DEVELOPMENT OF THE LOWER RESPIRATORY SYSTEM
The development of the respiratory system in humans is an interesting demonstration of ontogeny recapitulating phylogeny. The embryology of the system goes through the ﬁsh, amphibian, reptilian, and mammalian evolutionary stages of humans’ ancestry. In the change from an aqueous to an aerobic environment, many basic structures were modiﬁed but retained as parts of the respiratory system, and others became nonrespiratory structures. At the same time, entirely new respiratory structures evolved. The olfactory organ of aqueous forms was incorporated into the respiratory system of terrestrial forms, and the simple sphincter mechanism of the swim bladder of ﬁsh became the larynx of air breathers, which also took on the function of phonation. In contrast, the part of the respiratory system involved in the gas exchange vital to life has essentially not changed throughout vertebrate evolution. Exchange of oxygen and carbon dioxide between the external environment and the circulating bloodstream occurs through a wet epithelium in both gills and lungs.
The respiratory system in humans differs from the other major body systems in that it is not operational until birth. Therefore, development of the antenatal respiratory system is genetically determined independently of the functional demands of the growing embryo and fetus. The system’s physiologic development is mainly one of preparation for instant action at birth, a feat unmatched by any other system. When the fetus passes from the uterine aquatic environment, the partially collapsed, ﬂuid ﬁlled lungs immediately function efﬁciently to sustain life. The chief cause of perinatal death of human infants is failure of the respiratory system to work properly. In the majority of perinatal deaths, all other body systems are functioning normally.
Primitive Respiratory Tube
During the fourth gestational week, the ﬁrst indication of the future respiratory tree is a groove that runs lengthwise in the ﬂoor of the pharynx just caudal to the pharyngeal pouches. From the outside, this laryngotracheal groove appears as a ridge. The ridge grows caudally to become a tube, the lung bud, and the cranial or upper part of the tube becomes the larynx. The caudal part becomes the future trachea, which soon develops two knoblike enlargements at its distal end, the bronchial buds (Plate 1-33).
As the trachea lengthens, anterior to and parallel with the esophagus, the bronchial buds are carried progressively more caudal in the body until they reach their deﬁnitive position in the thorax. During this growth period, mesenchymal cells from the splanchnic mesoderm surround the tracheal tube of entoderm and give rise to the connective tissue, smooth muscle, and cartilage of the tracheal wall. By and during the eighth gestational week, the rudiments of the 16 to 20 C-shaped tracheal cartilages appear (see Plate 1-36). These mesenchymal rudiments transform into cartilage in a cranial to caudal direction up to the tenth week. Only the epithelial lining and glands of the trachea are derived from entoderm. The lining starts to become ciliated at 10 weeks, with the cilia beating toward the larynx. By 12 weeks, the mucosal glands begin to appear in a cranial to caudal direction. All major microscopic features are recognizable by the end of the ﬁfth month. However, the infantile trachea differs grossly from the adult form because it is short and narrow compared with a relatively very large larynx. This size difference continues for several months after birth.
The bronchial buds of the trachea become the two main bronchi. As soon as the right bronchus appears, it is a little larger than the left one and tends to be more vertically oriented (see Plates 1-33 and 1-36). These differences become more pronounced up to and after the time the bronchi mature, accounting for the fact that foreign bodies enter the right main bronchus much more often than the left.
During the ﬁfth week, each main bronchus gives rise to two bronchial buds. These buds develop secondary branches to the future lobes: the upper, middle, and lower lobes on the right side and the upper and lower lobes on the left (Plate 1-34). By the seventh week, tertiary branches appear (see Plate 1-35), 10 in the right lung and nine in the left. These tertiary branches will supply the clinically important broncho- pulmonary segments, which become separated from each other by tenuous connective tissue septa (see Plate 1-36). The tenuous connective tissue surrounding each segment delineates a separate respiratory unit of the lung, but some collateral ventilation does occur between segments. A branch of the pulmonary artery accompanies each segmental bronchus to serve as the independent blood supply to a bronchopulmonary segment. Again, some collateral circulation occurs across segments. The pulmonary veins do not accompany the segmental bronchi and arteries but run chieﬂy through the substance of the lung between the segments, as do the lymphatic vessels.
Branching of the segmental bronchi continues until, by the sixth month, about 17 orders of branching have been formed. Additional branching continues postnatally and until puberty, when about 24 orders of branches have been established. After the full complement of branches has appeared, no new ones will form to replace any lost through trauma or disease. The mature lung makes up for any branches lost by enlarging the remaining functional segments, which then do more work (compensatory hyperinﬂation).
Cartilage, Smooth Muscle, And Connective Tissue
Cartilage is present in the main bronchi by the tenth week and in the segmental bronchi by the twelfth week.
Cilia appear in the lining of the main bronchi at 12 weeks and in the segmental bronchi at 13 weeks. At birth, the ciliated epithelium extends to the terminal bronchioles.
Mucous glands appear in the bronchi at 13 weeks and actively produce mucus by 14 weeks. At 28 weeks, seven-eighths of the potential adult number of mucous glands is present in the respiratory tubes.
By the third gestational month, smooth muscle cells differentiate to form the posterior wall of the trachea and extrapulmonary main bronchi, which permanently lack cartilage. Smooth muscle cells form bundles arranged obliquely and circularly around the bronchi- oles, including the terminal bronchioles, whose entire walls have no cartilage. The smooth muscle that extends to the alveolar ducts acts as a sphincter. In an allergic reaction, such as bronchial asthma, smooth muscle spasm greatly increases airway resistance. High surface tension in the terminal airways containing a large accumulation of mucus then further reduces the smaller than normal bronchiolar diameter during expiration. Because inspiration is affected by contraction of powerful muscles and is associated with widening and lengthening of the bronchial tree muscles, individuals with asthma can usually inspire adequately. But these individuals have great difﬁculty exhaling because expiration normally results from passive recoil of the stretched thoracic wall and lungs. To overcome the increased airway resistance of an asthmatic attack, muscles of the anterior abdominal wall must be contracted and stabilized, thus allowing the diaphragm to push with greater force and drive air out of the lungs with maximum effort.
Autonomic innervation of the lungs is not extensive; all effects of both sympathetic and parasympathetic innervation are mild. Parasympathetic stimulation can cause moderate contraction of smooth muscle of the respiratory tubes and perhaps some dilatation of the blood vessels. In contrast, sympathetic stimulation may mildly dilate the tubes and mildly constrict the vessels. Therefore, sympathomimetic drugs may be helpful in inhibiting the spasmodic contraction of the respiratory tube smooth muscle during an asthmatic attack.
The pericardial, pleural, and peritoneal cavities develop as subdivisions of two primitive coclomic cavities that extend along the length of the embryo. Normally, each is only a potential space with serous lining that produces a slimy secretion. This reduces friction as the ordinarily apposed surfaces rub against each other. After trauma or other forms of pathology, the cavities may become actual spaces containing proteinaceous exudate, air, or blood.
During the second week of life, the two coelomic cavities in the region of the developing heart fuse into a single pericardial coelom. While the pericardial cavity is becoming established, it is in open communication caudally on each side with the still paired primitive coeloms in the embryo’s future abdominal region. Partitioning of the pericardial coelom from these primitive coeloms starts by the establishment of a shelf of mesenchyme, the transverse septum, into which the liver becomes incorporated as it is developing (see Plate 1-34). This transverse septum grows in from the anterior body wall toward the dorsal or posterior body wall but never reaches it and ﬁnally becomes part of the diaphragm. Therefore, the two channels of communication between the pericardial coelom and the two primitive coelomic cavities persist to become the pleural canals.
In the ﬁsh stage of vertebrate evolution, the transverse septum completely separates the pericardial and peritoneal cavities. Whereas in lungﬁsh the air bladder projects directly into a common pleuroperitoneal space, in amphibians and reptiles the lungs are found in a similar space caudal to the pericardial cavity. In humans, the amphibian and reptilian evolutionary stage of lung development occurs when the growing lungs project into the pleural canals. Each pleural cavity then becomes isolated by the growth of the pleuropericardial and pleuroperitoneal folds. These in turn become associated with the transverse septum (see below).
Pleuropericardial and Pleuroperitoneal Folds
The vertically oriented pleuropericardial folds arise on each side from the body walls where the common cardinal veins swing around to enter the sinus venosus, which subsequently becomes the right atrium. These body-wall folds bulge into the pleural canals between the lungs and the heart (see Plates 1-34 and 1-38). When the free borders of the pleuropericardial folds fuse with midline mesenchymal tissue at the base of the heart, they completely separate what is now the pericardial cavity from the pleuroperitoneal coelom (see Plate 1-38). At this time, the latter space contains the lungs as well as the abdominal and pelvic viscera.
The pleuroperitoneal folds are actually two horizontally oriented ridges of the dorsolateral body wall where the common cardinal veins are located (see Plate 1-34). Each fold grows anteriorly and medially to fuse with the transverse septum and mesenchymal tissue surrounding the aorta, esophagus, and inferior vena cava.
The two pleural canals are then walled off from the newly formed peritoneal cavity, and the formation of the pleural cavities and diaphragm is completed (see Plates 1-37 and 1-39).
A diaphragm is lacking in ﬁsh, amphibians, reptiles, and birds. In mammals, it is the principal respiratory muscle. Although there are numerous accessory respiratory muscles, they cannot support life to a normal degree without a functioning diaphragm. Reptiles have a dual muscular respiratory mechanism: the action of the trunk muscles creates negative pressure, and the ﬂoor of the mouth pushes air into the lungs under positive pressure. The reptilian action of the muscles of the ﬂoor of the mouth is also the chief respiratory muscular mechanism in amphibians (“frog breathing”).
In birds, which like mammals evolved from reptiles, respiration is accomplished chieﬂy by the intercostal trunk muscles that move the ribs, to which the lungs are attached.
In the evolutionary transition from gill breathing to lung breathing, original muscles from the mandibular arch gave rise to the musculature of the ﬂoor of the mouth, especially the mylohyoid muscle. In amphibians and reptiles, air brought in through the nares is forced into the lungs by the musculatory action of the ﬂoor of the mouth. In mammals, a new respiratory muscle the diaphragm evolved from structures lacking muscle in certain reptiles, speciﬁcally, the transverse septum and two unfused coelomic folds that are the pleuroperitoneal folds in mammalian development.
|SAGITTAL SECTION AT 6 TO 7 WEEKS
Diaphragmatic musculature in mammals develops from a common mass of mesoderm at the posterior region of the branchial arches from which the tongue and infrahyoid muscles are also derived (see Plate 1-39). The transverse septum, the largest single contribution to the diaphragm, develops in the neck or cervical region of the embryo (see Plates 1-34 and 1-39). The diaphragmatic striated musculature migrates to the transverse septum along with branches of the third, fourth, and ﬁfth cervical spinal nerves, which become its exclusive motor nerve through the phrenic nerve. By differential growth, especially an increase in size of the thoracic region, there is a so-called migration and descent of the diaphragm to a much more caudal position. At the end of the eighth gestational week, the diaphragm is attached to the dorsal body wall at the level of the ﬁrst lumbar segment. The phrenic nerves, which are located in the body wall where the pleuropericardial folds develop, lengthen as the diaphragm descends. They are, therefore, relocated to a position between the pericardium and the pleurae as the pleural cavities increase in size (see Plate 1-38).
After the transverse septum, the two pleuroperitoneal folds and the numerous other minor folds unite to complete the diaphragm at or during the seventh gestational week, the diaphragmatic musculature becomes peripherally positioned (see Plate 1-39), and its domelike central area remains tendinous. As soon as the diaphragm is completely developed, it begins to contract at irregular intervals. Near term, these contractions, which are essentially hiccups, become more vigorous and more frequent. They exercise the muscles for the time when air breathing begins at birth.
During inhalation, the diaphragm ﬂattens as it contracts. This action reduces the intrathoracic pressure by enlarging the thoracic cavity and with it the intrapulmonary space. The vocal folds are separated, and thus air rushes into the lungs at atmospheric pressure. Normal inspiration is caused chieﬂy by the contraction of the diaphragm. Other powerful striated muscles that assist the diaphragm are in the neck and chest region and are attached to the skull, clavicle, ribs, vertebral column, and upper limbs. Therefore, whereas inspiration is effected by the contraction of powerful muscles, expiration is largely a passive action caused by recoil of the stretched tissues of the thoracic wall and lungs.
The diaphragm is subject to developmental defects that permit herniation of abdominal viscera into the thorax. The most common diaphragmatic congenital hernia is related to defective development of the left pleuroperitoneal fold (see Plate 1-39).
Pleura And Mediastinum
The lungs develop much later than the heart, as was the case throughout their evolutionary history. The small lungs, posterior to a relatively very large heart, grow in an anterior direction on each side of it (Plate 1-38). The pleural cavities open in advance of the growing lungs so they are already prepared to receive them. By the eighth gestational week, the lungs are larger than the heart and nearly surround it. The pleural cavities now occupy the two sides of the thoracic cavity. All other thoracic viscera, including the heart, great vessels, esophagus, and associated connective tissue, are now between the two pleural cavities, from the vertebral column to the sternum. This broad medial septum of viscera and connective tissue is known as the mediastinum.
As the lungs protrude into the pleural canals (see Plate 1-34), they are invested by the lining mesothelium of these spaces, which becomes the visceral pleura (Plate 1-38). Before the pleuropericardial folds wall off the pleural canals from the pericardial coelom, the mesothelium lining the walls of these thoracic subdivisions is continuous (see Plates 1-34 and 1-38). As soon as the pleural canals become the pleural cavities, the lining of the walls of the canals becomes the parietal pleura. The region where the visceral pleura reﬂects off the lungs and becomes continuous with the parietal pleura shifts medially and becomes smaller to envelop the structures that constitute the root of the lung.
Throughout human development, the right lung is larger than the left, as is the case with the right and left pleural cavities. This size differential is related to the shift of the heart to the left side of the thorax. In adult mammals and reptiles, the right lung is also larger than the left lung. In adult humans, the space occupied by the heart produces the cardiac notch of the left lung.
Terminal Respiratory Tubes
The amphibian stage of development of portions of the respiratory tubes occurs at 4 to 5 weeks when the bronchial buds are present (see Plate 1-33). Amphibian lungs are essentially two air sacs, each with a large single lumen. In reptilians, segmental bronchi are present at 7 to 8 weeks (see Plate 1-36). The reptilian lung has branching respiratory tubes ending in terminal sacs that are similar to mammalian primitive alveoli. They add greatly to the surface area where gas exchange occurs; in contrast, the amphibian lung has only rudimentary alveoli.
Alveolar development does not begin in human fetuses until airway development is complete at 16 weeks. Between the fourth and sixth months of gestation, the last airway is transformed to a terminal or respiratory bronchiole. Generally, each respiratory bronchiole divides into three to six alveolar ducts (see Plate 1-40). Each alveolar duct ﬁrst ends in a bulging terminal sac lined by cuboidal or columnar epithelium that ultimately evolves into deﬁnitive alveoli. Capillaries multiply so that the region of terminal airspaces becomes highly vascularized.
During the sixth gestational month, the epithelium of the terminal sacs thins where it is in contact with a capillary (see Plate 1-40).The epithelial cells become so thin when the alveoli ﬁll with air that, before the advent of electron microscopy, there seemed to be breaks in the lining where only capillary endothelium separated the blood from the alveolar air (see Plate 1-41). The capillaries, covered by the thin epithelial cells, line the alveolar spaces (see Plate 1-41). These very thin cells, constituting the major part of the alveolar surface, are known as type I pneumocytes. Other cells, scattered along the lining of the alveoli, are cuboidal, have microvilli on their luminal surfaces, and contain osmiophilic inclusions of surfactant or its precursors. These cells are known as type II pneumocytes, and they also appear during the sixth gestational month.
The original mesenchyme that gives rise to the pulmonary capillaries and lymphatics is also the source of the ﬁbrocytes that produce an abundance of elastic ﬁbers in the lungs (see Plate 1-40). After the lungs become inﬂated with air, the elastic ﬁbers are constantly stretched and, by attempting to contract, contribute to the normal recoil or collapsing tendency of the lungs. On the other hand, the natural tendency of the chest wall is to expand. The resulting negative pressure in the pleural cavities helps to keep the lungs expanded. The visceral pleurae continually absorb ﬂuid so that only a small amount of it remains in the potential intrapleural space at all times. Because the elastic ﬁbers of the lungs are stretched even more during inspiration, they are the chief structures responsible for returning the enlarged alveoli and bronchioles to their more contracted resting dimensions during normal passive expiration.
Alveolar-Capillary (Respiratory) Membrane
By the 28th week, the lung has lost its glandular appearance. The respiratory airways end in a cluster of large thin-walled sacs separated from one another by a matrix of loose connective tissue. At this stage, respiration can be supported because gas exchange can occur at the terminal sacs, and surfactant is present to maintain alveolar stability. The primitive alveoli do not become deﬁnitive as true alveoli until after birth, at which time they are only shallow bulges of the walls of the terminal sacs and respiratory bronchioles. Even so, the thickness of the blood-air barrier, which is also known as the respiratory or alveolar-capillary membrane, is about 0.4 μm. This is within the range found in adults that is, 2.5 μm to smaller than 0.1 μm (1 μm is 0.001 mm). The lungs of a newborn infant contain 24 million primitive alveoli (see Plate 1-41).
During the ﬁrst 3 years of life, the increase in lung size is caused by alveolar multiplication rather than by greater alveolar size. From the third to the eighth year, the alveoli increase in size as well as in number until there are 300 million in the two lungs. After the eighth year, alveoli become larger only until the chest wall stops growing. At age 8 years, the diameter of the mature alveolus is 100 to 300 μm. Physical diffusion of oxygen from the alveolus into the red blood cell and of carbon dioxide in the opposite direction occurs through the respiratory membrane, which consists of an alveolar type I pneumocyte and a capillary endothelial cell and their respective basement membranes. Consequently, oxygen and carbon dioxide do not have to pass across a great distance between the erythrocyte and the alveolus, and gas diffusion can be accomplished very rapidly. The total surface area of the respiratory membrane of both lungs is about 70 m2, which is vast when compared with the 1.7 m2 of total body surface of an adult. The average diameter of a pulmonary capillary is only about 7 μm (see Plate 1-41). The extensive alveolar and associated capillary endothelial surface is also responsible for a large water vapor loss during respiration; adult lungs eliminate about 800 mL of water a day in expired air.
No matter how complete the development of the respiratory system at birth, one factor that determines whether it will support life is the presence of a substance known as pulmonary surfactant. Therefore, because of its functional implications, the most important morphologic event is the appearance at about the twentythird week of lamellar inclusion bodies in the type II pneumocytes of the lining of the terminal sacs. These bodies are precursors of surfactant, a lipoprotein mixture rich in phospholipids, especially dipalmitoyl lecithin. Surfactant has a “detergent” property of lowering surface tension in the ﬂuid layer that lines the primitive alveoli after air enters the lungs, and it acts as an antiatelectasis factor to maintain patency of terminal airspaces (see Plate 1-41).
Surface tension of ﬂuid is measured in dynes per centimeter. A drop of water on a sheet of glass tends to round up into a compact mass because of its surface tension of about 72 dynes/cm at the air water interface. If household detergent is added to the drop of water, its surface tension is reduces to about 20 dynes/cm, and it spreads into a very thin ﬁlm on the glass (see Plate 1-42). In a similar manner, surfactant reduces surface tension of the ﬂuid layer lining the alveolus to about 5 dynes/cm. Its ability to form a monomolecular layer at the interface between air and the alveolar lining ﬂuid (see Plate 1-41) allows some air to be retained within the alveolus at all times.
Although surfactant is present in the lungs as early as the twenty-third gestational week, the lungs at this stage are unable to retain air after inﬂation, and they collapse completely before 28 to 32 weeks. The quantity of surfactant within the lungs increases markedly toward term; this is one of the most important reasons why older fetuses have a better chance of survival as air breathers. Surfactant must be produced continually because it has a half-life of 14 to 24 hours. A deﬁciency of surfactant is associated with the infant respiratory distress syndrome (RDS), also known as hyaline membrane disease (see Plates 4-144 and 4-145). This is caused by the relative instability of the immature lung because of failure to produce surfactant in amounts sufﬁcient for neonatal respiration. Death from the disease occurs within a few hours to a few days after birth. The alveoli of the dead infants are ﬁlled with a proteinaceous ﬂuid that resembles a glassy or hyaline membrane.
The high incidence of RDS in premature infants is caused by their low initial concentrations of surfactant.
Prematurity, cesarean section, and perinatal asphyxia are recognized predisposing factors. Surface tension of lung extracts of newborn infants with birth weights of 1200 g or more is only about 5 dynes/cm. In extracts from infants with birth weights less than 1200 g who have hyaline membrane disease, it may be four times that value.
Before birth, the respiratory tubes are ﬁlled with ﬂuid, some of it amniotic ﬂuid brought in by “practice” inspiratory movements. However, most of the ﬂuid is produced by the lining of the respiratory tubes (as much as 120 mL/h near term). This pulmonary ﬂuid passes through the oral and nasal cavities to mix with the amniotic ﬂuid. Amniotic ﬂuid contains phospholipids, and amniocentesis before the thirty-ﬁfth week usually shows that the ratio of lecithin to sphingomyelin is less than or equal to 1 because the latter remains constant as gestation advances. Such a ratio indicates that the fetus is immature in regard to surfactant production. A ratio of more than 2 : 1 indicates that the fetal lungs are sufﬁciently mature to prevent the development of RDS.
The role of thyroxine and adrenal corticosteroids in stimulating lung maturation and surfactant production has not yet been settled and is still under investigation. Surfactant is present in the lungs of all vertebrate air breathers. The amount of surfactant correlates well with alveolar surface area and with the amount of certain saturated phospholipids in the lung tissue in a stepwise fashion up the phylogenetic scale from amphibians through reptiles to mammals.
Before the ﬁrst breath, the lungs are ﬁlled with ﬂuid. Therefore, the lungs of a stillborn infant who has not taken a breath of air differ from those of an infant who has. The lungs of a stillborn infant are ﬁrm; do not crepitate when handled; and because they contain no air, sink in water. Some of the ﬂuid normally within the lungs at birth is extruded from the mouth; most of it is removed through the lymphatic vessels in the region of the primitive alveoli. The pleural lymphatic vessels are relatively larger and more numerous in fetuses and newborn infants than in adults, and lymph ﬂow is high during the ﬁrst few hours after birth. The ﬂow is less 2 days later but is still higher than in adults.
A certain amount of ﬂuid must of necessity always remain in the alveoli, but in the partially atelectatic (collapsed) primitive alveoli, the surface tension of the viscid ﬂuid tends to hold the walls of the alveoli together. Therefore, the ﬁrst breath of some 30 to 40 mL in volume requires a tremendous physical effort, and a negative intrathoracic pressure as much as 40 to 100 cm of water is needed for expansion. This is about 14 times the pressure required to produce breaths of a similar volume subsequently (see Plate 1-42).
Contraction of the diaphragm is mainly responsible for the ﬁrst breath that is often associated with the ﬁrst good cry, but the accessory muscles of respiration offer little assistance at this time. Expansion of the chest wall is slight in the days just after birth. In fact, the thoracic skeleton contains so much ﬂexible cartilage that the chest wall tends to collapse ith each inspiration, especially in premature infants.
When air expands the primitive alveolus during the ﬁrst breath, surfactant (or its precursors stored in type II pneumocytes) is rapidly discharged into the alveolar space (Plate 1-42). This monomolecular layer prevents the development of an air-water interface that other wise would have seven to 14 times as much surface tension as does the air-surfactant interface.
According to the Laplace equation, the pressure required to prevent collapse of a bubble caused by surface tension is inversely proportional to the bubble’s radius. Because the radii of primitive alveoli are very small, the collapsing forces are correspondingly high. Therefore, as the lungs deﬂate, the alveolar radii are further reduced, and the collapsing forces are proportionately increased. Alveoli lacking surfactant thus cannot retain air after expiration, and they collapse (Plate 1-42); infants in whom hyaline membrane disease develops have so little air in their nonexpanded alveoli that at autopsy, the lungs immediately sink when placed in water. Surfactant has the fortunate property of increasing its activity as its surface area is reduced. Therefore, on expiration, the surfactant effectively lowers the alveolar surface tension so that air can be retained.
Without sufﬁcient surfactant, all breaths after the ﬁrst would require great physical effort. A negative pressure as great as 20 cm of water is required to reinﬂate a collapsed primitive alveolus with a radius of 25 μm and a minimal surface tension of 50 dynes/ cm. By contrast, with surfactant present, the alveolus of a deﬂated lung would have a radius of 50 μm, and its minimal surface tension would be only 5 dynes/cm or less. Thus, a negative pressure of only 2 cm of water is all that would be needed to maximally reinﬂate it under these conditions (Plate 1-42). The physical effort a premature infant lacking surfactant requires to breathe is so great that exhaustion of the infant will soon result unless mechanical support is provided.
Although the second breath is much easier for a normal full-term infant, breathing is usually not completely normal until about 40 minutes after birth. The entire lung does not become fully inﬂated as soon as respiration begins, and for the ﬁrst week to 10 days after birth, small parts of the lungs may still remain underinﬂated.
The onset of breathing at birth is accompanied by important and immediate circulatory system readjustments that allow adequate blood ﬂow through the lungs. During fetal life, only about 12% of the cardiac output goes to the lungs because most of the ﬂow from the right ventricle is shunted away from the pulmonary artery to the aorta through the large ductus arteriosus. The ﬂuid-ﬁlled atelectatic lungs create a high resistance in the pulmonary circulation by compressing the blood vessels. Expansion of the lungs induces vasodilation of the pulmonary vessels and results in a sudden increase in blood ﬂow up to 200% or more. This increased pulmonary blood ﬂow, coupled with the cutting off of the large placental circulation when the umbilical cord is tied, actually means that a smaller quantity of blood is propelled a shorter distance within the infant. Therefore, the most crucial event at birth is the expansion of the lungs with the ﬁrst breath of air, rather than the alterations occurring in the vascular system. After respiration has been established, the normal vascular system is well prepared to meet the functional demands imposed on it after birth.