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Respiratory problems in premature infants

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1 Respiratory problems in premature infants
Dr. Rozin Ilya Department of Neonatology Kaplan Medical Center

2 Respiratory problems Respiratory Distress Syndrome (RDS) or Hyaline Membrane Diseases (HMD) Broncho-Pulmonary Dysplasia (BPD)

3 Respiratory Distress Syndrome

4 Definition Also known as hyaline membrane disease
Deficiency of pulmonary surfactant in an immature lung Common respiratory disorder of premature infants RDS can also be due to genetic problems with lung development

5 Epidemiology Major cause of morbidity and mortality in preterm infants
20,000-30,000 newborn infants each year ( in US) Incidence and severity of RDS are related inversely to gestational age of newborn infant (most case before 37 weeks) 26-28 weeks gestation : 50% 30-31 weeks gestation : <30%

6 Epidemiology Overall incidence in 501-1500 grams: 42%

7 Other risk factors for RDS
Increased Risk Decreased Risk Prematurity Male gender Familial predisposition Cesarean section without labor Perinatal asphyxia Caucasian race Infant of diabetic mother Chorioamnionitis Non-Immune hydrops fetalis Multiple pregnancy (twins or more) Chronic intra-uterine stress Prolonged rupture of membranes Maternal hypertension or toxemia IUGR/SGA Antenatal glucocorticoids Maternal use of narcotics/cocaine Tocolytic agents Hemolytic disease of the newborn

8 Phases of Lung Development
Normal alveolar development occurs in 4 stages. Embryonic period – At about 26 days gestation, the embryonic stage begins with the first appearance of the fetal lung, which appears as a protrusion of the foregut. Initial branching of the lung occurs at 33 days gestation forming the prospective main bronchi, which begin to extend into the mesenchyme. Further branching forms the segmental bronchi as the lung enters the next stage of development. Pseudoglandular stage – 7th to 16th weeks of gestation, 15 to 20 generations of airway branching occur starting from the main segmental bronchi and ending as terminal bronchioles. end of the pseudoglandular stage, airways are surrounded by a loosely packed mesenchyme, which includes a few blood vessels, and is lined by glycogen-rich and morphologically undifferentiated epithelial cells with a columnar to cuboidal shape. In general, epithelial differentiation is centrifugal so the most distal tubules are lined with undifferentiated cells with progressive epithelial differentiation of the more proximal airways. Canalicular stage – 16th and 25 weeks gestation, transition from previable to a potential viable lung occurs as the respiratory bronchioles and alveolar ducts of the gas exchange region of the lung are formed. The surrounding mesenchyme becomes more vascular and condenses around the airways. The closer vascular proximity ultimately results in fusion of the capillary and epithelial basement membranes. After 20 weeks gestation, cuboidal epithelial cells begin to differentiate into alveolar type II cells with formation of cytoplasmic lamellar bodies [2]. The glycogen in these cells is used for surfactant production, which is stored in the lamellar bodies. Saccular stage – About 24 weeks gestation, there is potential for viability because gas exchange is possible due to the presence of large and primitive forms of the future alveoli. In this stage, formation of alveoli (ie, alveolarization) occurs by the outgrowth of septae that subdivide terminal saccules into anatomic alveoli, where air exchange occurs. The number of alveoli in each lung increases from zero at 32 week gestation to between 50 and 150 million alveoli in term infants and 300 million in adults. Alveolar growth continues for at least two years after birth at term.

9 Lung Development

10 Surfactant Complex lipoprotein Surfactant contains
Composed of 6 phospholipids and 4 apoproteins Surfactant contains 70-80% phospholipids, 8-10% protein, and 10% neutral lipids

11 Surfactant Metabolism

12 Surfactant Metabolism

13 4 surfactant apoproteins
Surfactant protein B (SP-B) Surfactant protein C (SP-C) for preventing atelectasis, and Surfactant protein A (SP-A) - facilitates phagocytosis of pathogens by macrophages and their clearance from the airways Surfactant protein D (SP-D) – if absent -increased surfactant lipid pools in the airspaces and emphysema in mice

14 Assessment of Fetal Lung Maturity
Lecithin / sphingomyelin (L/S) ratio Lamellar body counts Phosphatidylglycerol After 35 weeks gestation

15 L/S Ratio Amniotic fluid L/S ratio increases progressively with gestational age. L/S ratio greater than two signifies maturity of surfactant system of lung

16 Pathophysiology Hypoxia, acidosis, hypothermia, hypotension
- Surfactant deficiency - Inflammation and Lung injury - Pulmonary edema - Surfactant inactivation - Pulmonary function and gas exchange Impaired surfactant synthesis and secretion  atelectasis, V/Q inequality, hypoventilation  hypoxemia and hypercarbia Respiratory / metabolic acidosis  pulmonary vasoconstriction  impaired endothelial and epithelial integrity  leakage of proteinaceous exudate and formation of hyaline membranes Deficiency of surfactant  decreases lung compliance and FRC, with increased dead space Impair surfactant production and/or secretion Hypoxia, acidosis, hypothermia, hypotension Oxygen toxicity  influx of inflammatory cell  exacerbates vascular injury  BPD Antioxidant deficiency and free-radical injury worsen injury


18 Etiology Preterm delivery
Mutations in genes encoding surfactant proteins SP-B SP-C ATP-binding cassette (ABC) transporter A3 (ABCA3) - is critical for proper formation of lamellar bodies and surfactant function and may also be important for lung function in other pulmonary diseases

19 Lung Compliance Lungs with HMD require far more pressure than to achieve a given volume of inflation than do lungs obtained from an infant dying of a nonrespiratory cause. Arrows indicate inspiratory and expiratory limbs of the pressure-volume curves. Note the decreased lung compliance and increased critical opening and closing pressures, respectively, in the premature infant with HMD

20 Normal Lung

21 Hyaline Membranes line the alveoli (see the image below) may form within a half hour after birth. In larger premature infants, the epithelium begins to heal at hours after birth, and endogenous surfactant synthesis begins. The recovery phase is characterized by regeneration of alveolar cells, including type II cells, with a resultant increase in surfactant activity.

22 Surfactant Inactivation
Meconium and blood can inactivate surfactant activity (Full-term > Preterm) Proteinaceous edema and inflammatory products increase conversion rate of surfactant into its inactive vesicular form Oxidant and mechanical stress associated with mechanical ventilation that uses large TV

23 Clinical Manifestations
Tachypnea Nasal flaring Grunting Intercostal, sub xiphoid, and subcostal retractions Cyanosis Apnea

24 Differential Diagnosis
TTN MAS Pneumonia Cyanotic Congenital Heart Disease Pneumomediastinum, pneumothorax Hypoglycemia Metabolic problems Hematologic problems Anemia, polycythemia Congenital anomalies of the lungs

25 Diagnosis Onset of progressive respiratory failure shortly after birth
Characteristic chest radiograph Laboratory tests – rule out infection Analysis of blood gas: Hypoxia Hypercarbia

26 Chest X Ray “ground glass”
low lung volume and the classic diffuse reticulogranular ground-glass appearance with air bronchograms “ground glass”

27 Prevention Antenatal glucocorticoids
Enhances maturational changes in lung architecture and inducing enzymes Stimulate phospholipid synthesis and release of surfactant All pregnant mothers at risk for preterm delivery between 24 and 34 weeks gestation should receive ACS two doses of betamethasone administered 24 hours apart is currently the recommended steroid for antenatal use Antenatal steroid administration has been shown to be beneficial if provided fewer than 24 hours before delivery Furthermore, a reduction in RDS has been seen in infants born up to 7 days after the first dose of antenatal steroids was administered. (1) No benefit is seen in infants who receive the first dose of steroids more than 7 days before birth. They recommend repeat doses of corticosteroids in women at risk for preterm birth when the first course of steroids was administered more than 7 days previously because of the short-term benefits to the fetal lungs. They do, however, warn about the possibility of decreased birthweight and head circumference at birth, which has been reported.

28 Treatment Surfactant Therapy
Assisted Ventilation Techniques and Oxygen therapy (be careful) Supportive Care Thermoregulation Fluid Management Nutrition Antibiotic therapy Gentle handling Surfactant complications: apnea, brady, desats, pulm hemorrhage

29 Prognosis Acute complications of respiratory distress syndrome :
Alveolar rupture Infection Intracranial hemorrhage and periventricular leukomalacia Patent Ductus Arteriosus (PDA) with increasing left-to-right shunt Pulmonary hemorrhage Necrotizing enterocolitis (NEC) and/or gastrointestinal (GI) perforation Apnea of prematurity

30 Prognosis Chronic complications of respiratory distress syndrome :
Broncho pulmonary dysplasia (BPD) Retinopathy of prematurity (ROP) Neurologic impairment

31 Bronchopulmonary dysplasia
Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that develops in preterm neonates treated with oxygen and positive-pressure ventilation (PPV). The pathogenesis of this condition remains complex and poorly understood.

32 Pathogenesis

33 Definition 1967, Northway et al. : premature infants with RDS, resaved prolonged ventilation, with high concentration of oxygen and high peak inspiratory pressure All require oxygen at 28 days after birth and progressive change on chest x-ray

34 Definition 1979, Bancalari: same to Northway + tachypnea and crackles or retraction. 1988, new criterion: oxygen supplementation at 36 weeks postmenstrual age (PMA) - more accurately predicted abnormal pulmonary outcome at 2 years of age - with medical care more infant with oxygen at 28 days

35 Definition 2000, National Institute of Child Health and Human Development (NICHD)

36 Definition Because of absent specified in the consensus BPD definition, it was recommended that a physiologic test confirming the need for supplementation oxygen be performed

37 Epidemiology Incidence: 42-46% (BW-501-750g) 25-33% (BW=751-1000g)
Risk factors: Prematurity, low BW White boys Genetic heritability

38 Epidemiology By the NICHD at 2010 from Neonatal Research Network
BW gr GA 22 0/7 – 28 6/7 weeks BPD of all diagnosis - 68% Mild - 27% Moderate – 23% Severe – 18%

39 Pathology “Old” BPD: Airway inflammation Fibrosis
Smooth muscle hypertrophy “New” BPD: Lung development arrests before alveolarization: lung have larger but fewer alveoli than normal lung Pulmonary vasculature to be dysmorphic

40 Pathology “Old BPD” (before surfactant and steroids)
Cystic changes, heterogeneous aeration “New BPD” (after surfactant and steroids) More uniform inflation and less fibrosis, absence of small and large airway epithelial metaplasia and smooth muscle hypertrophy Some parenchymal opacities, but more homogenous aeration and less cystic areas PATHOLOGIC HALLMARKS: larger simplified alveoli and dysmorphic pulmonary vasculature

41 Pathology Old BPD: Airway injury, inflammation and parenchymal fibrosis due to mechanical ventilation and oxygen toxicity New BPD: Decreased septation and alveolar hypoplasia leading to fewer and larger alveoli, so less surface area for gas exchange Dysregulation of vascular development leading to abnormal distribution of alveolar capillaries and thickened muscular layer of pulmonary arterioles

42 Pathogenesis

43 Pathogenesis Chorioamnionitis – caused by an ascending infection, as possible cause But histologic chorioamnionitis to be protective ( same umbilical vasculitis) – potential role of transcription factor nuclear factor kB and inflammation Ureaplasma colonization Bacterial sepsis

44 Pathogenesis Hemodynamic significantly PDA and surgery ligation
Mechanical ventilation (volutrauma and barotrauma) Oxygen toxicity High volume of fluids intake n the first few days after birth Lower serum cortisol level (in VLBW) – early adrenal insufficiency

45 Outcomes Higher rate recurrent hospitalization in the first year after birth Lung disease in adulthood: airway obstruction, reactive airways, emphysema Affect growth Cardiovascular sequelae: pulmonary artery hypertension, cor pulmonale, systemic hypertension Poor neurodevelopmental outcomes: language delay, increased fine and gross motor impairment

46 Prevention and therapy
Antenatal: corticosteroids administration standard of care – 24 – 34 weeks effect on the incidence of BPD controversial in animals studies – arrest alveolarization and microvascular development

47 Prevention and therapy
Postnatal: postnatal corticosteroids therapy decreased time to extubation early use – poor neurodevelopmental outcomes (CP) adverse effects: hyperglycemia, hypertension, GI bleeding, hypertrophic cardiomyopathy, infection

48 Prevention and therapy
Azithromycin macrolides antibiotic anti-inflammatory effect active against Ureaplasma infection in a RCT no statistic significance (for 6 weeks of therapy)

49 Prevention and therapy
Vitamin A: regulation of lung development injury repair low level – increased risk to BPD Vitamin E and Selenium: study result have been mixed selenium works synergistically with Vit E to prevent peroxide formation – not show to reduce risk to BPD

50 Prevention and therapy
Caffeine: significant reduce in BPD Pentoxiphilline: non specific phosphodiesterase inhibitor decreased pulmonary inflammation Cromolyn: mast cell stabilizer non protective effect

51 Prevention and therapy
Nitric Oxide: benefit on oxidative stress and lung development – in animal studies not support the use in routine care Surfactant: not decreased incidence of BPD improving respiratory care prophylactic therapy is associated with lower risk of BPD

52 Prevention and therapy
Ventilatory strategies: permissive hypercapnia (pH>7.20 and pCO2 from 45 to 55 mmHg) gentle ventilation ( SIMV, HFV, Volume-targeted ventilation, NSIMV (NIPPV) or NCPAP) INSURE used adequate oxygenation – difficult

53 Prevention and therapy
Nutrition: excessive fluids intake – more risk for BPD if BPD – infant may need up to 20%-40% more kilocalories

54 Prevention and therapy
Therapy of established BPD: Inhaled steroids: evidence supporting is mixt RCT for early therapy – no support Diuretics: for decreased pulmonary alveolar and interstitial edema routine used loop diuretics not recommended Thiazide + Spironolactone Bronchodilators: most commonly β adrenergic agonist short term improvement for acute exacerbation care only

55 Thank you

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