what protein would you expect to find in the fetus to aid in lung inflation?
Clin Perinatol. Writer manuscript; bachelor in PMC 2013 Dec one.
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PMCID: PMC3504352
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Physiology of Transition from intrauterine to Extrauterine Life
Summary
The transition from a fetus to a newborn is the virtually complex accommodation that occurs in homo experience. Lung adaptation requires the coordinated clearance of fetal lung fluid, surfactant secretion, and the onset of consistent breathing. With the removal of the low-force per unit area placenta, the cardiovascular response requires hit changes in blood menstruation, pressures and pulmonary vasodilation. The newborn must also quickly control its energy metabolism and thermoregulation. The primary mediators that both prepare the fetus for birth and support the multi-organ transition are cortisol and catecholamine. Abnormalities in adaptation are oft institute following preterm birth or delivery by cesarean section at term, and many of these infants will need delivery room resuscitation to assist in this transition.
Keywords: Corticosteroids, catecholamines, lung function, cardiovascular, cesarean section
A. Overview
The transition from a fetus to a newborn is the almost complex physiologic adaptation that occurs in human experience. Prior to medicalization of delivery, the transition had to occur quickly for survival of the newborn. All organ systems are involved at some level, but the major immediate adaptations are the establishment of air breathing concurrently with changes in pressures and flows within the cardiovascular system. Other essential adaptations are striking changes in endocrine function, substrate metabolism, and thermogenesis (Box 1). Hospital based deliveries increment the difficulties for transition for many fetuses considering of the frequent use of Cesarean sections, deliveries prior to the onset of labor, rapid clamping of the string, and the anesthetics and analgesics associated with these hospital deliveries. The net result is the frequent need to assist the newborn with the birth transition. Preterm deliveries cause particular difficulties for transition and expose the preterm infant to lung injury from mechanical ventilation. These components of the fetal to neonatal transition volition be reviewed for preterm and term deliveries.
B. Endocrine adaptions to Nascency
1. Cortisol
Cortisol is the major regulatory hormone for concluding maturation of the fetus and for neonatal adaption at birth (1). The "cortisol surge" is initiated with the switch from maternal-transplacental derived corticosteroids to the power of the fetal adrenal to synthesize and release cortisol nether fetal hypothalamic control. Fetal cortisol levels in the human are depression (5–10ug/ml) relative to normal cortisol levels until about 30 weeks gestation. Cortisol levels progressively increase to almost 20ug/ml by about 36 weeks gestation and increase farther to about 45ug/ml prior to labor at term. Cortisol increases further during labor to peak at loftier levels of about 200ug/ml several hours after term delivery. The increase in fetal cortisol throughout late gestation supports multiple physiologic changes that facilitate normal neonatal adaption. For case over the concluding weeks of gestation, the conversion of Tfour to T3 increases, catecholamine release by the adrenal and other chromaffin tissues increases, glucose metabolic pathways in the liver mature, gut digestive chapters increases (enzyme induction), β-adrenergic receptor density increases in many tissues including the heart and the lungs, and the surfactant arrangement in the lungs is induced to mature (ii). Cortisol in association with increasing thyroid hormones activates the sodium pump that clears fetal lung fluid at nascence. These cortisol-modulated changes are ordinarily a progressive process of preparation for birth as the cortisol levels rise prior to birth and so peak soon later on commitment. This normal increment in cortisol supports an integrated transition following nativity (Box two) Cesarean section without labor at term blunts the postnatal rise in cortisol, and the cortisol responses to preterm birth also are attenuated because of unresponsiveness and immaturity of the adrenal gland (3). A particularly stressful delivery can uncover a "functional" adrenal insufficiency if the adrenal gland cannot reply to the increased stress. The very preterm infant may have depression cortisol levels effectually birth with symptoms such as depression blood force per unit area that are responsive to cortisol treatment. In dissimilarity antenatal exposure to chorioamnionitis may increment fetal cortisol levels prior to delivery (4).
2. Catecholamines
Despite the enthusiasm of clinicians to apply catecholamines infusions to increase the blood pressure of very preterm infants post-obit birth, the normal physiology of endogenous catecholamines during and afterwards birth are not reviewed in recent neonatology text books. The term human fetus can release catecholamines (norepinephrine, epinephrine, and dopamine) from adrenal medullary and other sympathetic tissues in response to fetal stresses of various sorts, as evaluated past catecholamine values in cord blood (v). The preterm fetus has college string catecholamine levels than the term fetus, and cesarean commitment is associated with lower cord catecholamine levels. The details of the catecholamine responses to term and preterm labor and commitment were characterized elegantly by Padbury and colleagues in a series of reports outset in the 1980s. Using catheterized fetal sheep that were transitioned through commitment, they demonstrated that norepinephrine and epinephrine increase to high levels within minutes of term delivery and string clamping (six). In contrast the catecholamines increased more slowly post-obit preterm delivery but to levels that were almost 3 fold higher for norepinephrine and 5 fold higher for epinephrine than later on term commitment. (Fig 1) The lower increases in catecholamines in the term newborn were associated with larger increases in plasma glucose and costless fat acids than in the preterm. Careful measurement of thresholds for responses of fetal sheep to epinephrine and norepinephrine infusion demonstrated that the term fetus had lower thresholds and greater responses for blood pressure, glucose, and free fatty acid increases than did the preterm fetuses (7). The catecholamine increases at delivery resulted primarily from adrenal release as adrenalectomy ablated the increment in epinephrine and norepinephrine and blunted blood pressure, glucose and fatty acids increases and pulmonary adaption (8). The fetus is in role protected from the cardiovascular and metabolic effects of stress mediated catecholamine release because the placenta increases catecholamine clearance (9).
Catecholamine response to delivery of term lambs, preterm lambs and term lambs following adrenalectomy. Fetal term (145±2 day gestation) and preterm (130±ane day gestation) lambs were delivered at 0 time following fetal catheter placement. The adrenalectomy lambs had adrenal glands removed at 138±1 days and received continuous cortisol supplemental until delivery at 142 days gestation. Epinephrine and norepinephrine values are expressed relative to the values measured 10 min prior to delivery. A. Epinephrine increased about 12 fold over the -ten min value for the term lambs, and this increase was ablated by adrenalectomy. The increase in epinephrine was much larger for the preterm lambs. B. There was a similar design for the norepinephrine responses. C. Claret pressure level increased in term and preterm animals only not in term adrenalectomized animals. D, East. Glucose and gratuitous fatty acids in claret increased more than for term than preterm lambs with minimal increases following adrenalectomy. Information from Padbury et al (6, 8).
These studies demonstrate the importance of a large catecholamine release as a normal response to the nascency procedure for fetal adaption. The catecholamine surge is primarily responsible for the increment in blood pressure post-obit nativity, adaption of free energy metabolism with back up of the primary substrates for metabolism later on birth – glucose and fat acids, and for initiating thermogenesis from brown fat. The preterm secretes more catecholamines considering the organ systems are less responsive – higher concentration thresholds for response and lower responses. Cesarean section of the unlabored fetus depresses catecholamine release. Catecholamine release at nascency tin can be viewed as the "gas" that drives the adaptive responses. Nevertheless, fetal exposure to cortisol is the "carburetor" that is the strong regulator of the responses of the newborn to catecholamines. Antenatal corticosteroid treatments decrease catecholamine levels in preterm infants compared with unexposed infants (10). Cortisol treatments of fetal sheep also greatly subtract the postnatal increase in both norepinephrine and epinephrine (eleven) (Fig 2). Still, the animals had better cardiovascular and metabolic accommodation to preterm nascence. These studies demonstrate the importance of both cortisol and catecholamines to adaptations to birth.
Antenatal cortisol alters postnatal catecholamine secretion and blood pressure responses to delivery in preterm lambs. Fetal sheep had vascular catheters placed at 122–125 days gestation, and the fetuses were randomized to a sixty hr cortisol or vehicle infusion at 128 days gestation. The fetuses were delivered and supported on mechanical ventilation. During transition, epinephrine (A) and norepinephrine (B) increased more in command lambs than in cortisol-exposed lambs. Nevertheless, blood force per unit area (c) was higher in the cortisol-exposed newborns than the command animals. Data from Stein et al (11).
Other vasoactive substances such equally angiotensin II and renin also increase greatly at birth in association with increases in claret pressure (12). The net effect is the normal exposure of the newborn to very high levels of multiple vasoactive substances to support adaption. The bones physiology of these agents was described over 20 years ago in beast models with confirmation in term and moderately preterm infants. Much of this piece of work could be profitably repeated for extremely depression nascence weight infants to better empathise how their catecholamines responses to preterm birth may be dysregulated and to ameliorate target therapies. For example, Ezaki and colleagues recently reported that very low birth weight infants with severe hypotension had a decreased conversion of dopamine to norepinephrine (13).
3. Thyroid Hormones
The thyroid centrality matures in tardily gestation in parallel to the increment in cortisol with increased thyroid simulating hormone (TSH), Tthree and Tiv levels, and decreased rT3 levels equally term approaches (14). Post-obit term nascence, TSH quickly peaks and decreases, and T3 and Tiv increment in response primarily to the increased cortisol, to string clamping and to the cold stimulus of nascence. Acute ablation of thyroid function at birth did not profoundly alter thermogenesis or cardiovascular adaptation in experimental animals. However, inhibition of thyroid function more than chronically prior to birth did interfere with postnatal cardiovascular adaptation and thermogenesis in newborn lambs (15). These results demonstrate a supportive and preparative part for thyroid hormones for birth rather than as astute modulators of endocrine adaptation to birth. For example, fetal infusions of T3 and cortisol can activate the Na+, Thousand+, ATPase that helps clear fetal lung fluid later on nascency (16). Term infants with congenital hypothyroidism generally do not accept abnormalities of early neonatal adaptation that are evident in the controlled environment of hospital deliveries. Very preterm infants take a blunted thyroid functional transition from fetal to newborn life with very low levels of plasma T3 and T4 relative to term infants. The effects of the depressed thyroid function on the early postnatal transition in the preterm are unclear but probably contribute to the depressed adaptive behavior of the preterm.
C. Metabolic Adaptations
one. Energy Metabolism
Fetal energy needs are supported primarily by the transplacental transfer of glucose to the fetus (17). Although the fetal liver is capable of gluconeogenesis from early gestation, gluconeogenesis is minimal during normal fetal homeostasis. Rather as term approaches glucose and other substrates are being stored as glycogen and fat in anticipation of birth in the high insulin and low glycogen fetal environment. With commitment and string clamping, the maternal glucose supply is removed, and plasma glucose levels normally fall over the early hours after birth. The glucose and free fat acid levels are accompanied by a fall in insulin, and increase in glycogen, the normal glucose homeostatic hormones. However, the big catecholamine release and increase in cortisol are probably the major acute regulators of plasma glucose and free fat acid levels in the firsthand newborn flow. For example, adrenalectomy of the fetal sheep who received cortisol replacement blunts and delays the post-delivery increase in plasma gratuitous fat acids and results in persistent hypoglycemia (8) (Fig. 1). Fetal treatments with cortisol decrease the catecholamine surge at birth, but increase both plasma glucose, and free fatty acids relative to control animals (xi) (Fig. 2). Therefore, the metabolic adaptations to birth are regulated by acute changes in insulin and glucogen, but as well past catecholamines and cortisol in term infants.
Cortisol and catecholamine responses to preterm birth are dysregulated with less cortisol and more than catecholamine release. The preterm also has minimal glycogen and fat stores (17). Therefore, the availability of free energy substrates during the nascence transition will be severely challenging for the preterm. This aspect of adaptation in the immediate newborn period is treated routinely with glucose infusion to forestall hypoglycemia. Still, the integrated effects of the endocrine abnormalities and responses to glucose infusions take not been well described in extremely low nascency weight infants.
two. Thermoregulation
Fetal body temperature is about 0.5°C above the maternal temperature. Although the fetus produces heat from metabolism, that heat is effectively dissipated across the placenta and fetal membranes. At birth the sympathetic release resulting from the redundant stimuli of increased oxygenation, ventilation, string occlusion and a cold stimulus to the skin activates thermogenesis by brown adipose tissue (18). This thermogenic response potential has developed during late gestation by an increase in brown adipose tissue effectually the kidney and in the intrascapular areas of the dorsum to get about 1% of fetal weight at term (19). Chocolate-brown adipose tissue generates estrus by uncoupling oxidative metabolism from ATP synthesis in the mitochondria, with the release of estrus (xviii). This uncoupling is mediated past the mitochondrial membrane protein uncoupling protein 1 (UCP1) which is activated by norepinephrine released past the sympathetic innervation of brown adipose tissue. UCP1 levels increase in the brownish adipose tissue during late gestation in response to a local conversion of T4 to T3 and to induction of UCP1 synthesis in response to the increasing cortisol levels in the fetal plasma as term approaches. Thus the aforementioned hormones that attune the fetal preparation for birth and the transition period are key to thermogenesis by dark-brown adipose tissue. The term infant as well tin generate some heat past shivering thermogenesis, which is an increase in not-purposeful skeletal muscle activity signaled by cutaneous nervus endings via primal motor neurons. Shivering thermogenesis seems to be of secondary importance to the newborn human. The preterm human is at a major disadvantage for thermoregulation following nascency equally brown adipose tissue has not developed in quantity or response potential for a cold stress.
D. Cardiovascular Adaptations
Profound changes in the cardiovascular organization occur after delivery in response to removal of the depression resistance placenta every bit the source of fetal gas exchange and nutrition. Much of our knowledge regarding cardiovascular adaptation after birth is based on studies in animals, especially the sheep. The major changes are an increase in the cardiac output and transition of fetal apportionment to an developed blazon of circulation. Increased cardiac output is required to provide for increases in basal metabolism, work of breathing, and thermogenesis. In the close-to-term fetus, the combined ventricular output is most 450 mL/kg/min, with the right ventricular output accounting for 2/3rd of the cardiac output and the left ventricle ejecting i/tertiary of the cardiac output (twenty). Presently after birth, the circulation changes from "parallel" to "series", where the correct ventricular output equals the left ventricular output. The cardiac output virtually doubles afterward nascence to most 400 mL/kg/min (for the right and the left ventricle). This marked increase in cardiac output parallels closely the rise in oxygen consumption. The organs experiencing increased blood catamenia after birth are the lungs, heart, kidney and the gastrointestinal tract (21). Although the precise mechanisms mediating increased cardiac output after nascence are not known, the increment in cortisol and vasoactive hormones, that include catecholamines, the rennin-angiotensin organization, vasopressin and thyroid hormone contribute to back up of blood pressure and cardiovascular function (20).
In the fetus, the relatively well-oxygenated blood from the placenta is delivered via the umbilical cord and ductus venous. This ductus venous blood enters the right atrium from the inferior vena cava and is directed preferentially to the left atrium by the foramen ovule and subsequently delivered preferentially to the brain and the coronary circulation by the fetal left ventricle. The right ventricle is the predominant ventricle in the fetus, and most of the right ventricular output goes to the descending aorta via the ductus arteriosus since very little blood enters the pulmonary circulation. With birth and removal of the low resistance placenta, blood flow increases to the pulmonary circulation. Soon after birth functional closure of ductus arteriosus begins. The mechanisms contributing to the high pulmonary vascular resistance in the fetal lung are primarily the depression oxygen tension and depression pulmonary blood period which suppresses the synthesis and release of nitric oxide (NO) and prostaglandin I2 from the pulmonary endothelium (22). Fetal exposure to hypoxia will increment the already loftier pulmonary vascular resistance and hyperoxia will decrease pulmonary vascular resistance and increase fetal pulmonary claret flow (23). Experimentally, ventilation of the fetal lung without changing oxygenation will decrease pulmonary vascular resistance and increase pulmonary blood flow by 400%. With delivery, ventilation, and oxygenation, NO and PGI2 increase with a rapid fall in pulmonary vascular resistance. The use of supplemental oxygen for the initiation of ventilation will cause pulmonary vascular resistance to decrease more rapidly with the resultant more rapid increase in pulmonary claret flow (24). Withal, there is no do good in systemic oxygenation, and the pulmonary vessels subsequently go more refractory to dilation by NO or acetylcholine.
The cardiovascular transition at nascence besides is modulated past corticosteroids. Exposure of fetal sheep to betamethasone increased fetal pulmonary blood flow but did not modify postnatal pulmonary vasodilation in preterm sheep (25). Center office subsequently preterm nativity is improved by antenatal exposure to corticosteroids (7). The fetal and newborn blood pressures increase, equally does cardiac output and left ventricular contractibility. These effects are partially explained by an increase in beta-receptor signaling to an increase in cyclic AMP. Similarly adrenalectomy ablates the increase in blood pressure that unremarkably occurs at nascency (8) (Fig. 2). Thus, although at that place are specific mediators such as NO and PGI2 that facilitate cardiovascular transition, the consistent theme is that the same mediators – corticosteroids and catecholines also facilitate this transition.
The normal oxygen saturation of fetal blood in the left atrium is about 65% (26). During labor the human fetus tolerates oxygen saturations as depression equally 30% without developing acidosis (27). After birth, the pre-ductal saturation in normal term infants gradually increases to about 90% at 5 minutes of age (28). This knowledge is important to avoid unnecessary assistants of supplemental oxygen during resuscitation.
E. Lung Adaptations
1. Fetal Lung Fluid
The most essential adaptation to birth is the initiation of breathing, but the airspaces of the fetal lung are filled with fetal lung fluid. What is fetal lung fluid and how is it cleared from the airspaces? Fetal lung fluid is secreted past the airway epithelium equally a filtrate of the interstitial fluid of the lung by the active ship of chloride (29). Consequently the chloride content of fetal lung fluid is high and poly peptide content is very low. The product rate is loftier, although direct measurements are not bachelor for the human fetus. The volume of lung fluid of the fetal sheep increases from mid gestation and the secretion rate increases to nigh 4ml/kg/hour by tardily gestation (30). Production and maintenance of the normal volume of fetal lung fluid is essential for normal lung growth. The electrochemical slope for the production of fetal lung fluid is substantial and can over-distend the airspaces. This behavior of the product of fetal lung fluid is used to advantage to obstruct the trachea, which volition distend the hypoplastic lungs of fetuses with diaphragmatic hernia.
In experiments with fetal rabbits and sheep, Bland and colleagues demonstrated that fetal lung fluid production decreased prior to the onset of labor, and the volume of lung fluid in the airspaces decreased from well-nigh 25 ml/kg to xviii ml/kg (31). The fetal lung fluid volume decreased further with labor such that the airways contained about 10 ml/kg at commitment. Harding and Hooper measured an airspace fluid volume of almost 50 ml/kg in fetal sheep at term and without labor, which is about twice the functional residual chapters of the newborn term lamb after accommodation to air breathing (30).
The endocrine adaptations that begin earlier delivery are critical to fluid clearance. Cortisol, thyroid hormones and catecholamines all increase and shut down the active chloride mediated secretion of fetal lung fluid and activate the basal Na+, One thousand+, ATPase of blazon II cells on the airway epithelium. Sodium in fetal lung fluid enters the apical surfaces of type II cells and is pumped into the interstitium with water and other electrolytes following passively, thus removing fluid from the airways. In preterm fetal sheep, infusion of cortisol and T3 will activate the sodium pump, which normally occurs at term(16). The components of fetal lung fluid then are cleared directly into the vasculature or via lymphatics from the lung interstitium over many hours.
This clearance of a large volume of airspace fluid is remarkably efficient usually. The essential contribution of activation of Na+ transport was demonstrated by respiratory distress in animals from amiloride inhibition of the Na+, Thousand+, and ATPase. Mice with defective Na+ transporters will die post-obit delivery because of failure to clear fetal lung fluid (32). The frequent clinical scenario where retained lung fluid contributes to poor respiratory adaptation is the operative delivery of infants who were not in labor. These infants do not increment their oxygen saturations as quickly every bit vaginally delivered term infants (28), and in that location is an increased incidence of transient tachypnea of the newborn and other respiratory morbidities (29)(Table 1). In experimental studies in sheep, the increased book of fetal lung fluid interferes with respiratory adaptation, and vaginal commitment facilitates adaptation relative to operative delivery at equivalent volumes of fetal lung fluid (33).
Table 1
respiratory morbidities are increased by Cesarean section deliveries without labor relative to vaginal births after a previous Cesarean section.†
| Cesarean Section | Vaginal Birth | |
|---|---|---|
| Number | 15212 | 8336 |
| Respiratory Distress Syndrome | 2.1% | 1.4%* |
| Transient tachypnea | 4.1% | 1.9%* |
| Oxygen therapy | 4.four% | two.v%* |
| Mechanical ventilation | i.three% | 0.8%* |
Transient tachypnea of the newborn is most frequent in belatedly preterm infants. This syndrome is thought to direct consequence from ineffective clearance of fetal lung fluid because of inadequate Na+ transport, either because of decreased numbers of transporters or lack of activation (34). Preterm infants also have decreased Na+ ship, and belatedly preterm infants with transient tachypnea of the newborn have low amounts of surfactant (35). Thus, the baby with transient tachypnea of the newborn has immaturity of Na+ transport and a tendency for surfactant deficiency while the infant with RDS has more than astringent surfactant deficiency that also includes immature Na+ transport. These ii diseases probably are, in fact, a continuum of these two abnormalities from mild to astringent.
A hypothetical calculation may help the clinician to empathise why lung fluid can compromise neonatal adaptation. If the 3 kg term infant has near 30 ml/kg of fetal lung fluid in the airspaces at Cesarean commitment without labor and that babe is intubated, and so no fluid tin passively drain from the lungs. Assuming that the blood book of this infant is lxxx ml/kg and the hematocrit is 50 %, so the plasma volume is 40ml/kg. The fetal lung fluid will motility from the airspace to the lung interstitium initially interfering with lung mechanics and gas exchange. This fluid then volition be transferred to the plasma, which if this occurred acutely would expand plasma volume from 40 ml/kg to 70 ml/kg. This transfer occurs over hours in reality. Nevertheless, the fetal lung fluid volume that must exist accommodated during neonatal accommodation is added stress for the newborn.
2. Breathing at Nativity
The essential component to neonatal accommodation to nativity is the maintenance of acceptable respiratory effort. The stimuli changing the fetal breathing pattern nearly instantaneously to continuous breathing remain incompletely defined and probably are redundant as are the stimuli for other adaptations to birth. Nigh of the information virtually fetal breathing and it's transition afterward nascency is from quite quondam studies using fetal sheep models, with some verification in the human being fetus (36). The fetal land in utero can be classified into REM sleep and quiet sleep with no clear periods of wakefulness. During REM sleep, the fetus has irregular breathing activity characterized past long inspiratory and expiratory times with movement of variable volumes of fetal lung fluid (mixed with amniotic fluid) into and out of the lung. Fetal animate, swallowing and licking activities are confined to REM sleep, with minimal movements during serenity slumber. Fetal hypoxia abolishes fetal breathing while high fetal PO2 values stimulate fetal breathing. With birth, the fetal sheep will not breathe consistently until the string is clamped. This observation has generated the hypothesis that animate is suppressed by a placentally derived substance except in the REM land. Fetal sheep given prostaglandin E2 infusions stop breathing, and treatment with prostaglandin synthetase inhibitors such as indomethacin cause continuous fetal animate (37). The net result is that the normal fetal to neonatal transition results in the rapid onset of vigorous breathing considering of the combined stimuli of string clamping (and the probable removal of rapidly catabolized prostaglandins that suppress breathing), diffuse tactile and common cold stimuli that act centrally, and changes in PCOii and PO2 levels in the claret. The newborn volition non initiate animate if hypoxia is astringent. Remarkably, in the absence of hypoxia, virtually all term infants will effectively initiate breathing. The majority of very preterm infants likewise will successfully initiate breathing if given opportunity (38).
3. Surfactant and Lung Accommodation
The adequate development of the fetal lung to back up gas exchange is the essential adaptation in grooming for birth. During the last third of gestation the fetal lung septates into most 4 1000000 distal saccules (respiratory bronchioles and alveolar ducts) derived from the 17 generations of airways by about 32 weeks and then further separates to grade alveoli (39). In parallel the lung parenchymal tissue mass decreases relative to body weight such that the potential gas volume of the airways and alveoli increase profoundly. Concurrently from about 22 weeks gestational historic period surfactant lipid and the lipophilic proteins SP-B and SP-C begin to exist synthesized and aggregated into lamellar bodies in the maturing type Two cells (40). The lamellar bodies are the storage and secretory packets for the essential biophysically active components of surfactant. As the lung matures, more and more of the lamellar bodies are released into fetal lung fluid and later on mix with amniotic fluid or are swallowed. By term blazon 2 cells in the fetal lung contain much more surfactant than does the adult lung, and this large pool of surfactant is poised for release prior to and at delivery.
As delivery approaches, fetal lung fluid secretion ceases (see above) and fetal lung fluid book may subtract. Simultaneously, surfactant is secreted into the fetal lung fluid with labor, which will increase the surfactant concentration in the fetal lung fluid(41). The presumed mediators of this secretion are the increases in catecholamines that stimulate Beta-receptors. Purinergic agonists such as ATP may likewise promote this pre-commitment secretion. Subsequently the initiation of ventilation following nascency causes alveolar stretch and therefore deformations of blazon 2 cells, another secretion signal. The large increase in catecholamines post-obit delivery probably further stimulates surfactant secretion. In term animals shortly afterward nativity, the alveolar pool size of surfactant is well-nigh 100 mg/kg. This value is v to 20 fold higher than the amount of surfactant in the alveoli of healthy adult animals or humans. Although no measurements are bachelor for the term human, a similar value is likely based on the amount of surfactant present in amniotic fluid at term. Thus the term fetus is bodacious of having adequate surfactant for the transition to air animate (42). The loftier surfactant puddle size decreases to adult levels over the kickoff week of life in animate being models. Post-obit operative delivery of preterm lambs, a stable surfactant puddle of alveolar surfactant is achieved in about 3 hours despite no labor (43). Although there has been no surfactant secretion prior to commitment, the endocrine and lung stretch effects allow the unlabored fetal lung to chop-chop adapt to air breathing. The secretory events concurrent with birth practise not appreciably deplete surfactant stores in type Two cells because surfactant synthesis and packaging into lamellar bodies continues and the surfactant that has been secreted also is recycled back into type II cells for secretion equally needed (44).
The preterm lung has several disadvantages for transition to air breathing. The structurally young lung has less potential lung gas volume relative to body weight and metabolic needs, and secretion of fetal lung fluid may not terminate prior to and later commitment, which will delay clearance of fetal lung fluid. Further, the amount of surfactant stored in blazon Ii cells is depression, and thus less surfactant can be secreted in response to birth. The result is a lower concentration of surfactant to course a surface film and stabilize the lung. Surprisingly many preterm lungs can adapt, perhaps with a chip of help from continuous positive airway pressure. The small alveolar surfactant puddle size need not exist more than about 5 mg/kg for the preterm lamb supported by continuous positive airway pressure (45). This result illustrates that the term infant has large excesses of surfactant to clinch a successful transition to air breathing.
four. Injury of the Preterm Lung
The transition from a fetus to a newborn requires the initiation of breathing, clearance of fluid from airways, and ventilation of the distal airspaces. Normal newborns inflate their lungs at birth by generating big negative pressure breaths, which pull the lung fluid from the airways into the distal airspaces. The infant continues to clear lung fluid with subsequent inflations (46, 47). Spontaneously animate newborn rabbits speedily movement fluid from their airways to the alveoli and subsequently into the interstitium at birth, with 50% of lung aeration occurring with the first iii breaths. They use an increased inspiratory volume to expiratory volume ratio to achieve functional residual capacity (FRC)(47). The majority of the clearance of fetal lung fluid occurs during inspiration, with a return of lung fluid into airways during expiration when PEEP is not used(47). In newborn preterm rabbits, the utilize of PEEP during initiation of ventilation facilitates the development of FRC and surfactant treatment creates more uniformed distribution of FRC (48, 49)
Many preterm or asphyxiated term infants do not have adequate spontaneous respirations at nascence and require positive pressure ventilation. Premature infants have immature lungs that are more difficult to ventilate due to inadequate surfactant to decrease surface tension and maintain FRC. The airways in the preterm lung stretch with positive force per unit area ventilation and the decreased surfactant pools contribute to non-uniform expansion of the lung with areas of focal over- distension and atelectasis (50, 51). The initial ventilation of the preterm lung volition occur before much of the endogenous surfactant is secreted and surfactant therapy cannot practically exist given before the initiation of ventilation. The movement of fluid at the air interface across epithelial cells generates high surface forces that misconstrue the cells and injure the epithelium of the small-scale airways, a feature prominent in infants in the lungs of infants who accept died of RDS (52, 53). CPAP or PEEP should minimize the movement of fluid in the airways, and surfactant will lower the pressure level required to move fluid into the pocket-sized airways and subtract the injury from fluid movement (48, 54). As few as six large tidal volume breaths at birth can eliminate the surfactant treatment in responses of preterm sheep because of acute lung injury (55). In preterm sheep models, nosotros demonstrated that airway stretch occurs during initiation of ventilation and initial injury is localized primarily to the bronchi and bronchioles (53). Astute stage response genes involved in inflammation, angiogenesis, vascular remodeling, and apoptosis were activated within the lung, and immunologically active proteins (HSP70, HSP60) were released past the airway epithelium into the airspace fluid (56).
As with preterm sheep, ventilated very low nativity weight (VLBW) infants have increased pro-inflammatory cytokines (IL-8, IL-1β, IL-half-dozen, and MCP-1) in tracheal aspirates soon later birth, which correlate with an increased risk of BPD (57). Ventilation of preterm infants with respiratory distress increased plasma levels of IL-1β, IL-8 and TNF-α and decreased levels of the anti-inflammatory cytokine IL-10 (58). We previously demonstrated that regardless of the tidal volume or PEEP used, initiation of ventilation in fluid-filled, surfactant deficient preterm lambs is injurious (56, 59). Minor increases in the endogenous surfactant pool size can increase the uniformity of lung expansion and thus decrease focal injury (lx). The preterm lung is likely at take a chance for small and big airway injury from initiation of ventilation during resuscitation.
Acknowledgments
Support: NIH R01-HD072842 (PI-Jobe), K08-HL097085 (Hillman-PI)
Footnotes
Disharmonize of interest: The authors have no conflicts of interest with this manuscript.
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