1. Pulmonary Physiology AnS 536 Spring 2014

2. Pulmonary Development in the Fetus • Fetal lung development • Accelerated through in utero treatment with corticosteroids and thyroid hormones • Factors enhancing pulmonary phospholipid metabolism • Catecholamines • Thyrotropin-releasing hormone • Estradiol • Heroin • Cyclic AMP

3. Pulmonary Development in the Fetus • Glucocorticoids • Contribute to the development of lung morphology and the surfactant system in type II cells • More stable lungs • Increased air space • Glucocorticoid action • Induction of an enzyme • Mediated by interaction of steroid with cytoplasmic glucocorticoid receptors • Receptors present in the lung, pulmonary fibroblasts, and type II cells

4. Pulmonary Development in the Fetus • Corticosteroid therapy • Used during premature labor • Reduces incidence of respiratory distress syndrome • Endogenous cortisol sources: • Fetal adrenal glands • Maternal adrenal glands • Conversion of cortisone to cortisol by amniotic membranes and lung fibroblasts

5. Pulmonary Development in the Fetus • Thyroid hormones • Effects similar to corticosteroids • Different biochemical steps • Synthetic analogues of triiodothyronine (T3) readily cross the placenta and accelerate surfactant synthesis and release • Act through nuclear receptors present in the lung • Thyroid treatment in utero appears to accelerate lung maturation and prevent respiratory distress syndrome in premature infants

6. Determinants of Alveolar Gas Composition • Inspired gas composition • Barometric pressure • Temperature • Respiratory quotient • Replenishment with fresh gas • Uptake of oxygen from alveoli into blood • Dependent on cardiac output and [Hb] • 4 through 6 are primary determinants

7. Respiratory Quotient • R=CO2 entering alveoli/O2 entering blood • Dependent on the metabolic substrate consuming oxygen and producing carbon dioxide • Glucose (R=1) • Lipids (R=0.7) • Mixed (R=0.825)

8. O2 Transport Across the Neonatal Lungs • Primary determinant of oxygen flow rate into a cell is the PO2 in the capillaries • Second determinant is rate that the cell consumes oxygen • Function of mitochondrial density • Oxygen consumption of newborns is extremely high • ~3-fold increase over fetal levels • Increase in oxygen consumption necessary primarily to maintain body temperature

9. O2 and CO2 Transport Across the Neonatal Lungs • Initial breath of the neonate promotes closure of the ductus arteriosus and increases blood flow into the lungs • O2 exchanged in alveoli to capillaries • CO2 generated from metabolism of CHO’s is unloaded in the alveoli • Fetal Hb important in binding O2 • HbF levels decrease with age

10. Surfactant • Complex mixture of phospholipids (especially dimalmitoyl lecithin) and proteins • Synthesized and stored by type II alveolar epithelial cells • Has the ability to reduce surface tension at the air-liquid interface • Maintains alveolar expansion and expiration • Increases pulmonary compliance • Reduces the work of inflating the lungs • Reduces the lungs’ tendency to recoil • Do not collapse as readily

11. Surfactant • Vital to neonatal survival • Essential in gas exchange • Allows exchange to occur at low trans-pulmonary pressures • Restores collapsed lung regions • Results in marked increase in oxygen saturation and perfusion • Glucocorticoid treatment • Increases surfactant associated proteins and phospholipids  increase surfactant production

12. Surfactant • Factors mediating production • Early gestation • Glucocorticoid • Receptor is expressed in the fetal lung • Stimulate the production of surfactant-associated proteins • Increases phospholipid synthesis by enhancing activity of phosphatidylcholine (main component of surfactant) • Late gestation • Surfactant production has been found at week 23 of gestation • Infants born before this time frame have difficulty surviving due to depressed surfactant levels

13. Surfactant http://www.youtube.com/watch?v=tLpUTL1-QEw&feature=player_detailpage

14. Normal Birth and the First Breath • Compression of thorax in birth canal eliminates much fluid and mucus especially in upper portions of respiratory tract • Thoracic recoil as fetus leaves birth canal helps produce “pull” on lungs (along with expansion by means of respiratory muscles) and dilates lymph and blood vessels • Assists in resorption of fluids and surfactant becomes plastered on walls of lungs

15. Stimulus for First Breath • Stoppage of umbilical circulation • Takes about a minute • Cold, especially in face and forehead regions • Heat produces apnea

16. The First Breath • Involves both diaphragm and upper airway muscles • Pleural pressure peaks at 30-100 cm H2O • Normal pleural pressure is 5-7 cm H2O • Tidal volume is 35-45 ml • Double the normal VT • Distribution of air is uneven • First expiration slow and long

17. After the First Breath • Respiratory pattern following the first breath • Slow and irregular pattern • Frequent interruptions in expiration (occluded breaths) • Causes gas trapping • Helps distribute lung volume evenly • Helps clear fluids • Respiratory function develops through rapidly increasing the lung volume • Resting volume stays small (high FRC) • Respiratory rate gradually increases • Premature infants have difficulty in adequate gas exchange due to their underdeveloped lungs

18. Neonatal Breathing Issues • Newborns are obligate nose breathers • Occlusion of nasal passages can theoretically result in suffocation • Can initially inhale through mouth only by extending the spine and opening mouth wide to retract epiglottis • Oral suction does more harm than good • Can switch to mouth breathing eventually, but switch takes longer than in adults

19. Evaluating Lung Function • Fetus • Measured through the L/S ratio test • Measures lecithin and sphingomyelin concentrations in the amniotic fluid • Helps determine maturity of fetal lungs prior to birth • Neonates • Pulse oximetry • Pulmonary Function Tests (PFT) • Measures lung function in ill neonates • Tests include: • Tidal volume • Minute ventilation • Respiratory rate • Pulmonary compliance • Resistance • Resistive work of breathing • Functional residual capacity

20. Amniocentesis http://www.youtube.com/watch?v=DjAXK4rY9qs&feature=player_detailpage

21. Respiratory Distress Syndrome (RDS) • Occurs in neonates with underdeveloped lungs • #1 complication in premature neonates • Affects 50% of babies born before 32 weeks • Significant cause of death and morbidity in preterm infants • Inability to exchange O2 and CO2 adequately due to underdeveloped or collapsed lungs

22. Respiratory Distress Syndrome (RDS) • Treatments • Initially high O2 and humidity concentrations are given • Severe cases may use ventilator to maintain adequate O2 concentrations and pressure levels • Exogenous surfactant therapy • Given to infants prior to 30 weeks of age • Preterm administration of corticosteroids • Dexamethasone and/or betamethasone • Lungs rich in glucocorticoid receptors