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Review Article Deborah J. Culley, M.D., Editor

ABSTRACT

Respiratory function is fundamental in the practice of anesthesia. Knowledge of basic physiologic principles of assists in the proper implemen- tation of daily actions of induction and maintenance of general anesthesia, Respiratory Physiology delivery of , discontinuation of mechanical and pharma- cologic support, and return to the preoperative state. The work pro- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/130/6/1064/455191/20190600_0-00035.pdf by guest on 24 September 2021 for the Anesthesiologist vides a review of classic physiology and emphasizes features important to the anesthesiologist. The material is divided in two main sections, Luca Bigatello, M.D., Antonio Pesenti, M.D. and respiratory mechanics; each section presents the physiology as the basis Anesthesiology 2019; 130:1064–77 of abnormal states. We review the path of from air to the artery and of dioxide the opposite way, and we have the causes of and of hypercarbia based on these very footpaths. We present the actions nesthesiologists take control of the respiratory func- of , flow, and volume as the normal determinants of ventilation, and Ation of millions of patients throughout the world each we review the resulting abnormalities in terms of changes of resistance and day. We learn to maintain gas exchange and use respiration compliance. to administer anesthetic gases through the completion of (ANESTHESIOLOGY 2019; 130:1064–77) surgery, when we return this vital function to its legitimate owners, ideally with a seamless transition to a healthy post- operative course. With this being the nature of our trade, it swift treatment is often simple: administer oxygen! In less is no surprise that a number of anesthesiologists have pro- immediate but often complex situations such severe acute vided major contributions to the advancement of respira- respiratory failure or intraoperative one- ventilation, tory physiology, from early pioneers of the measurement of understanding the physiology leading to hypoxemia is respiratory mechanics and gas exchange during anesthesia, essential for choosing effective therapy. to investigators of acute respiratory failure and extracor- poreal gas exchange. Yet this article is for the clinical anes- What Determines Pao2: How Oxygen Gets from Air to Arteries thesiologist: residents, educators, and those who fly solo, (fig. 2). Oxygen constitutes 21% of the air that we breathe assisting them in perfecting their practice so that they can and exerts 21% of the . At sea level rouse every day healthy and happy individuals improved (atmospheric pressure, 760 mmHg) once fully saturated by by their surgery. Aware that we cannot review every facet water vapor (47 mmHg), Po in the inspired air (Pio ) can of this physiology, we focused our work on gas exchange 2 2 then be calculated: 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 rec- PIO2 =−()760 47 mmHg × 0.21 ≈ 150 mmHg (1) ommend reading from classic textbooks of physiology.1–3 In the alveoli, oxygen is exchanged for at a Gas Exchange ratio of approximately 1.25:1, because a little more oxygen is used than carbon dioxide is produced. This phenome- Hypoxemia non reflects the physiologic (RQ), the ratio between carbon dioxide production ( V co ) and oxy- Hypoxemia deprives cells of their main source of 2 gen consumption ( V o ), normally approximately 0.8 when energy—oxygen. When the Pao decreases below normal 2 2 using a balanced diet. With a normal Paco of 40 mmHg, levels, the gradient that drives oxygen from the into 2 Pao at steady state will be the interstitium and finally to the narrows, and may 2 eventually compromise oxygen uptake. It is important in this context to differentiate the unique danger of a low PAO2 =−PPIO2 aRCO2 ×(/1 Q)≈102mmHg

Pao2 versus a decreased oxygen content; increasing oxygen content through, e.g., additional transfusions of red cells, This is a simplified version of the alveolar air equation suit- will provide little help to the crucial lack of sufficient able for clinical use. Further development includes Vo2 and . In situations of acute severe hypoxemia, Vco2:

This article is featured in “This Month in Anesthesiology,” page 1A. Submitted for publication March 12, 2018. Accepted for publication January 16, 2019. From the Department of Anesthesiology and Perioperative Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts (L.B.), and the Department of Emergency, Anesthesia and Critical Care, Foundation IRCCS Ospedale Maggiore Policlinico, and Department of Surgical Pathophysiology and Transplantation, University of Milan, Milan, Italy (A.P.). Copyright © 2019, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2019; 130:1064–77

1064 JUNE 2019 ANESTHESIOLOGY, V 130 • NO 6 Copyright © 2019, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Respiratory Physiology for Anesthesia

Mini-Summaries / Take Home Points

Hypoxemia.

• Hypoxemia is low arterial oxygen tension and harms by impeding oxygen transfer from blood to cells. Increasing oxygen content by, e.g., transfusion, does not cure hypoxemia. • Most common mechanism of hypoxemia is ventilation/ inequality, present in Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/130/6/1064/455191/20190600_0-00035.pdf by guest on 24 September 2021 acute respiratory failure, chronic lung , and during general anesthesia. • Induction of anesthesia reduces functional residual capacity predisposing to atelectasis. PEEP restores lung volume, prevents atelectasis, and avoids hypoxemia.

Hypercarbia.

• Hypercarbia per se threatens life only when severe enough to cause obtundation. With , even mild hypercarbia can precipitate herniation. • The danger of hypercarbia in hypoventilation is in the development of hypoxemia via decrease of alveolar PO2. • indicates lung ventilated but not perfused that causes hypercarbia. Standard computation of physiologic dead space includes PaCO2 from shunt and low ventilation.

Mechanics of Ventilation.

• Air moves in and out of the by changes of pressure, flow, and lung volume. Air movement is impeded by airways’ resistance and respiratory elastance (stiffness). • Respiratory mechanics can be measured during mechanical ventilation with an inspiratory pause (compliance and resistance) and an expiratory pause (auto-PEEP). • Auto-PEEP is positive pressure in the alveoli at end expiration, generally caused by high flow resistance. It may recruit or overstretch alveoli and increases work of .

Mechanics of Lung and Chest Wall.

• Lung and chest wall move in series during respiration. Inward recoil of the lung balances expanding of the chest wall at functional residual capacity, andalveolar pressure is 0. • Measuring pressure between lung and chest wall by an esophageal balloon allows to estimate transpulmonary pressure, which may vary in different regions of the lung. • Positive transpulmonary pressure keeps alveoli open; increasing it with PEEP during anesthesia opposes atelectasis in the dependent lung and prevents hypoxemia

Fig. 1. Mini summaries/take home points from the four main themes of the review. PEEP, positive end-expiratory pressure.

diaphragmatic veins, so that Pao decreases just under 100 PAO =−()760 47 ××FPIO − a/CO ()VV O CO 2 2 2 2 2 2 mmHg. Equation 2 also explains how may =−713 ××FPIO2 aCO2 (V/O2 /PVA ××aKCO2 ) increase Pao2 above 100 mmHg. The following paragraphs differentiate the main causes of hypoxemia based on the above schematic. where Vco2 is alveolar ventilation ( VA) × its carbon diox-

ide , with K = 1/760 mmHg; hence: Low Pio2. The most common cause of low Pio2 is breath- ing at high altitude4; in La Paz, Bolivia, and in Lhasa, Tibet (both approximately 12,000 feet/3,600 meters), Pio ≈ 100 PAO2 = 713 ××F-IO2 VVO2A/ K (2) 2 mmHg, versus 150 mmHg at sea level (fig. 2). At high alti- Under normal conditions, past the pulmonary capillaries, tudes, the main concern for the anesthesiologist who treats arterialized blood receives a small fraction of venous blood native populations or transient workforces is hypoxemia; from minimal alveolar shunt (2 to 3%, increasing with age) supplemental oxygen will be necessary for most patients and anatomic sources like bronchial, Thebesian, and some and may be beneficial for the medical staff to maintain full

L. Bigatello and A. Pesenti Anesthesiology 2019; 130:1064–77 1065 Copyright © 2019, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Review Article

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 Vo2 while achieving a very low VA (low natural lung Vco2) 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, Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/130/6/1064/455191/20190600_0-00035.pdf by guest on 24 September 2021

requiring increased Fio2 to maintain a constant Pao2 despite

an artificially normal or low Paco2. Impaired . Oxygen transfer from the alveolus to the circulating 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 oxy- gen is limited by pulmonary blood flow rather than dif- fusing capacity. However, regional capillary blood flow can vary substantially due to factors such as posture, alveolar pressure, and . Lung regions with short capillary tran- sit time will then yield desaturated blood, which will not be compensated by areas with prolonged transit time, because Fig. 2. The oxygen pathway of respiration. Drawing of an alve- hemoglobin will not saturate above 100%. Hence, any mea- surement of diffusion capacity, such as carbon monoxide olus adjoining a pulmonary capillary, where oxygen (O2) and car-

bon dioxide (CO2) are exchanged; blood flow exiting the alveolus diffusion, will be affected primarily by regional flow abnor- enters the arterial circulation (right), crosses through the intersti- malities rather than diffusion. Just like for oxygen, abnormal tium and tissues, and returns to the pulmonary capillary through transfer of carbon monoxide is mostly due to ventilation/ the venous system (left). Partial pressure values are in mmHg. perfusion ratio (V /Q ) inequality, and carbon monoxide dif- Pio2, Po2 in the inspired air; Pvco2, mixed venous carbon dioxide tension; Pvo , mixed venous oxygen tension. fusion may be used as a generic index of abnormal pulmo- 2 nary function, typically in the preoperative evaluation of patients scheduled to undergo pulmonary resections.10 physical and mental performance. Hypoxemia stimulates Shunt (or Venous Admixture) and V / Q Inequality. The basic V mainly through carotid chemoreceptors4; hyperventi- A principle for alveoli to work as gas exchangers is to match lation may be profound, and the consequent decrease in ventilation (provides inflow and outflow for gases from and Paco will limit the reduction of Pao according to equa- 2 2 to the air) with perfusion (provides inflow and outflow tion 2. Near the summit of Mount Everest, at approximately of gases to and from the tissues). The two systems cross 27,000 feet/8,200 meters and a barometric pressure of 284 paths in the alveoli, where blood enters with different oP mmHg, Pao and Paco measured in climbers breathing air 2 2 2 and Pco from the alveolar gas and exits with near equal 5,6 2 were 25 and 13 mmHg, respectively. . Normal V is approximately 4 l/min, and A low Pio at sea level may be related to the accidental A 2 normal pulmonary blood flow (cardiac output) approxi- administration of a hypoxic mixture. The remarkable level of mately 5 l/min, giving a V /Q of 0.8. In reality, each indi- safety of anesthesia machines and portable field devices makes vidual alveolus’s V /Q may differ substantially, from 0, that accidental delivery of a hypoxic mixture an exceptional event. is shunt, to ∞, that is dead space and infinite combinations in between. Low Pao2. In addition to causes of low Po2 upstream from The most practical approach to V /Q distribution is the alveoli (low Pio2), Pao2 decreases mainly in relation to still the three compartments model proposed by Riley an increase in Paco2. As per equation 2, Pao2 falls when VA and Cournand11,12 more than half a century ago: an ideal decreases, at any given Vo2 and any starting Paco2. Table 1 applies the alveolar air equation to representative physio- compartment, a nonventilated compartment, and a non- logic situations. Also, from equation 2, we appreciate the perfused compartment. In the nonventilated compartment, capillary blood reaches the pulmonary venous side (oxy- effect of fraction of inspired oxygen (Fio2): a simple increase genated blood) without participating at all in gas exchange. from 21 to 30% Fio2 raises Pio2 by 64 mmHg, which may The proportion of nonoxygenated blood mixing into the restore Pao2 to a value around 100 mmHg even in the pres- ence of extreme hypoventilation. arterialized side is defined as shunt or venous admixture In modern intensive care, we learn to take into account and represents the amount of blood that would justify the the possible contribution of extracorporeal carbon dioxide deficit in arterial oxygenation if it were to cross the lung

1066 Anesthesiology 2019; 130:1064–77 L. Bigatello and A. Pesenti Copyright © 2019, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Respiratory Physiology for Anesthesia

Table 1. Effects of Changes of Variables that Determine Pao According to the Alveolar Air Equation: Pao = Pio – ( o / K × V ) 2 2 2 V 2 A

o Patm – PH2O mmHg Fio2 Pio2 mmHg V 2 ml/min VA ml/min Pao2 mmHg

Normal 713 0.21 150 250 4,000 102

Hypoventilation 713 0.21 150 250 2,000 55 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/130/6/1064/455191/20190600_0-00035.pdf by guest on 24 September 2021

Hypoventilation, higher Fio2 713 0.30 214 250 2,000 119 Shivering 713 0.21 150 500 4,000 55 713 0.21 150 500 8,000 102 Shivering, higher VA Altitude 27,000 feet 237 0.21 50 250 4,000 2 237 0.21 50 250 8,000 26 27,000 feet, higher VA 237 0.30 71 250 8,000 47 27,000 feet, higher VA, Fio2

4 The Patm value at 27,000 feet is taken from West. The changes in Vo2 and in VA are double or half of baseline for easy comparisons. Note how the same increase of Fio2 from 21 to 30% is much less effective at high altitude because of the lower P . Fio , fraction of inspired oxygen; P , atmospheric pressure; P , water vapor pressure; Pio , partial pressure of atm 2 atm H2O 2 inspired oxygen; VA, alveolar ventilation; Vo2, oxygen consumption. K= 1/760.

without participating to gas exchange. The degree of shunt hypoxemia is the main result; this phenomenon is explained is computed when mixed venous blood gases are available: in terms of blood oxygen content and the hemoglobin–ox- ygen dissociation curve: QQVA / TOT =−()CcoC22ao / ()Cco22−Cvo (3) Arterial oxygen content ()CaO2

=+Hb ××1.34 SaO PaO × 0.003 (4) where QVA is the fraction of pulmonary blood flow exposed [] 2 2 to ventilation, QTOT is the total pulmonary blood flow, Cco2 is the oxygen content of ideal capillary blood computed In an alveolo-capillary unit with normal V/Q, Cao2 is =

from Pao2 of the ideal compartment (equation 2), Cao2 is 14 g/dl × 1.34 × 1 + 0.3 ≈ 19 ml of oxygen per dl, also the oxygen content of arterial blood, and Cvo2 is the oxy- expressed as 19 ml %. In a unit with low V/Q and, e.g.,

gen content of venous blood. arterial (Sao2) of 0.85, Cao2 will be 16 ml

In reality, hypoxemia and hypercarbia in lung disease %, close to a normal venous oxygen content (Cvo2) of result from infinite combinations ofV /Q relationships that 14 ml %. In a unit with high V/Q and a Pao2 of , e.g., 400

lie somewhere between shunt and dead space. The structure mmHg, Cao2 is almost 20 ml %, only slightly above normal. of the lung tends to predispose to V /Q inequality, with both The high V /Q unit cannot carry much more than 19 ml perfusion and ventilation being more efficient at the bases % of oxygen because once full saturation of hemoglobin

of the lungs, but the gradient of perfusion being steeper is reached, a higher Pao2 only increases dissolved oxygen, 13,14 than ventilation, creating a situation prone to mismatch. which contributes minimally to Cao2. It is important to appreciate that although V /Q inequality Clinical Evaluation of / Distribution. Measuring regional affects both oxygen and carbon dioxide exchange, the end V Q V /Q distribution is a complex task. The accepted standard result of is primarily hypoxemia, for two main reasons: has been the Multiple Inert Gas Elimination Technique, Increased Paco2 Stimulates Ventilation. When low V/Q based on the infusion of a mixture of six dissolved inert

develops in a portion of the lung, it decreases Po2 and gases with a known range of , then measuring 15,16 increases Pco2 of arterialized blood. In spontaneously their concentrations in arterial blood and expired gas.

breathing patients, the higher Paco2 stimulates ventilation, This technique has never been simplified enough for clin-

and Paco2—but not Pao2—will return toward baseline. If ical use, nor does it provide spatial information of the areas hypoxemia is severe, as at high altitudes, an additional stim- of V /Q inequality. Recently, the evolution of lung imag-

ulus to hyperventilation will further decrease Paco2. In fully ing with high-definition computerized tomography scan, ventilated patients, who cannot increase their minute venti- positron emission tomography, and electrical impedance 17 lation, Paco2 will indeed increase, but the gradient between tomography is taking the visualization of V/Q distri-

venous and arterial Pco2 (46 to 40 = 6 mmHg) is very bution closer to the clinical arena, although not yet to a small, and the change is difficult to detect. quantitative evaluation of the precision provided by the Multiple Inert Gas Elimination Technique. Opposite Changes in V /Q Do Not Cancel Each Other

Out. At first glance, it would seem that comparable but Clinical Indices of Oxygenation and the Effect of Fio2. Pao2 and opposite changes of V/Q would cancel each other out Sao2 are precise measurements of their respective physio- and yield normal gas exchange. This does not occur, and logic entity, but alone do not provide adequate description

L. Bigatello and A. Pesenti Anesthesiology 2019; 130:1064–77 1067 Copyright © 2019, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Review Article

of an ongoing respiratory impairment, nor allow accurate that under normal circumstances, approximately 25% of the comparison among patients. It is important to know par- available oxygen is taken up by tissues. With a lower cardiac tial pressure (mmHg) or fraction (%) of oxygen upstream output or hemoglobin concentration and constant Vo2, the 18 from the artery at which a certain Pao2 is obtained : a term Cao2 – Cvo2 widens and Pvo2 decreases, indicating

Pao2 of 100 mmHg has different physiologic implications an increased extraction of oxygen by the tissues. Note that

whether obtained at a Pio2 of 600 mmHg (Fio2 100%) ver- increased extraction does not automatically indicate insuffi-

22 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/130/6/1064/455191/20190600_0-00035.pdf by guest on 24 September 2021 sus a Pio2 of 150 mmHg (Fio2 21%). The alveolo-arterial oxy- cient perfusion; hence, monitoring Pvo2 or Svo2 provides gen gradient is the most time-honored index of oxygenation, information on the status of oxygen delivery but does

where Pao2 is estimated from equation 2; the wider the not necessarily indicate a need to normalize oxygen delivery. It alveolo-arterial oxygen gradient, the worse the performance is important to note that the mathematical effect of the same

of the lung as an exchanger. The most accurate application change of each component of oxygen delivery on Pvo2 may for this index is in patients intubated and breathing high differ greatly from the clinical effect. This is shown in table 2,

Fio2, where the linearity between this index and the level of where halving any of the terms of the equation will equally 18 venous admixture is best. More recently, the ratio between half oxygen delivery and decrease Pvo2. However, while halv-

Pao2 and Fio2 (Pao2/Fio2 or “P/F”) has largely substituted ing hemoglobin concentration may be a relatively minor event

alveolo-arterial oxygen gradient because it does not require in many critically ill patients, halving Sao2 may be deadly. equation 2 and its relationship with venous admixture is less Furthermore, the physiologic relationship among the variables 19,20 affected by Fio2. in discussion is complex and cannot be evaluated simply by the Fick’s equation. For example, accurate measurement of Low Mixed Venous Oxygen Tension (Pvo ). Normally, transfer 2 V o is elusive in the clinical setting,23 and it is often referred to of oxygen from air to blood reaches full equilibrium within 2 from tables; also, an increase in cardiac output in the presence the alveolo-capillary unit, and Pao ≈ Pao . Such degree of 2 2 of moderate shunt will generally increase shunt itself, negating efficiency allows for even a low Pvo to yield a normal Pao . 2 2 the assumption that the other variables are constant.24,25 However, in patients with intrapulmonary shunt, blood with

low Pvo2 enters the arterial stream without being saturated by General Anesthesia and Hypoxemia. A succession of physi- 26 alveolar oxygen and will decrease Pao2 to a degree depending ologic events decreases Pao2 during general anesthesia. on the magnitude of the shunt fraction: the higher the shunt, Shortly after induction of anesthesia, the resting volume

the more the Pao2 becomes dependent on the Pvo2. of the lung (functional residual capacity [FRC]), which is a reserve of oxygen, decreases by an average of 500 ml in The Physiology of Mixed Venous Po . The next logical ques- 2 adults; added to the volume lost by going from the erect tion is what causes a low Pvo The following equation 2. to the supine position,27 FRC is reduced from approxi- (Fick’s equation) illustrates the relationship between oxygen mately of 3,000 ml to just more than 2,000, i.e., close to delivery to the tissues (Cao × cardiac output) and oxygen 2 residual volume. The main cause is a loss of muscle tone utilization, or V o : 2 with consequent cephalad displacement of the diaphragm; it is largely independent of the type of anesthesia and 28 Cardiac output =−VOO22/()Ca CvO2 (5) unrelated to neuromuscular blockade, and is aggravated by pregnancy, obesity, and abdominal distention.29 The

Pvo2 and mixed venous oxygen saturation (Svo2) contribute decrease in resting lung volume causes a decrease in lung

to Cvo2 (equation 4) and are used interchangeably as indices compliance, promotes cyclic airway closure at end-expi- of tissue oxygen utilization.21 Unless indicated otherwise, ration and gas reabsorption, rapidly leading to atelectasis.

Pvo2 and Svo2 refer to mixed venous blood, which is blood Persistent blood flow during cyclic airway closure and distal to the right atrium, where full mixing has occurred. through atelectasis causes areas of low V /Q and shunt, Mixed venous blood can be sampled only via a pulmonary contributing to hypoxemia. In the supine position, atelec-

artery catheter. Central venous blood Po2 obtained via a tases are prevalently located in the dorsal areas of the lung; standard central venous catheter has been used as a surro- normally limited to less than 10% of the lung volume, gate, but it is not consistently accurate because is affected they may extend to 15 to 30% of it and be associated with by separate currents of blood coming from venous districts persistent hypoxemia and respiratory complications.30 22 with different oP 2. Almost paradoxically, a high Fio2 may add to lung collapse

Pvo2 may decrease for a defined number of factors: a low (absorption atelectasis) by substituting alveolar nitrogen with

Pao2, low hemoglobin concentration, low cardiac output, or oxygen, the former not taking part in gas exchange. An a high Vo2. With a low Pao2, the lower Pvo2 will further Fio2 of 80% may limit the degree of absorption atelectasis

decrease Pao2 until a new equilibrium of lower Pvo2 and compared to100%. The combination of an Fio2 not higher

Pao2 is reached. Normally, a Cao2 of ~ 19 ml/100 ml of blood than 60%, and positive end-expiratory pressure (PEEP) × cardiac output of 5 l/min yields a delivery of oxygen of during awakening from general anesthesia, may limit the ~ 1,000 ml/min; with a resting Vo2 of ~ 250 ml/min, the degree of atelectasis and the incidence and duration of 31,32 (Cao2 – Cvo2) × cardiac output term is 750 ml/min, meaning hypoxemia in the postoperative period.

1068 Anesthesiology 2019; 130:1064–77 L. Bigatello and A. Pesenti Copyright © 2019, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Respiratory Physiology for Anesthesia

Table 2. Effects of Changes in the Determinants of Oxygen Delivery on Mixed Venous Oxygen Partial Pressure (Pvo2) and

Saturation (Svo2)

V CO, l/min Hb, g/dl Oxygen delivery o2 Pvo2/Svo2

(× 10) (× 1.34) Sao2% ml/min 250 ml/min mmHg, % Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/130/6/1064/455191/20190600_0-00035.pdf by guest on 24 September 2021 Normal 5 14 100 938 26% 37/70 Severe anemia (50% Hb) 5 7 100 469 52% 23/40 Severe anemia (50% Hb), compensated 6 7 100 562 44% 29/55 Severe anemia (50% Hb), myocardial dysfunction 3.5 7 100 328 65% 20/30 Cardiogenic (50% CO) 2.5 14 100 469 52% 23/40

Severe hypoxemia (50% Sao2) 5 14 50 469 52% 23/40

The values of Pvo2 and Svo2 are estimated on the normal hemoglobin oxygen dissociation curve and may show variability in the clinical setting because of the steep slope of the curve, and the situational effects of and pH. Note how an identical decrease of oxygen delivery from 938 to 469 ml/min, and identical decrease in Pvo2 / Svo2, may produce rad- ically diverging clinical implications: in the case of a hemoglobin of 7 g/dl, the clinical picture is hardly critical, but in the case of Sao2 of 50% (Pao2 ~ 27 mmHg), the picture is deadly. For the case of severe anemia, we show the effects of normal physiologic compensation (increased cardiac output) and how the lack of such compensation (myocardial dysfunction) may significantly affect Pvo / Svo . CO, cardiac output; Hb, hemoglobin serum concentration; o , oxygen consumption. Oxygen delivery = oxygen content × cardiac output; oxygen 2 2 V 2 extraction = oxygen consumption / oxygen delivery.

Hypercarbia increases in Paco2 have immediate effect on the total min- ute ventilation: for each 1 mmHg Paco , Different from hypoxemia, hypercarbia is generally well 2 increases by 1 to 2 l/min, retuning Paco to its normal value tolerated unless severe enough (above 80 to 100 mmHg) 2 to cause obtundation and respiratory arrest. In suscepti- (fig. 3). Based on the above schematic, we can differentiate ble patients, hypercarbia may be perilous through various the main causes of hypercarbia. mechanisms, by increasing intracranial pressure in patients High co . Increased aerobic occurs in hyper- V 2 with cerebral edema or exacerbating pulmonary hyper- metabolic states such as exercise, fever, shivering, hyperthy- tension in adults with right ventricular dysfunction and roidism, excessive caloric/ intake and, to its in children with congenital heart disease. On the other maximum extent, in neuroleptic malignant syndrome and hand, moderate hypercarbia may be a favorable condition malignant . Except for the latter two enti- in a number of pathologic situations, such as in circulatory ties, increase of Vco2 is either mild, as in high carbohy- shock by improving local blood flow, and in acute respira- drate intake, or transient, as in shivering, and most of the tory distress syndrome (ARDS) as an accepted consequence time offset by the increase of V A. When ventilation is lim- of a ventilatory strategy of limited .33 ited by disease, sedation or residual anesthesia, an episode of high fever or shivering may overwhelm the capability 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, ions (buff- ered by hemoglobin), and bicarbonate ions, and is measured 34 in mEq/l as “total CO2” in a standard metabolic profile. From the pulmonary capillary, carbon dioxide transfers to the alveolus by the same physical 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 ( Vco2) and elimination by V A,

Fig. 3. The close relationship of arterial carbon dioxide (Paco2, independent variable) and minute ventilation (V ). The continu- E PACO2 = VVCO2A/ K (6) ous line is the normal, and the hashed line represents the effect of different conditions. The glow around both lines is a qualita- where K = 1/760 as in equation 2. tive representation of the variance present in both healthy and Elimination of carbon dioxide is the essential target affected individuals. in parentheses have a less pronounced effect. of breathing. Paco2 and V A are tightly bound, and small

L. Bigatello and A. Pesenti Anesthesiology 2019; 130:1064–77 1069 Copyright © 2019, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Review Article

of the and result in levels of hypercar- I, and alveolar Pco2 from the highest point (also end-tidal bia that require mechanical ventilatory support. Vco2 may Pco2, Petco2); substituting Peco2 with Petco2 in equation also change abruptly under non–steady state condition by 36 7, we measure VD/VT ALV continuously and noninvasively. changes in body carbon dioxide stores (bicarbonate and However, using Paco as a surrogate of Paco adds to V / carbonic acid) or by exogenous infusion. For example, the 2 2 D VT PHYS a source of carbon dioxide that does not contribute rapid administration of sodium bicarbonate with the aim of to Paco2 because it is not dead space but shunt and V/Q neutralizing a metabolic acidemia (i.e., converting bicarbon- inequality.35,37 Shunt widens the A - a gradient for carbon Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/130/6/1064/455191/20190600_0-00035.pdf by guest on 24 September 2021 ate to carbon dioxide and water) results in a stoichiometric dioxide just like the A - a gradient for oxygen, but the effect increase in carbon dioxide production: 100 mEq of sodium of shunt on Paco will be less visible than on Pao because bicarbonate more than 20 min may cause up to 50% increase 2 2 the difference in Pco2 between venous and arterial blood in Vco2 of the same duration (5 mEq/min). is much smaller than the difference in oP 2. For example, a Low . Hypoventilation causes hypercarbia and hypox- V A 30% shunt would increase Paco2 by only 2 mmHg, a barely emia, particularly at low Fio2. Looking at equation 2, at noticeable change; however, that would correspond to an constant V o , a decrease in V implies a decreased delivery 2 A increase in calculated VD/VT PHYS larger than 30% because of oxygen to the alveolus, while Paco increases because a 2 of the increase in gradient, not in absolute Paco2 value. higher carbon dioxide concentration in the expired air is Differentiating the mechanism leading to hypercarbia may necessary to eliminate the same amount of carbon diox- be important; for example, the magnitude of VD/VT PHYS 38 ide per unit time at constant Vco2. Common causes of has been correlated with the rate of mortality in ARDS; hypoventilation include a decreased central drive to breathe, given the high shunt fraction present in severe ARDS, part as it occurs with hypnotics, volatile anesthetics, and opiates of the increase in Paco2 that contributes to the high calcu- (fig. 3); respiratory muscle weakness, as in Guillain-Barré lated VD/VT PHYS may be due to decreased ventilation and syndrome, myasthenia, and polyneuropathy of critical ill- not decreased blood flow. Similarly, in lung disease char- ness; and high resistive (severe asthma) or elastic (abdominal acterized by major alterations in V /Q relationship, such as distention) ventilatory loads. severe chronic obstructive pulmonary disease (COPD), a low Petco may reflect the overall V /Q inequality in addi- Dead Space Ventilation and V/ Q Inequality. Ventilation is a 2 to and fro process that starts in the airways, which are one- tion to dead space. way conduits not involved in gas exchange. This fraction Occasionally, alveolar units with altered mechanics may of tidal ventilation (150 to 200 ml in adults) is thus “dead empty throughout expiration and add carbon dioxide, increasing Paco , and Petco may exceed Paco , the limit volume” or anatomic dead space of the airways (V /V ). 2 2 2 D T AW being mixed venous carbon dioxide tension (Pvco ). This is In mechanically ventilated patients, V /V also includes 2 D T AW rare, and Petco is normally equal to or lower than Paco ; any additional respiratory equipment where flow of gas is 2 2 bidirectional, such as masks and corrugated tubing added as long as the exhaled carbon dioxide trace on the capno- gram shows a stable plateau, the Petco2 can be accepted as distally to the Y-piece. In addition to VD/VT AW, where no carbon dioxide is ever exchanged, dead volume may also representative of alveolar carbon dioxide. occur at the alveolar level or alveolar dead space (V /V ), D T ALV Dynamic Changes of Carbon Dioxide. The above discussion where normally all carbon dioxide is exchanged, and rep- refers to steady state conditions, but we should also take resents a wasted fraction of V . In analogy with shunt in A into account the peculiarities of dynamic or transient car- the three compartments model of Riley and Cournand,11,12 bon dioxide changes.39 When ventilation increases, Pco V /V is the proportion of alveolar ventilation that could 2 D T ALV decreases rapidly, the rate of decrease being governed pri- justify the observed decrease in mixed Paco if it were to 2 marily by V . When ventilation decreases, the process is be expired with a Pco equal to the one of the inspired air. A 2 overall different, because the rate of increase of Pco is V /V + V /V is physiologic dead space (V /V ). 2 D T AW D T ALV D T PHYS governed only by V co . When an individual holds breath Measurement of V /V is commonly obtained from 2 D T PHYS for several seconds (), an initial increase of Paco a modification of the Bohr equation35 where Paco substi- 2 2 toward the Pvco value (an additional 6 mmHg or 21 ml tutes Paco , the latter being difficult to measure: 2 2 of carbon dioxide with an FRC is 2.5 l) will take place rap- idly—less than 6 s at constant cardiac output. However, past VVDT/ PHYS =−()PaCO2 PECOC22/Pa O (7) this equilibration time, any further increase of Pco2 takes place at a much slower speed (3 to 6 mmHg/min) due to

Peco2 is the mixed exhaled Pco2, which includes both the high capacity of the body stores for carbon dioxide.

alveolar (≈ arterial) CO2 and airways (≈ 0) CO2, where a Important dynamic changes in carbon dioxide occur also

normal value of 30 mmHg gives a VD/VT PHYS = (40 to with changes in pulmonary blood flow. A fall in cardiac 30)/40 = 1/4 = 25%, i.e., 150 to 200 ml. The availability of output at constant VE causes a decrease in carbon dioxide continuous capnography allows estimation of Peco from 2 transferred to the alveoli, reflected by lower etcoP 2 and the midpoint of the initial rise of exhaled trace, or Phase increased VD/VT ALV.

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Respiratory Mechanics occurrence: by including the zero-flow pause in the set inspiratory time, the ventilator must deliver the set volume Air moves in and out of the lungs by the cyclic action of the in a shorter time, which can only be done by increasing respiratory muscles. Each breath starts with pressure applied inspiratory flow, which in turn will result in higher PIP and by the respiratory muscles (negative pressure) or by a venti- sometimes in changes of P and V , altering the mea- lator (positive pressure), generating a flow of gas through the PLAT T surement of R and C . Most anesthesia ventilators do airways that expands the volume of the lung and surround- aw RS not display the actual value of R , but one can still get an Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/130/6/1064/455191/20190600_0-00035.pdf by guest on 24 September 2021 ing structures. This process is opposed each time by resistance aw approximate idea by assessing the difference between PIP to gas flow in the airways andelastance (stiffness) of the lung and P : when R is increased by, e.g., , sep- and surrounding structures. Note that the term elastance PLAT aw aration of PIP and P is clearly noticeable, and may subse- is seldom used in clinical lingo, in favor of its reciprocal, PLAT quently change with an intervention such as administering compliance; thus, an increased stiffness of the lung is a low a . Under the appropriate circumstances, compliance. These five variables—pressure, flow, volume, C (but not R ) can be estimated without performing resistance, and compliance—are intimately intertwined in RS aw an inspiratory pause, provided that the pressure trace shows determining the mechanical process of breathing, whether an identifiable plateau, as in figure 4C. This happens when it is during relaxed breathing, during arduous exercise, or flow is delivered with an initial peak followed by progressive supplied by a ventilator.40 decay throughout inspiration (“descending ramp” pattern), ideally reaching zero flow. This is the rule in pressure con- Bedside Measurement of Respiratory Mechanics Can trol ventilation and may be obtained also in volume control Be Carried Out with Nearly Any Modern Ventilator under appropriate settings. Mechanics of Inspiration. As the mechanics of alveolar units vary, the time required to move air in and out may also vary both within and Resistance = ()peak []PIP among areas of the lung. The time required by the respira- tory system to change volume is described by the concept − plateauP[]PLAT pressure)/flowrate (8) of time constant (τ):43

Compliance = tidalvolume/()P-PLAT PEEP (9) τ =×RcAW ()mH2RO/l/sCS2()l/cmHO (10) Normal (R ) is 1 to 3 cm H O/l/s; nor- aw 2 Time constants are used to describe the exponential time mal compliance of the respiratory system (C ), i.e., lung RS change of a dynamic system to reach a new steady state, in plus chest wall, is 80 to 100 ml/cm H O. 41 Separating PIP 2 our case filling or emptying of the lung or a lung unit. Oneτ and P is key for the correct measurement of R and PLAT aw is the time in seconds taken to achieve 63% of maximal vol- C .42 PIP is the highest pressure measured at the airway RS ume change of the lung unit; every successive τ will change during a mechanical breath and is determined by size of the 63% of the previous volume; hence it takes 4 τ’s to reach tidal volume (V ), inspiratory flow rate, R , and C . P T aw RS PLAT about 95% of the new steady state. The clinical relevance of is the pressure measured at the end of inspiration when flow this concept is that it allows to distinguish different forms of is held, i.e., zero flow, and is determined solely by V and T respiratory failure from a mechanical standpoint. For exam- C . Basic ventilatory settings do not separate PIP and P , RS PLAT ple, asthma and COPD have slow τ because they have high but most ventilators provide ways to measure and visualize R and normal or high C ; conversely, ARDS has fast them. An end-inspiratory pause closes the inspiratory valve aw L τ because C is low and R only moderately increased. without opening the expiratory valve, pausing flow for an L aw The slow τ of asthma and COPD is responsible for lung adjustable period of 0.5 to 2 s, and displays the values of R aw hyperinflation and expiratory flow limitation. The fastτ of and C . A typical inspiratory pause is executed with the RS ARDS is responsible for the short inspiratory time (when ventilator on volume control, constant flow rate (“square not assisted by the ventilator) and tendency to de-recruit. flow waveform”); if possible, setting the flow rate at 60 l/ During expiration, the most rele- min (1 l/s) simplifies awR calculation. We caution the practi- Mechanics of Expiration. tioner to examine the actual traces on the ventilator screen, vant measurement is auto-PEEP—also “intrinsic PEEP” or because inaccuracies do occur from unplanned changes in “occult PEEP.”44 Auto-PEEP is positive alveolar pressure

settings or artifacts due to spontaneous respiration, cough- (PALV) at end expiration, where normally we expect it to ing, or leaks. Most critical care ventilators add the pause to a be equal to the pressure measured at the airway opening

single breath without altering other parameters, thus allow- (PPLAT), i.e., 0 cm H2O (atmospheric pressure) or PEEP. ing measurement on the ongoing ventilatory settings. Most Auto-PEEP occurs by two main mechanisms, shown in anesthesia ventilators incorporate an end-inspiratory pause figure 5. First, there is insufficient time to exhale the full

as a percentage of the set inspiratory time to all subsequent VT because the relaxation time of the respiratory system is breaths; by doing so, the delivery of the breath changes, and longer than the allocated expiratory time, be it spontaneous with that the mechanics of the breath. Figure 4 shows such or set on the ventilator. Such is the situation of long τ in

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Fig. 4. Photographs of anesthesia ventilator screens during robotic abdominal hysterectomy; abdomen is insufflated, position steep Trendelenburg; traces are of airway pressure over time. Measured variables are in yellow over black background, set variables in black over

yellow. (A) Volume control constant flow ventilation; note peak inspiratory pressure (Pmax) of 30 cm H2O. (B) Same mode of ventilation with

end-inspiratory pause of 50% of inspiratory time. Note the higher Pmax (34 cm H2O) generated by the higher inspiratory flow necessary to

compensate for the pause in inspiratory flow. Tidal volume (Vte) remained the same, and plateau pressure (Ppl-50%, 28 cm H2O) nearly the same as the Pmax prior to inducing the inspiratory pause. (C) Pressure control ventilation set to generate the same Vte is nearly equal to Ppl- 50%, indicating that (1) with pressure control, the peak inspiratory pressure (Pmax in the figure) is the plateau pressure; and (2) the pressure that generates a certain tidal volume, which is the plateau pressure, is nearly the same in all three conditions. , minute ventilation. V E

pure bronchospasm. Second is by the presence of expiratory lung.46 Just like set PEEP, auto-PEEP may decrease car- flow limitation, characteristic of COPD due to loss of elastic diac output and arterial blood pressure.41 Differently from recoil of the lung and supporting structure of the airways. set PEEP, auto-PEEP increases : when As the volume of the lung decreases during , breathing normally from FRC or from a set PEEP, a min- so does the diameter of the airways, possibly down to full imal negative pressure starts inspiratory flow and initiates a collapse; this is often further amplified when the expira- breath; with auto-PEEP, this negative pressure has to over-

tory muscles are activated and generate a positive pressure come the positive PALV before decreasing to less than 0 and around the airways. starting inspiratory flow. This added pressure constitutes Auto-PEEP has some of the effects of set PEEP: it may wasted effort because it does not generate any volume, and recruit the lung and may damage the lung. When gener- may ultimately cause fatigue in susceptible patients.47 ated during mechanical ventilation by prolonging inspira- Measurement of auto-PEEP is carried out on a ventila- 42 tory time, auto-PEEP may improve Pao2 through alveolar tor through an expiratory pause, which closes the expi- recruitment45; when generated by trapped gas in status ratory valve without opening the inspiratory valve, and

asthmaticus, auto-PEEP may overstretch and damage the equilibrates PALV across different lung units; the positive

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Fig. 5. Mechanisms of auto-PEEP: persistence of expiratory flow at the end of expiration. In both panels, mode of ventilation is pressure control; upper trace is pressure, lower trace is flow;bottom trace in (A) is volume. (A) The flow trace is abruptly interrupted in both inspiration and expira- tion, suggesting an insufficient time to maintain a high minute ventilation (15 l/min), likely compounded by increased airway resistance. B( ) At a slightly lower minute ventilation (12.4 l/min), the expiratory flow trace shows an initial rapid drop followed by a long, nearly flat portion, eventually interrupted by the beginning of the successive breath. This pattern is suggestive of expiratory flow limitation characteristic of chronic obstructive . Note that at the time of expiratory flow changing direction upwards to pursue inspiration, flow rate is still substantial, 20 l/ min, suggesting a considerable amount of residual alveolar pressure at end expiration, auto-PEEP. V , tidal volume; , minute ventilation. TE V E TOT

airway pressure trace will rise to a plateau above 0 or PEEP, potential for lung damage, hypoventilation, and hemody- the difference being auto-PEEP. Just like an inspiratory namic compromise.

pause, this maneuver is optimal in the absence of sponta- Regional inhomogeneity of CRS during general anesthesia neous efforts and with a low respiratory frequency. Of note, and respiratory failure was demonstrated with the introduc- even during a pause, the value of positive airway pressure tion of lung computerized tomography in the 1980s,51,52 will still be the lowest measured, and if the pause is not opening the way to the understanding of alveolar recruit-

sufficiently long, there may be areas of the lung whereALV P ment and damage during mechanical ventilation, and to the is still higher than the measured auto-PEEP.48 When this development of innovative strategies of lung protective ven- maneuver is not available, as in most anesthesia ventilators, tilation.53 Figure 6 shows computerized tomography scans of the presence of auto-PEEP can be inferred, but not quan- patients with acute respiratory failure and severe hypoxemia

tified, by examining the expiratory flow trace, which will with similarly diminished CRS by bedside measurement, be truncated before reaching zero flow at end expiration, as whose regional mechanical characteristics are manifestly shown in both panels of figure 5. different. The “stiff” lungs will require high ventilating pres- sures that will distribute throughout severely diseased lung Regional Lung Mechanics: The Inhomogeneous Lung. Bedside tissue, possibly causing diffuse damage. The “small” lungs measurements of respiratory mechanics provide values that will receive ventilating intended to the entire lung pertain to the respiratory system as a whole. Similar to V /Q , but delivered mainly to a small portion of it, possibly caus- minor mechanical inequalities develop during normal respi- ing damage to the small lung and doing very little to the ration, and their impact is trivial; however, regional changes consolidated lung. The last set of lungs seems impossible to in mechanics develop with the onset progression of respira- ventilate, which was indeed the case: this patient was treated tory disease, affect respiratory function, and may invalidate by extracorporeal membrane oxygenation for three weeks. standard measurements. Further attention to ventilatory mechanics during Regional inhomogeneity in R develops in asthma and aw anesthesia and intensive care requires understanding the COPD due to weakened , active broncho- interaction between lung and chest wall.54 C measured spasm, inflammatory changes, and trapping of gas. A com- RS ordinarily at the bedside comprises the compliances in series mon result is regional lung hyperinflation, described during of lung (C ) and chest wall (C ). Like electrical capaci- spontaneous as well as general mechanical breathing,48,49 L CW tances in series, the reciprocal of each compliance adds up and visually confirmed by advanced imaging techniques.50 to the reciprocal of the total: Dynamic reduction in airway caliber may progress to com- plete obstruction and exclude hyperinflated areas of the lung from standard measurements, underestimating the 1/CLC+1/C WR=1/C S (11)

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Fig. 6. Regional inhomogeneity of . High resolution computerized tomography scans of three patients with acute respiratory failure and low lung compliance, with noticeably different patterns of distributions of lung injury. The patient on the left had fungal pneumonia in the setting of prolonged immunosuppression. The patient in the middle had bibasilar dorsal pneumonic infiltrates and a sizable left pleural effusion; note the stark demarcation between affected and (at least by imaging) spared lung. The patient on the right was approximately 10 days into the course of acute respiratory distress syndrome after near ; only small areas of apparently inflated lung are visible ventrally and possibly in the dorsal aspect of the left lung; also notice right subpleural loculated pneumothoraxes, possibly indicative of .

Normal values in ml/cm H2O are: CRS = 100, CL = 200, Clinically, PALV is reliably estimated by PPLAT, but PPL requires

and CCW = 200. During mechanical ventilation, we are indirect measurement by means of special thin-walled bal- interested in the lung: it is the lung that we want to expand loons positioned via the nares into the esophagus (esoph- 57 and we do not want to damage. By measuring CRS, we ageal pressure). The value of esophageal pressure as a

extrapolate to the lung what we are actually measuring on measurement of PPL has been somewhat controversial, but the lung and chest wall, and for the most part, the informa- recent studies have confirmed its reliability in selected sit- tion is valuable. uations with close attention to proper positioning and cali- 58,59 Under certain circumstances, understanding the bration. Measuring PTP as the target to PEEP titration in mechanics of ventilation may require knowledge of the patients with ARDS has revealed the need for higher PEEP separate contributions of lung and chest wall. During nor- to provide effective recruitment of regional lung collapse mal respiration, at FRC the inward elastic of the and allow protective ventilation.60,61 Under general anes- lung is equally balanced by the outward elastic force of thesia, the use of a lung protective strategy of higher PEEP

the chest wall, resulting in a PALV equal to atmospheric (0) with or without direct measurement of PTP seems to ideally 62,63 pressure, and a pressure in the pleural cavity (PPL) slightly suit morbidly obese patients and patients undergoing

less than atmospheric pressure. Due in part to gravity, PPL laparoscopic surgery, particularly in the steep Trendelenburg

is more negative in ventral than dorsal areas of the lung in position, where PPL increases further. the supine position, reversed in the prone position,55 and Contrasting Spontaneous Breathing and Controlled Mechanical again more negative in the nondependent lung than in the Ventilation. During a spontaneous inspiration, the chest dependent lung in the lateral position.47 As FRC decreases wall expands by its elastic recoil and by the action of the after induction of general anesthesia, P increases toward PL inspiratory muscles, making P , the pressure surrounding and above 0, promoting airway closure and atelectasis.26 The PL the lung, more negative than at end expiration. Since at key physiologic parameter here is the pressure generated the airway opening the pressure remains atmospheric, P across the lung, or transpulmonary pressure (P ): TP TP is positive and lung volume increases. During controlled

P = P- P mechanical ventilation, pressure is positive, PALV increases, TP ALV PL (12) PPL increases a fraction of PALV, and PTP is again positive.

A positive PTP keeps the alveoli open: under normal cir- For the same pressure applied and constant respiratory

cumstances at FRC, PALV is 0 and PPL slightly negative, mechanics, changes in PTP will be the same, and VT will be

hence PTP is positive; with PEEP, PALV is positive and PPL the same in spontaneous and mechanical breathing. During

less positive than PALV; with anesthesia, , assisted breathing, where tidal ventilation is the result of a

and abdominal distention, PPL increases above PALV and PTP cooperative effort of patient and ventilator, the mechanical turns negative, causing alveolar collapse and atelectasis.56 situation is more complex, with a few points worth noting.

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First, for the same VT, the change in PTP will be the same, exchange on the summit of Mount Everest. J Appl independent of the mode of ventilation (fig. 4), and so will Physiol Respir Environ Exerc Physiol 1983; 55:678–87 be the potential degree of lung damage. Second, when the 6. Grocott MP, Martin DS, Levett DZ, McMorrow R,

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