Carbon dioxide and water are the end-products of aerobic metabolism; carbon dioxide is the main source of acid in the body and requires a highly efficient system for removal. In plasma, dissolved carbon dioxide (Paco2 × 0.03) is in equilibrium with carbonic acid, hydrogen ions (buffered by hemoglobin), and bicarbonate ions, and is measured in mEq/l as “total CO2” in a standard metabolic profile.34 From the pulmonary capillary, carbon dioxide transfers to the alveolus by the same physical forces that transfer oxygen the other way. By the end of the capillary, carbon dioxide is in equilibrium in the two phases, and normally Paco2 ≈ Paco2. At steady state, Paco2 results from the equilibrium of production by cellular metabolism (co2) and elimination by VA,
where K = 1/760 as in equation 2.
Elimination of carbon dioxide is the essential target of breathing. Paco2 and VA are tightly bound, and small increases in Paco2 have immediate effect on the total minute ventilation: for each 1 mmHg Paco2, minute ventilation increases by 1 to 2 l/min, retuning Paco2 to its normal value (fig. 3). Based on the above schematic, we can differentiate the main causes of hypercarbia.
Increased aerobic metabolism occurs in hypermetabolic states such as exercise, fever, shivering, hyperthyroidism, excessive caloric/carbohydrate intake and, to its maximum extent, in neuroleptic malignant syndrome and malignant hyperthermia. Except for the latter two entities, increase of co2 is either mild, as in high carbohydrate intake, or transient, as in shivering, and most of the time offset by the increase of VA. When ventilation is limited by disease, sedation or residual anesthesia, an episode of high fever or shivering may overwhelm the capability of the respiratory system and result in levels of hypercarbia that require mechanical ventilatory support. co2 may also change abruptly under non–steady state condition by changes in body carbon dioxide stores (bicarbonate and carbonic acid) or by exogenous infusion. For example, the rapid administration of sodium bicarbonate with the aim of neutralizing a metabolic acidemia (i.e., converting bicarbonate to carbon dioxide and water) results in a stoichiometric increase in carbon dioxide production: 100 mEq of sodium bicarbonate more than 20 min may cause up to 50% increase in co2 of the same duration (5 mEq/min).
Hypoventilation causes hypercarbia and hypoxemia, particularly at low Fio2. Looking at equation 2, at constant o2, a decrease in VA implies a decreased delivery of oxygen to the alveolus, while Paco2 increases because a higher carbon dioxide concentration in the expired air is necessary to eliminate the same amount of carbon dioxide per unit time at constant co2. Common causes of hypoventilation include a decreased central drive to breathe, as it occurs with hypnotics, volatile anesthetics, and opiates (fig. 3); respiratory muscle weakness, as in Guillain-Barré syndrome, myasthenia, and polyneuropathy of critical illness; and high resistive (severe asthma) or elastic (abdominal distention) ventilatory loads.
Dead Space Ventilation and V̇/Q̇ Inequality.
Ventilation is a to and fro process that starts in the airways, which are one-way conduits not involved in gas exchange. This fraction of tidal ventilation (150 to 200 ml in adults) is thus “dead volume” or anatomic dead space of the airways (VD/VT AW). In mechanically ventilated patients, VD/VT AW also includes any additional respiratory equipment where flow of gas is bidirectional, such as masks and corrugated tubing added distally to the Y-piece. In addition to VD/VT AW, where no carbon dioxide is ever exchanged, dead volume may also occur at the alveolar level or alveolar dead space (VD/VT ALV), where normally all carbon dioxide is exchanged, and represents a wasted fraction of VA. In analogy with shunt in the three compartments model of Riley and Cournand,11,12 VD/VT ALV is the proportion of alveolar ventilation that could justify the observed decrease in mixed Paco2 if it were to be expired with a Pco2 equal to the one of the inspired air. VD/VT AW + VD/VT ALV is physiologic dead space (VD/VT PHYS).
Measurementof VD/VT PHYS is commonly obtained from a modification of the Bohr equation35 where Paco2 substitutes Paco2, the latter being difficult to measure:
Peco2 is the mixed exhaled Pco2, which includes both alveolar (≈ arterial) CO2 and airways (≈ 0) CO2, where a normal value of 30 mmHg gives a VD/VT PHYS = (40 to 30)/40 = 1/4 = 25%, i.e., 150 to 200 ml. The availability of continuous capnography allows estimation of Peco2 from the midpoint of the initial rise of exhaled trace, or Phase I, and alveolar Pco2 from the highest point (also end-tidal Pco2, Petco2); substituting Peco2 with Petco2 in equation 7, we measure VD/VT ALV continuously and noninvasively.36 However, using Paco2 as a surrogate of Paco2 adds to VD/VT PHYS a source of carbon dioxide that does not contribute to Paco2 because it is not dead space but shunt and / inequality.35,37 Shunt widens the A - a gradient for carbon dioxide just like the A - a gradient for oxygen, but the effect of shunt on Paco2 will be less visible than on Pao2 because the difference in Pco2 between venous and arterial blood is much smaller than the difference in Po2. For example, a 30% shunt would increase Paco2 by only 2 mmHg, a barely noticeable change; however, that would correspond to an increase in calculated VD/VT PHYS larger than 30% because of the increase in gradient, not in absolute Paco2 value. Differentiating the mechanism leading to hypercarbia may be important; for example, the magnitude of VD/VT PHYS has been correlated with the rate of mortality in ARDS;38 given the high shunt fraction present in severe ARDS, part of the increase in Paco2 that contributes to the high calculated VD/VT PHYS may be due to decreased ventilation and not decreased blood flow. Similarly, in lung disease characterized by major alterations in / relationship, such as severe chronic obstructive pulmonary disease (COPD), a low Petco2 may reflect the overall / inequality in addition to dead space.
Occasionally, alveolar units with altered mechanics may empty throughout expiration and add carbon dioxide, increasing Paco2, and Petco2 may exceed Paco2, the limit being mixed venous carbon dioxide tension (Pvco2). This is rare, and Petco2 is normally equal to or lower than Paco2; as long as the exhaled carbon dioxide trace on the capnogram shows a stable plateau, the Petco2 can be accepted as representative of alveolar carbon dioxide.
Dynamic Changes of Carbon Dioxide.
The above discussion refers to steady state conditions, but we should also take into account the peculiarities of dynamic or transient carbon dioxide changes.39 When ventilation increases, Pco2 decreases rapidly, the rate of decrease being governed primarily by VA. When ventilation decreases, the process is overall different, because the rate of increase of Pco2 is governed only by co2. When an individual holds breath for several seconds (apnea), an initial increase of Paco2 toward the Pvco2 value (an additional 6 mmHg or 21 ml of carbon dioxide with an FRC is 2.5 l) will take place rapidly—less than 6 s at constant cardiac output. However, past this equilibration time, any further increase of Pco2 takes place at a much slower speed (3 to 6 mmHg/min) due to the high capacity of the body stores for carbon dioxide. Important dynamic changes in carbon dioxide occur also with changes in pulmonary blood flow. A fall in cardiac output at constant VE causes a decrease in carbon dioxide transferred to the alveoli, reflected by lower Petco2 and increased VD/VT ALV.
Air moves in and out of the lungs by the cyclic action of the respiratory muscles. Each breath starts with pressure applied by the respiratory muscles (negative pressure) or by a ventilator (positive pressure), generating a flow of gas through the airways that expands the volume of the lung and surrounding structures. This process is opposed each time by resistance to gas flow in the airways and elastance (stiffness) of the lung and surrounding structures. Note that the term elastance is seldom used in clinical lingo, in favor of its reciprocal, compliance; thus, an increased stiffness of the lung is a low compliance. These five variables—pressure, flow, volume, resistance, and compliance—are intimately intertwined in determining the mechanical process of breathing, whether it is during relaxed breathing, during arduous exercise, or supplied by a ventilator.40
Bedside Measurement of Respiratory Mechanics Can Be Carried Out with Nearly Any Modern Ventilator
Mechanics of Inspiration.
Normal airway resistance (Raw) is 1 to 3 cm H2O/l/s; normal compliance of the respiratory system (CRS), i.e., lung plus chest wall, is 80 to 100 ml/cm H2O.41 Separating PIP and PPLAT is key for the correct measurement of Raw and CRS.42 PIP is the highest pressure measured at the airway during a mechanical breath and is determined by size of the tidal volume (VT), inspiratory flow rate, Raw, and CRS. PPLAT is the pressure measured at the end of inspiration when flow is held, i.e., zero flow, and is determined solely by VT and CRS. Basic ventilatory settings do not separate PIP and PPLAT, but most ventilators provide ways to measure and visualize them. An end-inspiratory pause closes the inspiratory valve without opening the expiratory valve, pausing flow for an adjustable period of 0.5 to 2 s, and displays the values of Raw and CRS. A typical inspiratory pause is executed with the ventilator on volume control, constant flow rate (“square flow waveform”); if possible, setting the flow rate at 60 l/min (1 l/s) simplifies Raw calculation. We caution the practitioner to examine the actual traces on the ventilator screen, because inaccuracies do occur from unplanned changes in settings or artifacts due to spontaneous respiration, coughing, or leaks. Most critical care ventilators add the pause to a single breath without altering other parameters, thus allowing measurement on the ongoing ventilatory settings. Most anesthesia ventilators incorporate an end-inspiratory pause as a percentage of the set inspiratory time to all subsequent breaths; by doing so, the delivery of the breath changes, and with that the mechanics of the breath. Figure 4 shows such occurrence: by including the zero-flow pause in the set inspiratory time, the ventilator must deliver the set volume in a shorter time, which can only be done by increasing inspiratory flow, which in turn will result in higher PIP and sometimes in changes of PPLAT and VT, altering the measurement of Raw and CRS. Most anesthesia ventilators do not display the actual value of Raw, but one can still get an approximate idea by assessing the difference between PIP and PPLAT: when Raw is increased by, e.g., bronchospasm, separation of PIP and PPLAT is clearly noticeable, and may subsequently change with an intervention such as administering a bronchodilator. Under the appropriate circumstances, CRS (but not Raw) can be estimated without performing an inspiratory pause, provided that the pressure trace shows an identifiable plateau, as in figure 4C. This happens when flow is delivered with an initial peak followed by progressive decay throughout inspiration (“descending ramp” pattern), ideally reaching zero flow. This is the rule in pressure control ventilation and may be obtained also in volume control under appropriate settings.
As the mechanics of alveolar units vary, the time required to move air in and out may also vary both within and among areas of the lung. The time required by the respiratory system to change volume is described by the concept of time constant (τ):43
Time constants are used to describe the exponential time change of a dynamic system to reach a new steady state, in our case filling or emptying of the lung or a lung unit. One τ is the time in seconds taken to achieve 63% of maximal volume change of the lung unit; every successive τ will change 63% of the previous volume; hence it takes 4 τ’s to reach about 95% of the new steady state. The clinical relevance of this concept is that it allows to distinguish different forms of respiratory failure from a mechanical standpoint. For example, asthma and COPD have slow τ because they have high Raw and normal or high CL; conversely, ARDS has fast τ because CL is low and Raw only moderately increased. The slow τ of asthma and COPD is responsible for lung hyperinflation and expiratory flow limitation. The fast τ of ARDS is responsible for the short inspiratory time (when not assisted by the ventilator) and tendency to de-recruit.
Mechanics of Expiration.
During expiration, the most relevant measurement is auto-PEEP—also “intrinsic PEEP” or “occult PEEP.”44 Auto-PEEP is positive alveolar pressure (PALV) at end expiration, where normally we expect it to be equal to the pressure measured at the airway opening (PPLAT), i.e., 0 cm H2O (atmospheric pressure) or PEEP. Auto-PEEP occurs by two main mechanisms, shown in figure 5. First, there is insufficient time to exhale the full VT because the relaxation time of the respiratory system is longer than the allocated expiratory time, be it spontaneous or set on the ventilator. Such is the situation of long τ in pure bronchospasm. Second is by the presence of expiratory flow limitation, characteristic of COPD due to loss of elastic recoil of the lung and supporting structure of the airways. As the volume of the lung decreases during exhalation, so does the diameter of the airways, possibly down to full collapse; this is often further amplified when the expiratory muscles are activated and generate a positive pressure around the airways.
Auto-PEEP has some of the effects of set PEEP: it may recruit the lung and may damage the lung. When generated during mechanical ventilation by prolonging inspiratory time, auto-PEEP may improve Pao2 through alveolar recruitment45 ; when generated by trapped gas in status asthmaticus, auto-PEEP may overstretch and damage the lung.46 Just like set PEEP, auto-PEEP may decrease cardiac output and arterial blood pressure.41 Differently from set PEEP, auto-PEEP increases work of breathing: when breathing normally from FRC or from a set PEEP, a minimal negative pressure starts inspiratory flow and initiates a breath; with auto-PEEP, this negative pressure has to overcome the positive PALV before decreasing to less than 0 and starting inspiratory flow. This added pressure constitutes wasted effort because it does not generate any volume, and may ultimately cause fatigue in susceptible patients.47
Measurement of auto-PEEP is carried out on a ventilator through an expiratory pause,42 which closes the expiratory valve without opening the inspiratory valve, and equilibrates PALV across different lung units; the positive airway pressure trace will rise to a plateau above 0 or PEEP, the difference being auto-PEEP. Just like an inspiratory pause, this maneuver is optimal in the absence of spontaneous efforts and with a low respiratory frequency. Of note, even during a pause, the value of positive airway pressure will still be the lowest measured, and if the pause is not sufficiently long, there may be areas of the lung where PALV is still higher than the measured auto-PEEP.48 When this maneuver is not available, as in most anesthesia ventilators, the presence of auto-PEEP can be inferred, but not quantified, by examining the expiratory flow trace, which will be truncated before reaching zero flow at end expiration, as shown in both panels of figure 5.
Regional Lung Mechanics: The Inhomogeneous Lung.
Bedside measurements of respiratory mechanics provide values that pertain to the respiratory system as a whole. Similar to /, minor mechanical inequalities develop during normal respiration, and their impact is trivial; however, regional changes in mechanics develop with the onset progression of respiratory disease, affect respiratory function, and may invalidate standard measurements.
Regional inhomogeneity in Raw develops in asthma and COPD due to weakened elastic recoil, active bronchospasm, inflammatory changes, and trapping of gas. A common result is regional lung hyperinflation, described during spontaneous as well as general mechanical breathing,48,49 and visually confirmed by advanced imaging techniques.50 Dynamic reduction in airway caliber may progress to complete obstruction and exclude hyperinflated areas of the lung from standard measurements, underestimating the potential for lung damage, hypoventilation, and hemodynamic compromise.
Regional inhomogeneity of CRS during general anesthesia and respiratory failure was demonstrated with the introduction of lung computerized tomography in the 1980s,51,52 opening the way to the understanding of alveolar recruitment and damage during mechanical ventilation, and to the development of innovative strategies of lung protective ventilation.53 Figure 6 shows computerized tomography scans of patients with acute respiratory failure and severe hypoxemia with similarly diminished CRS by bedside measurement, whose regional mechanical characteristics are manifestly different. The “stiff” lungs will require high ventilating pressures that will distribute throughout severely diseased lung tissue, possibly causing diffuse damage. The “small” lungs will receive ventilating pressures intended to the entire lung but delivered mainly to a small portion of it, possibly causing damage to the small lung and doing very little to the consolidated lung. The last set of lungs seems impossible to ventilate, which was indeed the case: this patient was treated by extracorporeal membrane oxygenation for three weeks.
Further attention to ventilatory mechanics during anesthesia and intensive care requires understanding the interaction between lung and chest wall.54 CRS measured ordinarily at the bedside comprises the compliances in series of lung (CL) and chest wall (CCW). Like electrical capacitances in series, the reciprocal of each compliance adds up to the reciprocal of the total:
Normal values in ml/cm H2O are: CRS = 100, CL = 200, and CCW = 200. During mechanical ventilation, we are interested in the lung: it is the lung that we want to expand and we do not want to damage. By measuring CRS, we extrapolate to the lung what we are actually measuring on the lung and chest wall, and for the most part, the information is valuable.
Under certain circumstances, understanding the mechanics of ventilation may require knowledge of the separate contributions of lung and chest wall. During normal respiration, at FRC the inward elastic force of the lung is equally balanced by the outward elastic force of the chest wall, resulting in a PALV equal to atmospheric (0) pressure, and a pressure in the pleural cavity (PPL) slightly less than atmospheric pressure. Due in part to gravity, PPL is more negative in ventral than dorsal areas of the lung in the supine position, reversed in the prone position,55 and again more negative in the nondependent lung than in the dependent lung in the lateral position.47 As FRC decreases after induction of general anesthesia, PPL increases toward and above 0, promoting airway closure and atelectasis.26 The key physiologic parameter here is the pressure generated across the lung, or transpulmonary pressure (PTP):
A positive PTP keeps the alveoli open: under normal circumstances at FRC, PALV is 0 and PPL slightly negative, hence PTP is positive; with PEEP, PALV is positive and PPL less positive than PALV; with anesthesia, pulmonary edema, and abdominal distention, PPL increases above PALV and PTP turns negative, causing alveolar collapse and atelectasis.56 Clinically, PALV is reliably estimated by PPLAT, but PPL requires indirect measurement by means of special thin-walled balloons positioned via the nares into the esophagus (esophageal pressure).57 The value of esophageal pressure as a measurement of PPL has been somewhat controversial, but recent studies have confirmed its reliability in selected situations with close attention to proper positioning and calibration.58,59 Measuring PTP as the target to PEEP titration in patients with ARDS has revealed the need for higher PEEP to provide effective recruitment of regional lung collapse and allow protective ventilation.60,61 Under general anesthesia, the use of a lung protective strategy of higher PEEP with or without direct measurement of PTP seems to ideally suit morbidly obese patients62,63 and patients undergoing laparoscopic surgery, particularly in the steep Trendelenburg position, where PPL increases further.
Contrasting Spontaneous Breathing and Controlled Mechanical Ventilation.
During a spontaneous inspiration, the chest wall expands by its elastic recoil and by the action of the inspiratory muscles, making PPL, the pressure surrounding the lung, more negative than at end expiration. Since at the airway opening the pressure remains atmospheric, PTP is positive and lung volume increases. During controlled mechanical ventilation, pressure is positive, PALV increases, PPL increases a fraction of PALV, and PTP is again positive. For the same pressure applied and constant respiratory mechanics, changes in PTP will be the same, and VT will be the same in spontaneous and mechanical breathing. During assisted breathing, where tidal ventilation is the result of a cooperative effort of patient and ventilator, the mechanical situation is more complex, with a few points worth noting. First, for the same VT, the change in PTP will be the same, independent of the mode of ventilation (fig. 4), and so will be the potential degree of lung damage. Second, when the lung volume increases during spontaneous ventilation, PPL becomes more negative; when the lung volume increases during controlled tidal ventilation, PPL becomes more positive; in both cases, PALV must be lower than the pressure in the airways for inspiratory flow to occur. Therefore, while during controlled mechanical ventilation PALV is higher than the set end expiratory pressure throughout the respiratory cycle, during spontaneous inspiration, PALV must become lower than the end expiratory pressure.
These differences have profound influences on the interaction between heart and lung function, and ultimately on hemodynamics and on the fluid balance of the lung interstitium. In particular, when spontaneous breathing generates significant decreases in intrathoracic and/or alveolar pressures, these may contribute to the generation of pulmonary edema, cardiogenic and not,64,65 and may worsen lung injury.66
Support for the preparation of this manuscript was provided solely from institutional and/or departmental sources.
The authors declare no competing interests.