1. Pulmonary Physiology AnS 536 Spring 2015

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 (T 3 ) 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=CO 2 entering alveoli/O 2 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. O 2 Transport Across the Neonatal Lungs Primary determinant of oxygen flow rate into a cell is the PO 2 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. O 2 and CO 2 Transport Across the Neonatal Lungs Initial breath of the neonate promotes closure of the ductus arteriosus and increases blood flow into the lungs O 2 exchanged in alveoli to capillaries CO 2 generated from metabolism of CHO’s is unloaded in the alveoli Fetal Hb important in binding O 2  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 H 2 O  Normal pleural pressure is 5-7 cm H 2 O Tidal volume is 35-45 ml  Double the normal V T 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=DjAXK4r Y9qs&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 O 2 and CO 2 adequately due to underdeveloped or collapsed lungs

22. Respiratory Distress Syndrome (RDS) Treatments  Initially high O 2 and humidity concentrations are given  Severe cases may use ventilator to maintain adequate O 2 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