perinatal and pediatric respiratory care ch. 1 fetal lung development

Perinatal and Pediatric Perinatal and Pediatric Respiratory CareRespiratory Care

Ch. 1 Ch. 1

Fetal Lung DevelopmentFetal Lung Development

•https://www.youtube.com/watch?v=RS1ti23SUSw

Introduction• The bronchial tree develops by week 16 of

intrauterine life• Birth does not signal the end of lung

development• After birth the alveoli develop in increasing

numbers until the age of 8 years, and increase in size until growth of the chest wall is finished

• Preacinar arteries and veins develop after the alveoli are generated

Introduction

• Term infants have approximately 50 million alveoli which undergo increases in surface area and number, increasing to 250 million at maturity

• There are more than 40 cell types in the lung• There are 5 well recognized stages of lung

development: Embryonal, pseudoglandular, canalicular, saccular and alveolar

Stages of Fetal DevelopmentEmbryonal Phase (Day 26 to Day 52)

Embryonal Stage (Day 26 to Day 52)

• Covers first two months of gestation• The lung emerges as a bud from the pharynx 26 days

after conception• This bud elongates and forms two bronchial buds and

the trachea which then separates from the esophagus through the development of the transeoesophageal septum

• Growth factors such as fibroblasts mediate morphogenesis of the tubular epithelium which result in airway branching (10 on the right and 9 on the left)

• http://commons.wikimedia.org/wiki/File:Shape-Self-Regulation-in-Early-Lung-Morphogenesis-pone.0036925.s007.ogv

• http://www.youtube.com/watch?v=_y4-bfWB5C4

Transesophageal fistula (TEF)

• Malformation of septum during embryonal development

• Causes a congenital defect which can lead to stomach content aspiration

• Treatment involves surgical repair• https://www.youtube.com/watch?v=A-

WlveIxOKM


• The left and right pulmonary arteries form plexuses (A plexus is a branching network of axons outside of the central nervous system)

• Left and right pulmonary veins start to develop about 5 weeks from the SA node area of the heart

• Respiratory epithelium develops from the foregut bud; The foregut is the anterior part of the alimentary canal, from the mouth to the duodenum at the entrance of the bile duct. At this point it is continuous with the midgut. Pain in the foregut is typically referred to the epigastric region, just below the intersection of the ribs.


• Respiratory epithelium is a type of epithelium found lining the respiratory tract, where it serves to moisten and protect the airways. It also functions as a barrier to potential pathogens and foreign particles, preventing infection and tissue injury by action of the mucociliary escalator

• Respiratory epithelium also lines the nasal cavities and the paranasal sinuses in continuity with the mucosa of the nasal cavity.

• Respiratory epithelium is pseudostratified, which means that on histological section, resembles layers upon a basement membrane. In reality, each cell is in contact with the basement membrane.


• Three primary germ layers– Endoderm– Mesoderm– Ectoderm– http://www.youtube.com/watch?

v=UTNBq5IUtwoRespiratory epithelium derives from the

endodermal layer construct of the foregut and interacts with the bronchial mesoderm

Embryonal Stage (Day 26 to Day 52)• The Mesenchyme is a network of embroyic connective

tissue in the mesoderm which causes development of the pulmonary interstitium, smooth muscle, blood vessels, and cartilage

• Mesenchyme is a type of undifferentiated loose connective tissue that is derived mostly from mesoderm, although some is derived from other germ layers

• The term mesenchyme essentially refers to the morphology of embryonic cells, however, they do persist as stem cells into adulthood. Mesenchymal cells are able to develop into the tissues of the lymphatic and circulatory systems, as well as connective tissues throughout the body, such as bone and cartilage. A sarcoma is a cancer of mesenchymal cells.

Embryonal Stage (Day 26 to Day 52)• Mesenchyme is characterized morphologically

by a prominent ground substance matrix containing a loose aggregate of reticular fibrils and unspecialized cells

• Mesenchymal cells can migrate easily, in contrast to epithelial cells, which lack mobility and are organized into closely adherent sheets, are polygonal in shape, and are polarized in an apical-basal orientation.

Embryonal Phase (Day 26 to Day 52)

• Review: – Lung and esophagus emerge and develop– Pulmonary arteries and veins develop– Pulmonary interstitium, smooth muscle, blood

vessels, and cartilage develop

Stages of Fetal DevelopmentPseudoglandular Phases (Day 52 to Week 16)

• Lungs have gland like appearance• Histologic structures are separated by

mescenchyme. • Second month to sixteenth week• Subdividing of conducting airways• Acinus may appear• Cilia are seen on the epithelium• Development of goblet, submucosal

glands, and airway cartilage

123

Lung mesenchymaType II pneumocytes Capillaries

Pseudoglandular Phases (Day 52 to Week 16)

• Extensive subdivsion of conducting airway system (as a person grows, the size of these conducting airways increases but the number does not)

• The entire air-conducting bronchial tree up to the terminal bronchioli are set down in this phase (16 generations). Recent morphometric studies have shown that with the end of the pseudoglandular phase 20 generations are partially present in the lungs, which means that at this point in time the respiratory ducts have already been formed.


• Terminal bronchioles differentiate into the respiratory bronchioles and alveolar ducts

• Gas exchanging pulmonary acini/terminal respiratory units are also laid down

• Growth factors and chemical mediators develop tracheal epithelium into respiratory type II cells

• Also Ciliated epithelium and of the secretory cells develop, the first ciliated epithelial cells can be found in the 13th week of pregnancy

Primary ciliary dyskinesia (PCD),• also known as immotile ciliary syndrome, is a

rare, ciliopathic, autosomal recessive genetic disorder that causes a defect in the action of the cilia lining the respiratory tract (lower and upper, sinuses, Eustachian tube, middle ear) and fallopian tube, and also of the flagella of sperm in males.

• Malformation occurs in the Pseudoglandular Phases http://www.youtube.com/watch?v=RakqKYHenxU


• Goblet cells develop and appear in the bronchial epithelium at 13-14 weeks and submucosal glands arise as solid buds from basal layers of the surface epithelium at 15-16 weeks

• Smooth muscle cells derive from the primitive mesenchyme at the end of week 7 and by week 12 form the posterior wall of the large bronchi


• The development of cartilage is present at 24 weeks, but may develop earlier in a immature form

• Lymphatics appear in the hilar region of the lung during week 8

• The cells developed during this stage contain glycogen (Glycogen is a multibranched polysaccharide that serves as a form of energy storage in humans, glycogen is made and stored primarily in the cells of the liver and the muscles, and functions as the secondary long-term energy storage (with the primary energy stores being fats held in adipose tissue).


• By the end of this stage, the airways, arteries, and veins have developed in the pattern corresponding to that found in an adult

• By 14 weeks the immune system develops, including T lymphocytes

• Fetal immune responses to allergens develop early and can be detected in cord blood (fetus is exposed through the placenta or fetal gut by swallowing amniotic fluid)


• Review– Conducting airways further develop– Respiratory airways develop– Cilia, cartilage, goblet cells and submucosal glands

develop– Immune system develops, lymphatic system

appears

Stages of Fetal DevelopmentCanalicular Phase (Week 17 to week 26)

• Growth of vascular bed – Air exchange

• Capillaries have sufficient surface area• Proximity to alveoli• Lobules containing 3-5 terminal bronchioles,

25,000 terminal bronchioles by 28 weeks• Extrauterine viability

– 22 to 24 weeks– Vascularity development– Surfactant production creating a air-blood

barrier


• Appearance of vascular channels/capillaries at 20 weeks, forming a capillary network around air passages, surfactant also develops (capillaries and surfactant = this is what makes them viable for life at around 22-24 weeks)

• Blood vessels grow alongside conducting airways and undergo muscularization

• Bronchial artery system develops

123

Type I pneumocytes Type II pneumocytes Capillaries


• Along the acinus, which develops from the terminal bronchiolus, an invasion of capillaries into the mesenchyma occurs. The capillaries surround the acini and thus form the foundation for the later exchange of gases. The lumen of the tubules becomes wider and a part of the epithelial cells get to be flatter. From the cubic type II pneumocytes develop the flattened type I pneumocytes


• A sufficient differentiation of the type II pneumocytes into the type I pneumocytes and the proliferation of the capillaries into the mesenchyma marks an important step towards the fetus being able to survive outside the uterus after roughly the 24th week of pregnancy.

• The first breathing movement can be registered • They are controlled by a breathing center in the brain

stem. Nevertheless, these breathing movements are paradoxical in that when the diaphragm contracts, the thorax moves inwardly and vice versa.

Stages of Fetal DevelopmentSaccular Stage (Week 26 to week 36)

• The major changes that occur during the saccular stage are further compression of the intervening interstitium, thinning of the epithelium, and the beginning of alveolar septation, with the formation of small mesenchymal ridges

Stages of Fetal DevelopmentSaccular Stage (Week 26 to week 36)

• There is lengthening and widening of saccules distal to the terminal bronchioles and the addition of the last generations of future alveolar spaces.

• Continual differentiation of type I and II alveolar cells occurs during this period, so that the alveolar epithelial cells become the most abundant epithelial cells in the lung. The flattened type I alveolar cells make up the majority of these cells.

• Type II cells, ultrastructurally distinguished by their production of lamellar bodies, expand in size and number, with increased storage of surfactant lipids and less cytoplasmic glycogen

Stages of Fetal DevelopmentAlveolar Stage (Week 36 to term)

• Not easily distinguishable from Saccular phases

• About 36 weeks to 18 months postnatal

Stages of Fetal DevelopmentAlveolar Stage (Week 36 to term)

• Several million alveoli form before birth although this final stage of lung development primarily occurs during postnatal life

• The beginning of this stage is not sharply defined• Alveolar formation is closely linked to the deposition of• elastin in the saccular lung.• Terminal saccules become invaginated by protrusions

from the wall of epithelial cells and contain a double-walled capillary system

• These protrusions elongate and thin, forming primitive alveoli that at first resemble shallow cups and then become deeper as development continues.

Postnatal Lung Development

• Continued growth of lungs and number of alveoli– 80% of alveoli develop after birth

• Factors affecting lung development– Hypoxia or hyperoxia– Nutrition– Maternal smoking

Postnatal Lung Development

• During the postnatal phase, lung growth is geometric, and there is no increase in airway number. There is proportionately less growth in the conducting airways in comparison with alveolar-capillary tissue. Estimates of the number of alveoli at birth vary widely, but an average of 50 million is generally accepted

Postnatal Lung Development• Alveoli greatly increase in number after birth, to• reach the adult range of 300 million by 2 years of

age and the surface area of 75 to 100 m2 by adulthood.

• There is substantial remodeling of the parenchyma after birth, with morphologic changes in the septa.

• Alveolarization occurs through the formation of numerous short, blunt tissue crests or ridges, and their protrusion into alveolar sacs increases the internal surface of the lung.

Pulmonary Hypoplasia

• Causes of decreased lung development– Compression– Oligohydramnios– Decreased respiration– Metabolic disorders

Pulmonary hypoplasia

• Pulmonary hypoplasia is incomplete development of the lungs, resulting in an abnormally low number or size of bronchopulmonary segments or alveoli. A congenital malformation, it most often occurs secondary to other fetal abnormalities that interfere with normal development of the lungs. Primary (idiopathic) pulmonary hypoplasia is rare and usually not associated with other maternal or fetal abnormalities.

Oligohydramnios

• The amniotic fluid is part of the baby’s life support system . It protects your baby and aids in the development of muscles, limbs, lungs and digestive system.

• Amniotic fluid is produced soon after the amniotic sac forms at about 12 days after conception. It is first made up of water that is provided by the mother, and then around 20 weeks fetal urine becomes the primary substance. As the baby grows he or she will move and tumble in the womb with the help of the amniotic fluid. In the second trimester the baby will begin to breathe and swallow the amniotic fluid. In some cases the amniotic fluid may measure too low or too high. If the measurement of amniotic fluid is too low it is called oligohydramnios. If the measurement of amniotic fluid is too high it is called polyhydramnios.

Oligohydramnios• Oligohydramnios is the condition of having too

little amniotic fluid. Doctors can measure the amount of fluid through a few different methods, most commonly through amniotic fluid index (AFI) evaluation or deep pocket measurements. If an AFI shows a fluid level of less than 5 centimeters (or less than the 5th percentile), the absence of a fluid pocket 2-3 cm in depth, or a fluid volume of less than 500mL at 32-36 weeks gestation, then a diagnosis of oligohydramnios would be suspected.

Oligohydramnios• About 8% of pregnant women can have low levels

of amniotic fluid, with about 4% being diagnosed with oligohydramnios. It can occur at any time during pregnancy, but it is most common during the last trimester. If a woman is past her due date by two weeks or more, she may be at risk for low amniotic fluid levels since fluids can decrease by half once she reaches 42 weeks gestation. Oligohydramnios can cause complications in about 12% of pregnancies that go past 41 weeks.

Oligohydramnios Causes

• Birth defects – Problems with the development of the kidneys or urinary tract which could cause little urine production, leading to low levels of amniotic fluid.

• Placental problems – If the placenta is not providing enough blood and nutrients to the baby, then the baby may stop recycling fluid.

• Leaking or rupture of membranes –This may be a gush of fluid or a slow constant trickle of fluid. This is due to a tear in the membrane. Premature rupture of membranes (PROM) can also result in low amniotic fluid levels.

Oligohydramnios • The risks associated with oligohydramnios often depend on

the gestation of the pregnancy. The amniotic fluid is essential for the development of muscles, limbs, lungs, and the digestive system. In the second trimester, the baby begins to breathe and swallow the fluid to help their lungs grow and mature. The amniotic fluid also helps the baby develop muscles and limbs by providing plenty of room to move around. If oligohydramnios is detected in the first half of pregnancy, the complications can be more serious and include:

• Compression of fetal organs resulting in birth defects • Increased chance of miscarriage or stillbirth • http://www.youtube.com/watch?v=nDQguqtooBM

Other Causes of Pulmonary Hypoplasia

• Prenatal and postnatal nutritional deprivation• High concentrations of oxygen are toxic to

pulmonary tissue; leads to development of bronchopulmonary dysplasia

• Cigarette smoke• Chest wall compression (diaphragmatic

hernia)• Metabolic issues

CDH

• http://www.youtube.com/watch?v=Q6pOL_SR_8k

Leprechaunism• a rare lethal familial condition marked by slow

physical and mental development, the elfin facies suggested by the name (wide-set eyes, low-set ears, and hirsutism), and severe endocrine disorders, such as enlargement of the clitoris and breasts in females and of the phallus in males. Also called Donohue's syndrome.

Down Syndrome

• Postnatal growth issues, fewer alveoli than normal

Pulmonary Surfactant Development

• Type II pneumocytes– Production, secretion, storage, reuse

• Prevents alveolar collapse• Early stimulation of surfactant production

– Beta agonists– Prostaglandins– Epidermal growth factor– Mechanical ventilation

– http://www.youtube.com/watch?v=TDrpPjQ1IPc– http://www.youtube.com/watch?v=j9z3fb3dV1A– http://www.youtube.com/watch?v=4VwdsdOBwtQ

Surface tension/surfactant• Pascal's principle requires that the pressure is

everywhere the same inside the balloon at equilibrium. But examination immediately reveals that there are great differences in wall tension on different parts of the balloon. The variation is described by Laplace's Law.

• tension, pressure and radius have a definite relationship and could be used to measure tension or pressure.

La Place• The larger the vessel radius, the larger the

wall tension required to withstand a given internal fluid pressure.

• For a given vessel radius and internal pressure, a spherical vessel will have half the wall tension of a cylindrical vessel.

Assessing lung maturity

• Lecithin–sphingomyelin ratio (LS ratio)• a test of fetal amniotic fluid to assess for fetal lung

immaturity.• Lungs require surfactant, a soap-like substance, to

lower the surface pressure of the alveoli in the lungs. This is especially important for premature babies trying to expand their lungs after birth. Surfactant is a mixture of lipids, proteins, and glycoproteins, lecithin and sphingomyelin being two of them. Lecithin makes the surfactant mixture more effective.

Lecithin–sphingomyelin ratio (LS ratio)

• The lecithin–sphingomyelin ratio is a marker of fetal lung maturity. The outward flow of pulmonary secretions from the fetal lungs into the amniotic fluid maintains the level of lecithin and sphingomyelin equally until 32–33 weeks gestation, when the lecithin concentration begins to increase significantly while sphingomyelin remains nearly the same.

• As such, if a sample of amniotic fluid has a higher ratio, it indicates that there is more surfactant in the lungs and the baby will have less difficulty breathing at birth.

Lecithin–sphingomyelin ratio (LS ratio)

• An L–S ratio of 2 or more indicates fetal lung maturity and a relatively low risk of infant respiratory distress syndrome, and an L/S ratio of less than 1.5 is associated with a high risk of infant respiratory distress syndrome.

• If preterm delivery is necessary (as evaluated by a biophysical profile or other tests) and the L–S ratio is low, the mother may need to receive steroids such as betamethasone to hasten the fetus' surfactant production in the lungs.

Phosphatidylglycerol (PG)

• Not useful unless gestational age ≥35 weeks• Rapid, sensitive• The PG test is administered via an

amniocentesis that carries slight risks. There is a chance it can induce labor when carried out near term, as in the case of a PG test. This is clearly undesirable if the lungs of the baby have not matured.

SurfactantSurfactant is a complex system of lipids, proteins and glycoproteins which are produced in Type II cells or Type II pneumocytes. The surfactant is packaged by the cell in structures called lamellar bodies, and extruded into the air-spaces. The lamellar bodies then unfold into a complex lining of the air-space. This layer reduces the surface tension of the fluid that lines the air-space. Surface tension is responsible for approximately 2/3 of the elastic recoil forces.

Immature surfactant

• Microscopically, a surfactant deficient lung is characterized by collapsed air-spaces alternating with hyper-expanded areas, vascular congestion and, in time, hyaline membranes. Hyaline membranes are composed of fibrin, cellular debris, red blood cells, rare neutrophils and macrophages.

• They appear as an eosinophilic, amorphous material, lining or filling the air spaces and blocking gas exchange.

Immature Surfactant = RDS• Previously called hyaline membrane disease (HMD), is a

syndrome in premature infants caused by developmental insufficiency of surfactant production and structural immaturity in the lungs. MOST COMMON pathology of prematurity; more severe under 30 weeks

• It can also result from a genetic problem with the production of surfactant associated proteins. IRDS affects about 1% of newborn infants and is the leading cause of death in preterm infants.

• The incidence decreases with advancing gestational age, from about 50% in babies born at 26–28 weeks, to about 25% at 30–31 weeks. The syndrome is more frequent in infants of diabetic mothers and in the second born of premature twins.

Immature Surfactant = RDS

• RDS rarely occurs in full-term infants. The disorder is more common in premature infants born about 6 weeks or more before their due dates.

• RDS is a common lung disorder in premature infants. In fact, nearly all infants born before 28 weeks of pregnancy develop RDS.

• RDS might be an early phase of bronchopulmonary dysplasia BPD

RDS• Structural immaturity, as manifest by decreased number of gas-

exchange units and thicker walls, also contributes to the disease process. Therapeutic oxygen and positive-pressure ventilation, while potentially life-saving, can also damage the lung.

• The diagnosis is made by the clinical picture and the chest xray, which demonstrates decreased lung volumes (bell-shaped chest), absence of the thymus (after about 6 hours), a small (0.5–1 mm), discrete, uniform infiltrate (sometimes described as a "ground glass" appearance) that involves all lobes of the lung, and air-bronchograms (i.e. the infiltrate will outline the larger airways passages which remain air-filled). In severe cases, this becomes exaggerated until the cardiac borders become inapparent (a 'white-out' appearance).

RDS prevention• Most cases of infant respiratory distress syndrome can

be ameliorated or prevented if mothers who are about to deliver prematurely can be given glucocorticoids, one group of hormones.

• This speeds the production of surfactant. For very premature deliveries, a glucocorticoid is given without testing the fetal lung maturity. The American College of Obstetricians and Gynecologists (ACOG), have recommended antenatal glucocorticoid treatment for women at risk for preterm delivery prior to 34 weeks of gestation

RDS Detection• In pregnancies of greater than 30 weeks, the fetal lung maturity

may be tested by sampling the amount of surfactant in the amniotic fluid by amniocentesis

• include the lecithin-sphingomyelin ratio ("L/S ratio"), the presence of phosphatidylglycerol (PG), and more recently, the surfactant/albumin (S/A) ratio.

• For the L/S ratio, if the result is less than 2:1, the fetal lungs may be surfactant deficient. The presence of PG usually indicates fetal lung maturity. For the S/A ratio, the result is given as mg of surfactant per gm of protein. An S/A ratio <35 indicates immature lungs, between 35-55 is indeterminate, and >55 indicates mature surfactant production(correlates with an L/S ratio of 2.2 or greater).

RDS treatment• Oxygen is given with a small amount of continuous positive airway

pressure ("CPAP"), and intravenous fluids are administered to stabilize the blood sugar, blood salts, and blood pressure. If the baby's condition worsens, an endotracheal tube is inserted and exogenous preparation of surfactant, either synthetic or extracted from animal lungs, is given into the lungs. One of the most commonly used surfactants is Survanta 4ml/kg then 2 ml/kg; Curosurf 2.5 ml/kg/then 1.25ml/kg

• Chronic lung disease including bronchopulmonary dysplasia are common in severe RDS. The etiology of BPD is problematic and may be due to oxygen, overventilation or underventilation. The mortality rate for babies greater than 27 weeks gestation is less than 10%.

• Other treatments: ECMO, HFV, Nitric Oxide

Surfactant Delivery• Always given down ETT, research continues on

effectiveness of aerosolized surfactant• Synthetic version no longer available in the US• Can be given up to three times; typically though 1 or

2 doses are suffice • After delivery the patient is not to be suctioned for

at least 2 hours, a CXR should be taken 1-2 hours after delivery. The first dose should be given within the 1st hour of life and the second within 12 hours and 3rd within 24 hours

Surfactant Delivery• Typically the surfactant is delivered through a special adaptor

(looks like a inline suction ballard) that is used to push the medication to the distal end of the ETT

• Usually it is bagged in, and given to 4 general areas of the lungs: RUL, RLL, LUL and LLL.

• The neonate is positioned so that via gravity the medication flows into the correct lung lobe (they are tilted up/down or moved to one side during delivery)

• It is delivered slowly, to one lobe at a time, after each lobe delivery the baby is placed in neutral position for 30 seconds before delivering the next ¼ dose

Surfactant Delivery• Surfactant is extremely frothy, do not mix or shake the medication; it is

also expensive, do not open the container unless you are certain it will be used. Keep it refrigerated, but warm it to at least room temp before use

• During delivery, the surfactant can in fact increase RAW, increasing PIP and decreasing lung expansion.

• You may have to adjust the ventilator accordingly in the immediate minutes following delivery to prevent collapse

• Watch for sudden increase in compliance as the surfactant absorbs quickly, you will have to readjust your vent settings to prevent over distension

• Assess/evaluate the neonate closely for 1 hour after delivery for compliance changes

• Obtain a blood gas (CBG or ABG) about 1 hour after delivery

Surfactant Composition

Surfactant Hormonal Effects

• Antenatal steroids (speeds up production)

• Thyroid hormones

Surfactant Dysfunction

Transient tachypnea of the newborn (TTN)

• Can be seen in the newborn shortly after delivery, typically after a cesarean section, from retention of amniotic fluid due to the lack of vaginal squeeze

• Amongst causes of respiratory distress in term neonates, it is the most common

• It consists of a period of tachypnea >60, mild retractions and grunting. It is likely due to retained lung fluid, and is most often seen in 35+ week gestation babies who are delivered by caesarian section without labor.

• Usually, this condition resolves over 24–48 hours. Treatment is supportive and may include supplemental oxygen, CPAP and antibiotics.

• The chest X-Ray shows hyperinflation of the lungs including prominent pulmonary vascular markings, flattening of the diaphragm, and fluid in the horizontal fissure of the right lung.

• http://www.youtube.com/watch?v=NBA9iigiDgk

Transient tachypnea of the newborn (TTN)

• Due to the higher incidence of TTN in newborns delivered by caesarean section, it has been postulated that TTN could result from a delayed absorption of fetal lung fluid from the pulmonary lymphatic system. The increased fluid in the lungs leads to increased airway resistance and reduced lung compliance.

• It is thought this could be from lower levels of circulating catecholamines after a caesarean section, which are believed to be necessary to alter the function of the ENaC channel to absorb excess fluid from the lungs.

• Pulmonary immaturity has also been proposed as a causative factor.

• Mild surfactant deficiency has also been suggested as a causative factor.

Fetal Lung Liquid• Lungs’ secretion 250 to 330 ml/day• Swallowed or expelled into amniotic

fluid• Essential for normal lung development• Removal after birth

– Blood and lymphatic vessels

perinatal and pediatric respiratory care ch. 1 fetal lung development

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