BRONCHOPULMONARY DYSPLASIA HISTORY
Category: Child Health
Abstract : bronchopulmonary dysplasia history: BPD is a CLD that develops in both preterm and term neonates treated with oxygen and PPV for a primary lung disorder. Northway originally described BPD in 1967 with characteristic clinical, radiographic, and histologic lung changes in preterm infants who had RDS and were treated with oxygen and mechanical ventilation. • bronchopulmonary dysplasia -
bronchopulmonary dysplasia history: BPD is a CLD that develops in both preterm and term neonates treated with oxygen and PPV for a primary lung disorder. Northway originally described BPD in 1967 with characteristic clinical, radiographic, and histologic lung changes in preterm infants who had RDS and were treated with oxygen and mechanical ventilation.
• bronchopulmonary dysplasia - Definition and frequency
o The frequency of BPD is dependent upon the definition used and can vary significantly between NICUs. Other investigators have modified Northway's original definition of oxygen requirement at 28 days. Bancalari expanded Northway's definition to include the need for mechanical ventilation, oxygen requirement at 28 days (to maintain arterial oxygen >50 mm Hg), and an abnormal finding on chest radiography. In 1988, Shennan suggested that the need for supplemental oxygen at 36 weeks postconceptual age may be a more accurate predictor of long-term pulmonary outcome. In 1998, Palta and colleagues indicated that repeated episodes of wheezing (consistent with a diagnosis of asthma) severe enough to require treatment with bronchodilators or corticosteroids by age 1-2 years appears to be the most reliable way of predicting long-term pulmonary function.
o Preterm infants are treated with oxygen and PPV. These infants may require only short periods of PPV and supplemental oxygen during the first 1-2 weeks of life. Other infants with severe RDS may respond poorly to surfactant replacement and have high ventilator and oxygen requirements, which increase toward the latter part of the first week or early in the second week of life. Chest radiography may reveal pulmonary interstitial emphysema (PIE), wandering atelectasis with concomitant hyperinflation, and cyst formation.
• Volutrauma and barotrauma
o The mainstay of treatment for RDS has been surfactant replacement along with oxygen supplementation, continuous positive airway pressure (CPAP), and mechanical ventilation. The PPV required to recruit alveoli and prevent atelectasis in the immature lung may cause lung injury and activate the inflammatory cascade. Trauma secondary to PPV is generally referred to as barotrauma. With the more recent return to volume ventilation and the low versus high tidal volume ventilation strategy, some investigators have adopted the term volutrauma. Volutrauma suggests lung injury secondary to excess tidal volume from PPV.
o The severity of lung immaturity and the effects of surfactant deficiency determine the need for PPV, surfactant supplementation, and resultant barotrauma/volutrauma. With severe lung immaturity, total alveolar number is reduced, thereby increasing the positive pressure transmitted to distal terminal bronchioles. In the presence of surfactant deficiency, surface tension forces are increased; some compliant alveoli may become hyperinflated, while other saccules with increased surface tension remain collapsed. With increasing PPV to recruit alveoli and improve gas exchange, the compliant terminal bronchiole and alveolar ducts may rupture, leaking air into the interstitium, with resultant development of PIE. The development of PIE was well demonstrated by Ackerman in 1984. The occurrence of PIE greatly increases the risk of BPD development.
o Many different modes of ventilation as well as ventilator strategies have been studied to reduce barotrauma. In 1996, Bernstein compared synchronized intermittent mechanical ventilation (SIMV) to intermittent mechanical ventilation (IMV) in preterm infants with RDS. Infants weighing less than 1000 g ventilated with SIMV had less BPD. Others have employed high-frequency jet ventilation (HFJV) or high-frequency oscillatory ventilation (HFOV) to prevent barotrauma or to rescue infants when conventional ventilation (CV) has failed; results have been mixed.
o Comparisons of these studies are difficult secondary to the ventilator strategy employed and the definition of BPD used. After surfactant administration, infants in the Provo multicenter HFOV trial were randomized to CV or HFOV with a lung recruitment strategy. This study found that patients randomized to HFOV had no CLD at age 30 days and needed less oxygen at discharge. Similarly, in 1997, Keszler and colleagues studied HFJV versus CV in preterm infants with RDS who were treated with surfactant. Although the study was terminated early, secondary to neurologic complications of another HFV trial using a different ventilator strategy, infants treated with HFJV had less BPD (ie, oxygen requirement at 36 weeks corrected age), less need for supplemental home oxygen therapy, and had no difference in severe neurologic injury (eg, grade III or IV intraventricular hemorrhage or periventricular leukomalacia [PVL]).
o Regardless of the HFV strategy that was used, avoidance of hypocarbia and optimization of alveolar recruitment may decrease the risk of BPD development and CNS abnormalities.
• Oxygen and antioxidants: Oxygen (O2) can accept electrons in its outer ring to form oxygen free radicals. Oxygen free radicals can cause cell membrane destruction and DNA abnormalities. Neonates live in an oxygen-rich environment as compared to the fetus.
Oxygen is ubiquitous and necessary for extrauterine survival. All mammals have antioxidant (AO) defense to mitigate oxygen free radical injury. Neonates are relatively AO deficient. The major AOs in humans are superoxide dismutase (SOD), glutathione peroxidase, and catalase. Antioxidant enzyme (AOE) levels tend to increase during the last trimester of pregnancy, similar to surfactant production. Increases in alveolar size and number, surfactant production, and AOEs prepare the fetus for transition from a relatively hypoxic placental respiratory environment to a relatively hyperoxic extrauterine life. Preterm birth exposes the neonate to high oxygen concentrations with low AO reserves, thereby increasing the risk of oxygen free radical injury.
Animal and human studies of supplemental SOD and catalase supplementation have shown reduced cell damage, increased survival, and possible prevention of lung barotrauma. Lipid peroxidation is increased in neonates who develop BPD. Lipid peroxidation can be measured in vivo by measurement of expired pentane and ethane. In 2000, Davis and others studied SOD supplementation in ventilated preterm infants with RDS.
• Inflammation
o Activation of inflammatory mediators has been demonstrated in humans and animal models of acute lung injury. Activation of leukocytes perhaps by oxygen free radicals, barotrauma, infection, and other stimuli may begin the process of destruction and abnormal lung repair that results in acute lung injury followed by development of BPD.
o Radiolabeled activated leukocytes have been recovered by bronchoalveolar lavage (BAL) in preterm neonates receiving oxygen and PPV. These leukocytes, as well as lipid byproducts of cell membrane destruction, activate the inflammatory cascade and are metabolized to arachidonic acid (AA) and lysoplatelet factor. AA is catabolized by lipoxygenase, resulting in cytokines and leukotrienes. These byproducts may also be metabolized by cyclooxygenase to produce thromboxane, prostaglandin, or prostacyclin. All of these substances have potent vasoactive and inflammatory properties and are elevated in tracheal aspirates of newly ventilated preterm infants who subsequently develop BPD.
o Metabolites of AA, lysoplatelet factor, prostaglandin, and prostacyclin may cause vasodilatation, increased capillary permeability with subsequent albumin leakage, and inhibition of surfactant function, thereby potentiating barotrauma.
o Collagenase and elastase are released from activated neutrophils and may destroy lung tissue directly. Hydroxyproline and elastin (breakdown products of collagen and elastin) have been recovered in the urine of preterm infants who develop BPD. Alpha1-proteinase inhibitor mitigates the action of elastases and is activated by oxygen free radicals. Increased activity as well as decreased alpha1-proteinase inhibitor function may worsen lung injury in neonates. A decrease in the prevalence of BPD and in the need for continued ventilator support has been found in neonates treated with alpha1-proteinase inhibitor supplementation.
o Di(2-ethylhexyl)phthalate (DEHP), a degradation product of used endotracheal tubes, may cause lung injury. Increases in alveolar growth, alveolar number, and surfactant production occur from 24-40 weeks' gestation. The self-perpetuating cycle of lung injury is accentuated in the extremely preterm neonate with immature lung development.
o By contrast, in 1996, Yoon and colleagues found increased interleukin-6 in umbilical cord plasma of preterm infants who subsequently developed BPD, suggesting that intrauterine activation of the inflammatory cascade may predispose these infants to BPD.
• Infection: Maternal cervical colonization, preterm neonatal tracheal colonization, or both with Ureaplasma urealyticum have been implicated in BPD development. In 1988, Cassel and others found an 82% rate of U urealyticum colonization in infants who developed BPD as opposed to those infants with negative cultures. Heggie et al disputed these findings in 1994. Infection alone may activate the inflammatory cascade and damage the preterm lung, resulting in BPD. In 2000, Couroucli et al performed polymerase chain reaction (PCR) for some viruses, U urealyticum, and Mycoplasma species on tracheal aspirates within the first week of life in preterm ventilated infants. Positive PCR results for adenovirus were noted in infants who developed BPD.
• Nutrition
o Inadequate nutritional supplementation in the preterm neonate may compound the damage caused by barotrauma, inflammatory cascade activation, and deficient AO stores. Acute CLD may increase energy expenditures by preterm infants with limited reserves. Animal studies of newborn rats that were nutritionally deprived revealed decreased lung weights. AOE may protect the lung and help prevent or mitigate BPD. Trace elemental deficiency, especially copper, zinc, and manganese, in preterm neonates may predispose the infant to lung injury, and supplementation may provide protection. Vitamins A and E are nutritional AOs that may help prevent lipid peroxidation and maintain cell integrity. Supplementation of vitamin E in preterm neonates does not prevent BPD. Preterm neonates may be deficient of vitamin A, and trials of vitamin A supplementation to prevent BPD in preterm infants are ongoing.
o Extremely preterm infants may require large amounts of free water secondary to increased insensible water loss through thin immature skin. Excessive fluid administration increases the risk of symptomatic patent ductus arteriosis (PDA) development and pulmonary edema (PE). Increased ventilator settings and oxygen requirements necessary to treat PDA and PE may worsen pulmonary injury and increase the risk of BPD. Early PDA treatment may improve pulmonary function but does not affect the incidence of BPD.
• Genetics: Families with a strong family history of atopy and asthma may be at increased risk for BPD development, as well as increased severity. The histocompatability subtype locus anthocyanins 2 (A2) has been found in infants with BPD.
o In 1967, Northway and associates first described 4 different stages of severity. Stage 1 was similar to uncomplicated RDS. Stage 2 revealed pulmonary parenchymal opacities and a bubbly appearance to lungs. In stages 3 and 4, patients had areas of lung with atelectasis, areas of hyperinflation, bleb formation, and fibrous sheaths. Edwards in 1979 and Toce in 1984 have subsequently redefined Northway's original findings and correlated BPD scores with illness severity.
o More recently, CT scanning and MRI studies of infants with BPD have provided more detailed images of the damaged airway and lung. In 1999, Aquino and colleagues demonstrated scarring and air trapping with architectural distortion in 26 patients with a median age of 10 years who had a clinical history of BPD. The degree of abnormalities correlated with the physiologic assessments of pulmonary function.
• Cardiovascular changes: Endothelial cell proliferation, smooth muscle cell hypertrophy, and vascular obliteration have been demonstrated in infants with BPD who have died. Cor pulmonale may result from these vascular alterations. Serial ECG may reveal right ventricular hypertrophy, and echocardiography may demonstrate abnormal right ventricular systolic function and left ventricular hypertrophy. Persistent right ventricular hypertrophy or fixed pulmonary hypertension unresponsive to oxygen supplementation on cardiac catheterization portends a poor prognosis.
• Pulmonary mechanics: Increased resistance and airway activity may be evident in the early stages of BPD. With worsening severity, airway obstruction can become significant, with expiratory flow limitations. In the early and mild stages of BPD, FRC can be increased; however, increases in FRC are noted in severe BPD secondary to air trapping and hyperinflation. Lung compliance is reduced in infants with BPD. Changes on PFT results correlate with radiographic findings. Compliance is often reduced in infants with BPD secondary to increased resistance, resulting in frequency dependence and tachypnea often observed in these infants. Serial PFTs may help assess therapeutic modalities employed to treat BPD, but they are fraught with variability and error from excessive chest wall distortion as well as the locations from which measurements are made.
• Airway
o The upper proximal airway (trachea and mainstem bronchi) of infants with BPD may have mild-to-severe abnormalities depending on the duration and frequency of intubation and ventilation. Diffuse or focal areas of mucosal edema, necrosis, or ulceration may be observed. The earliest changes noted on light microscopy include loss of cilia from columnar epithelium, dysplasia, or necrosis of these cells with breakdown of epithelial lining. Neutrophil and lymphocyte infiltration into the affected areas may be noted, along with goblet cell hyperplasia and increased mucus production. Granulation tissue and upper airway scarring may occur from deep suctioning and repeated endotracheal intubation, which may result in laryngotracheomalacia, subglottic stenosis, and vocal cord paralysis.
o The terminal bronchioles and alveolar ducts may reveal the most significant pathophysiologic changes. Hyaline membranes appear during the acute phase of RDS, which may be incorporated into the underlying airway. Necrotizing bronchiolitis may occur as a result of edema, inflammatory exudate, and necrosis of epithelial cells. Inflammatory cells, exudate, and cellular debris may obstruct the terminal airways, thereby simultaneously resulting in airway obstruction and providing alveolar protection from oxygen and barotrauma/volutrauma. Activation and fibroblast proliferation may result in peribronchial fibrosis and obliterative fibroproliferative bronchiolitis, leading to airway narrowing and restriction in some conducting channels with obstruction in others.
• Alveoli: In the acute phase of RDS, some alveoli are collapsed secondary to increased surface tension and surfactant deficiency, while compliant alveoli may become hyperinflated and even rupture. Focal atelectasis, areas of hyperinflation, and inflammatory exudate may be observed. Normal alveolar architecture is subsequently distorted. Emphysematous blebs and alveolar and capillary destruction is observed with moderate-to-severe disease.
• Incidence: Determining the incidence of BPD is confounded by the definition used as well as the population being studied. An analysis of several surfactant trials reveals an incidence of BPD (ie, oxygen requirement at age 28 d with abnormal findings on chest radiography) ranging widely from 17-57%, with no significant difference between placebo- and surfactant-treated survivors. In 1998, Kresch et al performed a more recent meta-analyses of surfactant replacement therapy for infants weighing less than 2 kg, which demonstrated improved survival without BPD in infants receiving modified natural surfactant. Infants with severe BPD are often extremely immature and of very low birth weight, although term infants with significant respiratory failure may also be at increased risk. In fact, since the survival of very low birth weight infants has improved by surfactant supplementation, the actual prevalence of BPD has increased.
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