Respiratory problems in premature infants

Dr. Rozin IlyaDepartment of Neonatology Kaplan Medical Center

Respiratory problems

• Respiratory Distress Syndrome (RDS) or Hyaline Membrane Diseases (HMD)

• Broncho-Pulmonary Dysplasia (BPD)

Respiratory Distress Syndrome

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

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%

Epidemiology

• Overall incidence in 501-1500 grams: 42%

• 501-750 grams: 71%• 751-1000 grams: 54%• 1001-1250 grams: 36%• 1251-1500 grams: 22%

Other risk factors for RDS

Increased 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)

Decreased Risk• 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

Phases of Lung Development

Lung Development

Surfactant

• Complex lipoprotein • Composed of 6

phospholipids and 4 apoproteins

• Surfactant contains• 70-80%

phospholipids, • 8-10% protein, and• 10% neutral lipids

Surfactant Metabolism

Surfactant Metabolism

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

Assessment of Fetal Lung Maturity

• Lecithin / sphingomyelin (L/S) ratio

• Lamellar body counts

• Phosphatidylglycerol• After 35 weeks gestation

L/S Ratio

Pathophysiology

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

Lung Compliance

Normal Lung

Hyaline Membranes

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

Clinical Manifestations

• Tachypnea• Nasal flaring• Grunting• Intercostal, sub xiphoid, and

subcostal retractions • Cyanosis • Apnea

Differential Diagnosis

• TTN• MAS• Pneumonia• Cyanotic Congenital Heart Disease• Pneumomediastinum, pneumothorax• Hypoglycemia• Metabolic problems• Hematologic problems

• Anemia, polycythemia• Congenital anomalies of the lungs

Diagnosis

• Onset of progressive respiratory failure shortly after birth

• Characteristic chest radiograph• Laboratory tests – rule out infection • Analysis of blood gas:

• Hypoxia• Hypercarbia

Chest X Ray

“ground glass”

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

Treatment

• Surfactant Therapy• Assisted Ventilation Techniques and Oxygen

therapy (be careful) • Supportive Care

• Thermoregulation• Fluid Management• Nutrition• Antibiotic therapy• Gentle handling

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

Prognosis

• Chronic complications of respiratory distress syndrome :

• Broncho pulmonary dysplasia (BPD)

• Retinopathy of prematurity (ROP)

• Neurologic impairment

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.

Pathogenesis

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

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

Definition

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

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

Epidemiology

• Incidence:• 42-46% (BW-501-750g)• 25-33% (BW=751-

1000g)• 11-14%

(BW=1001=1250g)• 5-6% (BW=1251-1500g)

• Risk factors:• Prematurity, low BW• White boys• Genetic heritability

Epidemiology

• By the NICHD at 2010 from Neonatal Research Network

• BW 401-1500 gr• GA 22 0/7 – 28 6/7 weeks• BPD of all diagnosis - 68%• Mild - 27%• Moderate – 23%• Severe – 18%

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

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

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

Pathogenesis

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

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

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

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

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

Prevention and therapy

Azithromycin• macrolides antibiotic• anti-inflammatory effect • active against Ureaplasma infection• in a RCT no statistic significance (for

6 weeks of therapy)

Prevention and therapy

Vitamin A:• regulation of lung development • injury repair • low level – increased risk to BPDVitamin 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

Prevention and therapy

Caffeine: • significant reduce in BPDPentoxiphilline:• non specific phosphodiesterase inhibitor • decreased pulmonary inflammation Cromolyn:• mast cell stabilizer

• non protective effect

Prevention and therapy

Nitric Oxide:• benefit on oxidative stress and lung

development – in animal studies• not support the use in routine careSurfactant:• not decreased incidence of BPD• improving respiratory care • prophylactic therapy is associated with

lower risk of BPD

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

Prevention and therapy

Nutrition:• excessive fluids intake – more risk

for BPD• if BPD – infant may need up to 20%-

40% more kilocalories

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

Thank you