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