Lung mechanics: compliance, surfactant, the work of breathing, and spirometry values

Intuition Beginner

Think of the lungs as a pair of balloons inside a rigid box (the ribcage). A muscular sheet called the diaphragm forms the floor of the box. When the diaphragm contracts and flattens, the box gets bigger, the balloons expand, the pressure inside them drops below atmospheric pressure, and air rushes in through the airways. When the diaphragm relaxes, the stretched lung tissue recoils inward, pressure rises, and air flows out. This is the bellows mechanism of breathing.

The lung tissue itself is stretchy, like a rubber band. Compliance describes how easily the lungs expand for a given change in pressure. A highly compliant lung inflates with little effort; a stiff (low-compliance) lung requires more work. Diseases can push compliance in either direction: emphysema makes the lungs floppy and over-compliant, while pulmonary fibrosis makes them stiff and hard to inflate.

Inside the 300 million tiny air sacs called alveoli, a soapy film called surfactant coats the inner surface. Without surfactant, the surface tension at the air-liquid interface would be so high that small alveoli would collapse into larger ones — like tiny soap bubbles emptying into bigger neighbours. Surfactant lowers surface tension most when the alveolus is small, exactly when the collapse risk is greatest. Premature babies born before their lungs have made enough surfactant develop respiratory distress syndrome because their alveoli collapse.

Doctors measure how well the lungs work using a spirometer — a device that records how much air you can blow out and how fast. The most important number is the FEV1/FVC ratio: the fraction of your total exhaled air that comes out in the first second. If that fraction drops, something is blocking the airways (asthma, COPD). If both the total and the one-second volumes shrink together, the lungs themselves are restricted (fibrosis).

Visual Beginner

The spirometry trace shows volume on the vertical axis and time on the horizontal axis. After a maximal inhalation, the subject exhales as hard and fast as possible. The curve rises steeply at first (the FEV1 portion is measured at the one-second mark) and then tapers off as the lungs empty. A healthy trace shows a tall, rapid rise; an obstructive trace rises more slowly, giving a lower FEV1/FVC ratio.

A second panel shows the pressure-volume compliance curve. The horizontal axis is transpulmonary pressure and the vertical axis is lung volume. The curve is S-shaped: flat at low and high volumes, steep in the middle where the lung normally operates. The inflation path sits below the deflation path, forming a hysteresis loop whose enclosed area represents the energy dissipated as heat during each breath.

Worked example Beginner

A patient exhales maximally into a spirometer. The forced vital capacity (FVC) is 3.5 litres and the forced expiratory volume in one second (FEV1) is 2.8 litres. Calculate the FEV1/FVC ratio and interpret the result.

Step 1. Compute the ratio:

$${\text{FEV}}_1/\text{FVC}=2.8/3.5=\mathrm{0.80.}$$

Step 2. Compare with the normal cutoff. A ratio above 0.75 is considered normal. This patient's ratio of 0.80 falls in the healthy range, suggesting no significant airflow obstruction.

Step 3. Compare absolute values to predicted normals (which depend on age, sex, and height). If both FVC and FEV1 are below 80% of their predicted values but the ratio is preserved, the pattern is restrictive. If the ratio is reduced, the pattern is obstructive.

Check your understanding Beginner

Formal definition Intermediate+

Compliance

Lung compliance is the change in lung volume per unit change in transpulmonary pressure:

$$C_L=\frac{\Delta V}{\Delta P_{tp}},$$

where $P_{tp}=P_{alv}-P_{pl}$ is the difference between alveolar pressure and intrapleural pressure. A healthy adult lung at functional residual capacity has $C_L\approx 0.2{\text{ L/cm H}}_2\text{O}$. The pressure-volume relationship is nonlinear: the compliance curve is steep (high compliance) in the mid-volume range and flat (low compliance) at very low and very high volumes. The curve exhibits hysteresis — the inflation limb lies below the deflation limb — because more pressure is required to open collapsed alveoli than to keep them open.

Total respiratory system compliance combines lung compliance ($C_L$) and chest-wall compliance ($C_{cw}$) in series:

$$\frac{1}{C_{rs}}=\frac{1}{C_L}+\frac{1}{C_{cw}}.$$

Normal chest-wall compliance is roughly equal to lung compliance ($\sim 0.2{\text{ L/cm H}}_2\text{O}$), giving a total respiratory system compliance of about $0.1{\text{ L/cm H}}_2\text{O}$.

Surface tension and the Laplace law

For a thin-walled sphere of radius $r$ with surface tension $\gamma$ at the air-liquid interface, the pressure inside exceeds the pressure outside by:

$$P=\frac{2\gamma }{r}.$$

This relationship creates a stability problem. If two alveoli of different radii share the same surface tension, the smaller one has higher internal pressure and will empty into the larger one. Pulmonary surfactant solves this: its surface tension is area-dependent, dropping to near zero when the alveolus is small (molecules packed tightly) and rising toward water-level values when the alveolus is large (molecules spread apart). This makes $P=2\gamma (r)/r$ roughly constant across alveolar sizes, stabilising the alveolar population.

Surfactant is a phospholipid-protein mixture (~90% dipalmitoylphosphatidylcholine, DPPC, with surfactant proteins SP-A through SP-D) secreted by type II pneumocytes in the alveolar epithelium. Production matures around 32 weeks of gestation; premature infants born before this point are at risk for neonatal respiratory distress syndrome (NRDS).

Airway resistance

Airway resistance follows the Poiseuille analogy (see 18.02.03 pending):

$$R_{aw}=\frac{8\eta \ell }{\pi r^4},$$

where $\eta$ is gas viscosity, $\ell$ is airway length, and $r$ is airway radius. Total airway resistance in a healthy adult is approximately $1-2{\text{ cm H}}_2\text{O/(L/s)}$. The medium-sized airways (generations 4-8) contribute the largest fraction; the small airways (generations 16-19) contribute little in health because their enormous parallel number compensates for small individual radii.

Work of breathing

The mechanical work of one breath cycle is the area enclosed by the pressure-volume loop:

$$W=\oint PdV.$$

This work has three components: elastic work (overcoming tissue and surface-tension recoil), resistive work (overcoming airway and tissue viscous resistance), and a negligible inertial component at normal breathing frequencies. At rest, elastic work dominates ($\sim 65\%$); resistive work accounts for $\sim 35\%$. Total work is small ($\sim 0.3-0.5$ J per breath), consuming only $\sim 3\%$ of resting oxygen uptake. In severe obstructive disease, resistive work can dominate, and the oxygen cost of breathing may rise to $30\%$ of total consumption.

Static lung volumes and capacities

The standard spirometric volumes and capacities (typical healthy adult values):

• Tidal volume (TV): $\sim 500\text{ mL}$ — air moved per normal breath.
• Inspiratory reserve volume (IRV): $\sim 3000\text{ mL}$ — additional air above tidal inspiration.
• Expiratory reserve volume (ERV): $\sim 1200\text{ mL}$ — additional air below tidal expiration.
• Residual volume (RV): $\sim 1200\text{ mL}$ — air remaining after maximal exhalation.
• Inspiratory capacity (IC): $\text{TV}+\text{IRV}\approx 3500\text{ mL}$.
• Functional residual capacity (FRC): $\text{ERV}+\text{RV}\approx 2400\text{ mL}$.
• Vital capacity (VC): $\text{TV}+\text{IRV}+\text{ERV}\approx 4700\text{ mL}$.
• Total lung capacity (TLC): $\text{VC}+\text{RV}\approx 5900\text{ mL}$.

RV and FRC cannot be measured by spirometry alone. Two methods are used: helium dilution (a closed-circuit technique in which a known concentration of helium equilibrates with the unknown lung volume) and body plethysmography (Boyle's law applied to the small pressure changes in a sealed chamber during panting manoeuvres).

Dynamic spirometry: FEV1/FVC

Forced vital capacity (FVC) is the total volume exhaled during a maximal forced expiration. Forced expiratory volume in one second (FEV1) is the volume expelled in the first second. The FEV1/FVC ratio is the key diagnostic index:

• Normal: FEV1/FVC $>0.75$ (often expressed as a percentage $>75\%$).
• Obstructive pattern (asthma, COPD): FEV1/FVC is reduced. FEV1 falls more than FVC.
• Restrictive pattern (pulmonary fibrosis, neuromuscular disease): Both FEV1 and FVC fall proportionally; the ratio is preserved or elevated.

Flow-volume loops

A flow-volume loop plots expiratory and inspiratory flow rates against exhaled and inhaled volume during a maximal effort manoeuvre. The expiratory limb shows a sharp peak (peak expiratory flow, PEF) followed by a nearly linear decline. In obstructive disease, the expiratory limb is concave ("scooped out") and peak flow is reduced. In restrictive disease, the loop is narrowed in volume but the flow rates relative to volume are preserved or increased.

Key mechanism Intermediate+

Proposition (Alveolar stability via area-dependent surface tension). If two alveoli of radii $r_1<r_2$ are connected by an open airway, and the surface tension $\gamma$ is constant (as at a pure water-air interface), the smaller alveolus has higher transmural pressure ($P_1=2\gamma /r_1>2\gamma /r_2=P_2$) and will empty into the larger one, causing collapse. If the surface tension is a decreasing function of area, $\gamma (A)$, such that $\gamma$ drops faster than linearly with shrinking radius, the ratio $2\gamma (r)/r$ can be made constant or decreasing with decreasing $r$, restoring stability.

Argument. Substitute the Laplace law for a sphere, $P(r)=2\gamma (r)/r$. Stability requires $dP/dr\ge 0$ — larger alveoli should have equal or higher pressure, not lower:

$$\frac{dP}{dr}=\frac{2}{r}\frac{d\gamma }{dr}-\frac{2\gamma }{r^2}.$$

For stability, $dP/dr\ge 0$:

$$\frac{d\gamma }{dr}\ge \frac{\gamma }{r}.$$

At a pure water-air interface, $d\gamma /dr=0$ and $\gamma \approx 70\text{ dyne/cm}$, violating the condition. With surfactant, as the alveolus shrinks, the phospholipid molecules pack tightly and $\gamma$ drops sharply — to as low as $5\text{ dyne/cm}$ or less at minimum area. Since $A\propto r^2$, and $\gamma$ drops faster than $r^2$ shrinks, the condition $d\gamma /dr\ge \gamma /r$ is satisfied. The small alveolus no longer has higher pressure than the large one, and both remain inflated.

Bridge. This mechanism explains why premature infants lacking surfactant (type II pneumocytes mature around 32 weeks) develop progressive alveolar collapse: without the area-dependent $\gamma (A)$, the bare water-air interface is unstable and alveoli empty one into another. Exogenous surfactant replacement therapy directly addresses the root cause by restoring the area-dependent surface tension function.

Exercises Intermediate+

Lung mechanics in disease — surfactant deficiency, COPD, asthma, and respiratory failure Master

Neonatal respiratory distress syndrome (NRDS)

Premature infants born before $\sim 32$ weeks of gestation have immature type II pneumocytes that produce insufficient surfactant. Without surfactant, alveolar surface tension approaches that of a pure water-air interface ($\sim 70\text{ dyne/cm}$), and the Laplace pressure $P=2\gamma /r$ in small alveoli becomes prohibitively high. Alveoli collapse progressively over the first hours of life, producing diffuse atelectasis, intrapulmonary shunting, and severe hypoxaemia. The hyaline membranes that give the condition its alternative name (hyaline membrane disease) are composed of plasma proteins that leak into the alveolar space through the injured epithelium.

Treatment with exogenous surfactant (beractant, poractant alfa, calfactant — animal-derived phospholipid preparations introduced by Fujiwara et al. in 1980) delivered directly into the trachea dramatically improves alveolar stability and reduces mortality. Antenatal corticosteroid administration to the mother accelerates fetal type II pneumocyte maturation and is standard of care for threatened preterm delivery. The combination of these two interventions has transformed NRDS from one of the leading causes of neonatal mortality to a largely manageable condition.

Acute respiratory distress syndrome (ARDS)

Adult ARDS shares surfactant dysfunction as a component but arises from a fundamentally different mechanism: direct or indirect inflammatory injury to the alveolar-capillary barrier (pneumonia, aspiration, sepsis, trauma). The resulting increased permeability produces protein-rich pulmonary oedema that inactivates surfactant and floods alveoli. The Berlin definition (2012) classifies ARDS by the ratio of arterial $P_{O_2}$ to fractional inspired oxygen (${\text{PaO}}_2/{\text{FiO}}_2$): mild ($200-300$), moderate ($100-200$), and severe ($<100$).

Mechanical ventilation in ARDS must balance two competing goals: maintaining adequate alveolar recruitment (positive end-expiratory pressure, PEEP) while avoiding ventilator-induced lung injury from overdistension (volutrauma) and cyclic opening-closing of alveoli (atelectrauma). The ARDS Network (2000) demonstrated that low tidal volumes ($6\text{ mL/kg}$ predicted body weight) reduce mortality compared with traditional $12\text{ mL/kg}$, presumably by limiting overdistension of the remaining functional lung tissue — a smaller, normal-compliance "baby lung" within the anatomically full-sized lung.

COPD pathophysiology

Chronic obstructive pulmonary disease encompasses two overlapping phenotypes: chronic bronchitis (airway inflammation, mucus hypersecretion, airway-wall remodelling) and emphysema (destruction of alveolar walls by an imbalance between proteases, primarily neutrophil elastase, and antiproteases, primarily ${\alpha }_1$-antitrypsin). The mechanical consequences are:

1. Loss of elastic recoil. Destruction of alveolar septa eliminates elastin, reducing the lung's ability to spring back during expiration. Lung compliance increases. The pressure-volume curve shifts leftward and upward.

2. Air trapping and increased FRC. Without adequate recoil, the lung does not empty passively. Patients breathe at higher lung volumes (dynamic hyperinflation), placing the respiratory muscles at a mechanical disadvantage (shorter, less efficient diaphragm fibres).

3. Reduced FEV1/FVC. The combination of airway inflammation (increased resistance) and loss of recoil (reduced driving pressure for expiration) produces the obstructive spirometric pattern. The flow-volume loop shows the characteristic concave expiratory limb.

4. Increased work of breathing. Resistive work dominates. The oxygen cost of breathing may rise to $30\%$ of total oxygen consumption during exacerbations, creating a positive-feedback trap: the harder the patient works to breathe, the more oxygen the respiratory muscles consume, leaving less for other tissues.

5. Cor pulmonale. Chronic hypoxaemia drives hypoxic pulmonary vasoconstriction throughout the lung, raising pulmonary vascular resistance and pulmonary arterial pressure. The right ventricle hypertrophies and eventually fails (cor pulmonale), the cardiac mechanism linking lung disease to cardiovascular death.

Asthma

Asthma is characterised by reversible airway obstruction, airway hyperresponsiveness, and chronic airway inflammation (eosinophilic, Th2-driven in the classic phenotype). The mechanical abnormalities are:

1. Bronchoconstriction. Smooth-muscle contraction in medium-sized airways narrows the lumen. Because airway resistance scales with $1/r^4$ (Poiseuille), even modest bronchoconstriction produces large increases in resistance.

2. Airway-wall oedema and mucus hypersecretion. Inflammatory mediators (histamine, leukotrienes, interleukins) increase vascular permeability and mucus gland secretion, further narrowing the airway and reducing $r$.

3. Reversibility. Unlike COPD, the obstruction in asthma improves substantially with bronchodilators (${\beta }_2$-agonists, anticholinergics) and anti-inflammatory treatment (inhaled corticosteroids). Spirometry before and after bronchodilator administration shows a significant increase in FEV1 ($\ge 12\%$ and $\ge 200\text{ mL}$), which is the diagnostic criterion for reversibility.

4. Airway remodelling. Chronic uncontrolled asthma leads to structural changes: subepithelial fibrosis, smooth-muscle hypertrophy, and goblet-cell hyperplasia. These changes produce a component of fixed obstruction that does not fully reverse.

Flow-volume loops and the equal pressure point

The flow-volume loop provides the most complete graphical summary of mechanical lung function. During a forced expiratory manoeuvre, flow rises rapidly to peak expiratory flow (PEF) and then declines progressively. The declining portion is effort-independent: beyond a certain expiratory effort, increasing pleural pressure does not increase flow because it also compresses the airway downstream of the equal pressure point (dynamic compression). Maximum expiratory flow at any given lung volume is determined by the elastic recoil pressure and the upstream (alveolar-to-equal-pressure-point) resistance, not by expiratory muscle strength.

This effort-independence has a diagnostic implication: the shape of the expiratory flow-volume limb reflects lung mechanics rather than patient effort. The scooped-out pattern of obstructive disease and the narrow-but-tall pattern of restrictive disease are reproducible findings that do not depend on cooperation.

Upper-airway obstruction produces a distinct flow-volume pattern: a blunted, flattened inspiratory limb (if the obstruction is extrathoracic and variable) or a blunted expiratory limb (if intrathoracic and variable), or both (if fixed). This pattern is diagnostically useful in identifying tracheal stenosis, goitre, or vocal-cord paralysis.

Mechanical ventilation

Invasive mechanical ventilation delivers positive pressure to the airway, replacing or augmenting the patient's own ventilatory effort. The primary modes include:

1. Volume-controlled ventilation (VCV). A set tidal volume is delivered regardless of airway pressure. The pressure waveform reflects compliance and resistance. Risk: high pressures in stiff lungs cause barotrauma.

2. Pressure-controlled ventilation (PCV). A set inspiratory pressure is applied, and the delivered volume depends on compliance and resistance. Tidal volume varies with lung mechanics, requiring close monitoring.

3. Pressure-support ventilation (PSV). The patient triggers each breath and the ventilator provides a set pressure boost. This is a weaning mode that allows the patient to control rate and inspiratory time.

4. PEEP (positive end-expiratory pressure). Maintains positive airway pressure throughout expiration, preventing alveolar collapse and improving oxygenation. The optimal PEEP level trades off alveolar recruitment against overdistension and haemodynamic compromise (increased intrathoracic pressure reduces venous return).

The ventilator pressure-volume curve provides a bedside assessment of lung mechanics: the lower inflection point on inspiration suggests the pressure at which collapsed alveoli begin to recruit (setting PEEP above this point avoids atelectrauma), while the upper inflection point suggests the onset of overdistension (tidal volume should stay below this).

Respiratory muscle fatigue

The diaphragm is a skeletal muscle with a mix of fatigue-resistant type I fibres ($\sim 55\%$) and fatigue-prone type II fibres. It is uniquely adapted for continuous rhythmic activity, but its capacity can be overwhelmed. Respiratory muscle fatigue occurs when the ratio of inspiratory pressure to maximum inspiratory pressure ($P_i/P_{i,\max }$) exceeds a critical threshold ($\sim 0.4$ for sustained breathing). In obstructive and restrictive diseases, the pressure demand rises (stiffer lungs, higher resistance) while the maximum pressure-generating capacity falls (hyperinflation shortens the diaphragm, moving it down its length-tension curve). When demand chronically exceeds capacity, the respiratory muscles fatigue, ventilation becomes inadequate, and hypercapnic respiratory failure ensues. Non-invasive ventilation (NIV) or intubation with mechanical ventilation unloads the respiratory muscles, allowing recovery.

Connections Master

1. 18.03.01 Respiratory physiology — gas exchange. The mechanics developed here deliver fresh air to the alveoli. Compliance, resistance, and the work of breathing determine the alveolar ventilation available for gas exchange. The FEV1/FVC ratio is a mechanical measurement whose clinical significance derives entirely from its implications for alveolar ventilation and hence gas exchange.

2. 18.02.03 pending Hemodynamics. Airway resistance follows the same Poiseuille framework as vascular resistance. The Laplace law applies to both alveolar walls (this unit) and vessel walls (hemodynamics). The parallel between the $r^4$ dependence in airways and blood vessels underscores the shared fluid-mechanics foundation.

3. 18.02.01 Cardiovascular physiology. Cor pulmonale — right-heart failure secondary to lung disease — connects lung mechanics directly to cardiac function. Chronic hypoxic pulmonary vasoconstriction raises pulmonary arterial pressure, increasing right-ventricular afterload. Mechanical ventilation affects cardiac output by altering intrathoracic pressure and hence venous return.

4. 18.04.01 Skeletal muscle physiology. The diaphragm and intercostal muscles obey the same length-tension, force-velocity, and fatigue principles as other skeletal muscles. Hyperinflation in COPD shortens the diaphragm, reducing its force-generating capacity — a direct application of the length-tension relationship.

5. 18.08.01 Renal physiology. Chronic hypercapnia in COPD leads to respiratory acidosis, to which the kidneys respond by retaining bicarbonate (renal compensation). This cross-link between ventilatory failure and renal acid-base handling is covered in the renal unit.

6. 18.10.01 Immunology. The eosinophilic inflammation, Th2 cytokine profile, and IgE-mediated hypersensitivity underlying asthma are immunological mechanisms with mechanical consequences (bronchoconstriction, oedema, mucus). COPD inflammation involves neutrophils, macrophages, and CD8+ T cells — a different immunological pattern producing different mechanical derangements.

Historical notes Master

John Clements, working at the National Institutes of Health in the 1950s, discovered that lung extracts had a surface tension far below that of water or plasma. His 1957 paper in the Proceedings of the Society for Experimental Biology and Medicine showed that the surface tension of pulmonary extracts varied with area — falling to near zero when the film was compressed — and proposed that this was essential for alveolar stability. This was the discovery of surfactant's physical properties. Richard Pattle, working independently in Cambridge, demonstrated the same phenomenon using frog lung foam and published his findings in 1955. The biochemical characterisation of surfactant as a phospholipid (predominantly DPPC) with associated proteins (SP-A, SP-B, SP-C, SP-D) followed over the next three decades.

Mary Ellen Avery, at Harvard in 1959, made the clinical connection: she demonstrated that the lungs of infants who had died of hyaline membrane disease lacked the low surface-tension extract that Clements had described. This established surfactant deficiency as the cause of neonatal respiratory distress syndrome and opened the path to replacement therapy. Tetsuro Fujiwara and colleagues administered the first successful exogenous surfactant preparation to premature infants in 1980, reducing mortality dramatically.

John West, working at the Royal Postgraduate Medical School in London and later at the University of California San Diego, systematised the mechanical and gas-exchange physiology of the lung across his career. His Respiratory Physiology: The Essentials (first edition 1974, now in its 10th edition) remains the standard concise text. West's own contributions include the gravitational model of pulmonary perfusion (the West zones, described in 1964) and the multiple inert gas elimination technique (MIGET, with Wagner and Saltzman, 1974).

The spirometric measurement of lung function has its origins in the water spirometer developed by John Hutchinson in 1846. Hutchinson, a British surgeon, measured the vital capacity of over 4000 subjects and demonstrated its correlation with height and its reduction in disease. He coined the term "vital capacity" to reflect his belief that it was a measure of longevity. The timed vital capacity (FEV1) was introduced by Tiffeneau and Pinelli in 1947 and refined by Gaensler in 1951, establishing the FEV1/FVC ratio as the cornerstone of spirometric diagnosis. Robert Hyatt's work on flow-volume loops in the 1960s added the graphical dimension that remains standard in pulmonary function testing.

The equal pressure point theory, which explains effort-independent expiratory flow limitation, was developed by Peter Macklem and Jere Mead in 1967. Their insight — that expiratory flow is limited by airway compression downstream of the point where intraluminal pressure equals pleural pressure — unified the mechanical and clinical observations of obstructive lung disease into a single coherent framework.

Bibliography Master

1. Clements, J. A. (1957). Surface tension of pulmonary extracts. Proceedings of the Society for Experimental Biology and Medicine, 95, 170–172.

2. Avery, M. E. and Mead, J. (1959). Surface properties in relation to atelectasis and hyaline membrane disease. American Journal of Diseases of Children, 97, 517–523.

3. Pattle, R. E. (1955). Properties, function and origin of the alveolar lining layer. Nature, 175, 1125–1126.

4. Fujiwara, T., Maeta, H., Chida, S., Morita, T., Watabe, Y., and Abe, T. (1980). Artificial surfactant therapy in hyaline-membrane disease. Lancet, 315, 55–59.

5. Hutchinson, J. (1846). On the capacity of the lungs, and on the respiratory functions, with a view of establishing a precise and easy method of detecting disease by the spirometer. Medico-Chirurgical Transactions, 29, 137–252.

6. Tiffeneau, R. and Pinelli, A. (1947). Air circulant et air captif dans l'exploration de la fonction ventilatrice pulmonaire. Paris Medical, 133, 624–628.

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8. West, J. B. (2016). Respiratory Physiology: The Essentials (10th ed.). Wolters Kluwer.

9. Sherwood, L. (2016). Human Physiology (9th ed.). Cengage.

10. Silverthorn, D. U. (2019). Human Physiology: An Integrated Approach (8th ed.). Pearson.

11. The ARDS Network (2000). Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New England Journal of Medicine, 342, 1301–1308.

12. Guyton, A. C. and Hall, J. E. (2021). Textbook of Medical Physiology (14th ed.). Elsevier.

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