Bronchopulmonary Dysplasia

John Salyer RRT-NPS, MBA, FAARC

Director Respiratory Therapy

Seattle Children’s Hospital and Research Institute

A Little History

Originally described by Northway in 1967

• Report of a series of 32 patients in NEJM, average gestational age 32 weeks

• All were treated with 100% oxygen, then prolonged mechanical ventilation with 80-100% oxygen

• Before mechanical ventilation was available the usual course of RDS was several days of severe lung disease to which the infant either succumbed or recovered completely in 7-10 days

History (cont.)

• The addition of mechanical ventilation led to appearance of a new syndrome

– Stage I, days 1-3, HMD (RDS)

– Stage II, days 4-10, opacification of lungs, with bronchiolar and alveolar necrosis

– Stage III, days 10-20, transition to a CXR with a reticular network of small rounded areas of radiolucency, emphysematous and atelectatic airspaces, with pulmonary fibrosis

– Stage IV, hyperexpanded and cystic lungs. cor pulmonale

Definition

• Shennan noted that if oxygen requirement at 36 weeks used as threshold over 50% of infants would have abnormal pulmonary follow-up (Shennan, 1988)

• Now usually defined as requirement for supplemental oxygen at:

– 36 weeks postmenstrual age if born at or before 32 weeks’ gestational age

– 4 weeks of age if born after 32 weeks’ gestational age

Physiologic Test

• BPD if at 35-37 weeks post menstrual age:

– receiving mechanical ventilation, or

– CPAP, or

– >30% oxygen with saturation <96%

– If infant is receiving <30% oxygen or ≥30% oxygen with saturation >96% then:

• Wean O2 to room air

• No BPD if saturation > 90% in room air for 30 minutes

Pathology Classic BPD

• Airway injury

• Epithelial metaplasia with type II cell hyperplasia

• Smooth muscle hypertrophy

• Parenchymal fibrosis, alternating with emphysema

• Capillary dysplasia

Low power view of lung from infant who died from BPD at 2.5 months of age. Note alternating areas of emphysema and atelectasis, and strands of fibrosis.

Smooth Muscle Hyperplasia

Albertine et al., Am J Respir Crit Care. 2008

Histology of BPD

Classic BPD

Classic vs. New BPD• Much of the histologic findings of “old

BPD” seen in animal models with oxygen toxicity

• New epidemiology

– Most common in ELBW infants

– Risk factors: low gestational age, postnatal infection, maternal chorioamnionitis, PDA, mechanical ventilation

– Some ELBW infants do not have RDS, with minimal early oxygen or mechanical ventilation

Clinical Presentation “New” BPD

• Hazy lungs on CXR, with minimal cystic emphysema, or hyperinflation

• Less airway reactivity

• Less pulmonary hypertension (blue spells, “twits”)

• Pathology

– Minimal fibrosis, minimal airway injury

– Decreased alveolar septation and microvascular development

CXR New BPD Old BPD

Division of Respiratory Bronchioles

• 20 to 32-36 weeks 3 generations of saccular septations, forming 524,000 respiratory bronchioles

• Hypothesized that the further septation of respiratory bronchioles disrupted by inflammation/injury in new BPD

Pathology New BPDArrest of Alveolarization

• Increased saccular diameters, fewer saccules (alveoli)

• Collagen network disrupted, elastin not localized to fibers for secondary septation

• No severe inflammation

• Saccules lined with dysplastic type II cells

• Seen in post-natal mice and rats exposed to inflammation or hyperoxia

Pathogenesis “New” BPD:Overview

• Immaturity of structure and function before about 32 weeks’ gestation

– Poorly developed airway supporting structures

– Surfactant deficiency

– Decreased compliance

– Underdeveloped antioxidant mechanisms

– Inadequate fluid clearance

• Inflammation

– Mechanical ventilation

– Oxygen toxicity

– Infection

Pathogenesis:Mechanical Injury

• Over-distension of airways and airspaces (Volutrauma)– Excessively large tidal volumes, not pressure

(Hernandez, 1989)– Association of decreased PCO2 with increased

risk BPD (Garland, 1995)– Maximum end-inspiratory volume more important

than tidal volume or FRC (Dreyfuss, 1993)– As few as 6 large manual inflations was enough to

increase the lung damage premature lambs (Bjorklund, 1997)

– Positive pressure causes bronchiolar lesions (Nilsson, 1978)

Pathogenesis:Oxygen Toxicity

• Safe FiO2 level and duration are unknown

• Cell damage from reactive oxygen metabolites– Cell enzyme inactivation

• Preterm infants may have inadequate antioxidant defenses– Nutrient deficiencies– Immature enzyme development

Pathogenesis:Infection

• Four-fold increase in BPD incidence with sepsis (Rojas, 1995)

• Due to increased concentration of proinflammatory cytokines in amniotic fluid?

• Association with Ureaplasma urealyticum (Hannaford, 1999)

• Maternal chorioamnionitis associated with decreased RDS, but increased risk of BPD

Pathogenesis:Inflammation

• Macrophages, lymphocytes, platelets in lung will release inflammatory mediators– Cytokines– Lipid mediators– Platelet factors (Ozdemir, 1997)

• Complement activation• Increased vascular permeability• Protein leakage• Mobilization of neutrophils into interstitial

and alveolar compartments– Release of reactive oxygen radicals, elastase,

collagenase– Increased MIP-1 and IL-8, reduced IL-10 (Jobe

2001)

Normal Alveolus

Injured Alveolus (Acute Phase)

Alveolar air spaceType I cell

Surfactant Layer

Type II cell

Interstitium

Capillary

Alveolar macrophage

Sloughing bronchial epithelium

Edema fluid

Necrotic or Apoptotic Type I cell

Red cell

Cellular debris

Hyaline membrane

Fibrin

Widened, edematous interstitium(interstitial pneumonia)

TNFIL

Red cell

Inactivated surfactant

Activated neutrophil

Cardiopulmonary function in BPD

• Decreased tidal volume• Increased airway resistance• Decreased dynamic lung

compliance• Uneven airway obstruction

– Gas trapping– Hyperinflation– Abnormal distribution of

ventilation

• Bronchomalacia

Pulmonary Edema in BPD

• Reduced cross sectional area of pulmonary vessels causes increased pulmonary vascular resistance

• Alveolar hypoxia induces local vasoconstriction

• Intact vessels must accept remaining pulmonary blood flow, which leads to– elevated pressure and RV afterload

– increased fluid filtration in interstitium

Clinical Course of BPD

• Most: gradual improvement over weeks or months

• Some: marked pulmonary instability in first few weeks followed by weeks or months of ventilator dependence

• Few: pulmonary hypertension and cor pulmonale

Prevention of BPD

• Antenatal glucocorticoid steroids - lead to decreased incidence RDS, but only modest decrease in BPD

• Nutrition – although poor growth is associated with BPD, no studies show impact of nutrition in altering risk for BPD

• Vitamin A – Slight decrease in BPD with IM supplementation in ELBW infants (Darlow, 2011), UW study showed increased sepsis with IM vit A (48.5% vs. 12%), but no decrease BPD

• Surfactant – decreases risk of pneumothorax, improves survival, decreases need for oxygen and ventilation, but no decrease in rate of BPD.

Prevention of BPD (cont.)

• Limited oxygen – SUPPORT trial with lower oxygen targets saw decreased incidence of ROP, but increased mortality and no decrease in BPD

• Permissive hypercapnea – Target of pCO2>52 vs. <48 not associated with decreased BPD in ELBW, but decreased ventilation at 36 wks (Carlo, 2002)

• HFOV – not associated with decreased BPD compared to modern conventional ventilation

Prevention of BPD (cont.)

• PDA treatment – incidence of PDA goes up with ligation (Chorne, 2007)

• Inhaled Nitric Oxide – NO-CLD trial showed decreased BPD in treatment group. Survival without BPD 43.9% vs. 36.8% (Ballard, 2006)

Ventilation Strategy for CLD

Settings

1. Slow Respiratory Rates– < 40 breaths/min

2. PIP (lowest required)

– target VT 5-10 mL/kg

– Not ECLS candidate

3. PSV/VG

4. PEEP – 5-6 (up to 12 for bad TM)

5. Short Inspiratory Times– 0.4-0.7 s

Blood Gases

1. Permissive Hypercapnea– pCO2 levels 45-65*

– pH 7.25-7.35

2. Less Aggressive Oxygenation Goals– paO2 45-55*

– Saturations 85-92%

p=< 0.05

Management of established BPD:Bronchodilators

• Beta-2 agonists (albuterol, terbutaline) acutely decrease airway resistance and increase compliance

• Only one controlled clinical study of outcomes (Denjean, 1992)– 173 infants < 31 weeks, vent at 10 days– No effect on survival, severity of BPD,

duration of vent or oxygen use

Management of established BPD:Bronchodilators

• Recommendation (not evidenced-based!)– Use albuterol for short-term

effects or to treat acute deterioration

– Discontinue if no improvement in gas exchange, work of breathing, or number of respiratory decompensations

– Watch for tachycardia, arrhythmia, hypokalemia, irritability

Management of established BPD:Acute Exacerbations

• Consider viral infections (usually not bacterial)

• Consider tracheitis if purulent secretions

• Obtain CXR (although rarely helpful)• Culture and gram stain of tracheal

secretions if purulent (often misleading)

• Try dose of furosemide• Try inhaled albuterol, and if poor

response, try ipratropium• Consider inhaled corticosteroids• Consider systemic corticosteroids

for 5 days, esp. if at term corrected age

Web Resources for Parents

• http://www.nhlbi.nih.gov/health/dci/Diseases/Bpd/Bpd_WhatIs.html– Excellent description of BPD for lay audience from the National

Heart Lung and Blood Institute

• http://www.nlm.nih.gov/medlineplus/ency/article/001088.htm– Very brief review of BPD from National Library of Medicine’s

Medline Plus website

• http://depts.washington.edu/growing/Assess/BPD.htm– Description of BPD with emphasis on home care and nutritional

issues from Donna Johnson at the University of Washington

The End