Classic and “New” BPD

Journal of Neonatology

0971-2179

National Neonatology Forum

jn-21-2-010

REVIEW ARTICLE

Bronchopulmonary Dysplasia-Emerging trends

Singh

Jaideep

¹Sinha

Sunil

^2,*

¹Birmingham Heartlands Hospital, Birmingham, B9 5ST, United Kingdom.²University of Durham and The James Cook University Hospital, Middlesbrough, TS4 3BW, United Kingdom.

*E-mail: sunil.sinha@stees.nhs.uk

4–62007

212121126

Classic and “New” BPD

The term broncho-pulmonary dysplasia (BPD) was used initially by Northway in 1967 to describe prolongation of the healing phase of Respiratory distress syndrome (RDS) in preterm infants who had been ventilated in 80–100% oxygen with high positive airway pressures¹. These infants had severe respiratory symptoms and abnormal chest X-rays which at the extreme stages showed hyperinflation along with emphysematous bullae, described as classic BPD. However, as smaller and more premature infants are surviving with improvements in neonatal intensive care, the classic presentation of BPD has become uncommon. A change has also been seen in the pathology of BPD from that described by Northway in these more premature infants. This form of BPD is often referred to as the ‘new BPD’ ². The use of antenatal glucocorticoids and surfactant results in these infants to have a mild initial course of RDS and they are therefore not exposed to high ventilatory pressures and oxygen concentrations. Their chest radiographs frequently show only haziness and not hyperinflation and cystic changes of classic BPD. Therefore, it seems that factors other than oxygen and pressure are important contributors to lung damage in these infants.

In addition, there is another group of infants who develop the so called ‘atypical BPD’³. These infants have minimal respiratory symptoms and oxygen requirements in the first few days of life but subsequently go on to develop features of respiratory distress and oxygen requirements and even ventilatory needs.

Normal lung development and pathology of BPD

Fetal and neonatal lung development has been divided into four phases⁴.

The pseudoglandular period, from 7 to 17 weeks gestation when the bronchi and terminal bronchioles form. Pulmonary arteries grow along with the airways

The canalicular period, from 16–25 weeks gestation when the lumina of the bronchi and terminal bronchioles enlarge, the respiratory bronchioles and alveolar ducts develop and the lung tissue becomes highly vascular. In this phase pre-viable lung transforms to viable lung that can exchange gas.

Terminal sac period - 24 weeks to term when the alveolar ducts give rise to terminal air sacs (primitive alveoli). During this period the type II alveolar epithelial cells or pneumocytes produce surfactant.

Alveolar phase from 30 weeks gestation to 18 months age when the characteristic pulmonary alveoli develop with the lining of the alveoli becoming increasingly thin. A number of factors that interfere with alveolarisation have been identified and these include mechanical ventilation, glucocorticoids, pro-inflammatory cytokines, hyperoxia and hypoxia as well as poor nutrition⁵.

Pathology

Coalson showed that 7 days of mechanical ventilation with high oxygen concentrations in preterm baboons reduced the number of alveoli^6,7. Repeating the experiment in more preterm baboons who were treated with surfactant the same interference with septation was seen but without exposure to high concentrations of oxygen. There was also abnormal and dysmorphic pulmonary vasculature seen in the animal model of BPD. Infants with severe BPD have pulmonary hypertension and abnormal pulmonary vascular development.

Hussain⁸ described the pathology seen in these more preterm infants who die of the ‘new’ BPD. As compared to the findings of Northway in the pre surfactant era where airway injury, inflammation and fibrosis were the prominent findings, the infants with new BPD have less fibrosis and more uniform lung inflation. The airways of these infants have very little epithelial metaplasia and smooth muscle hypertrophy. There are however fewer and larger alveoli which indicates an interference with the normal septation of the alveoli pointing towards an ‘‘arrest in development’’. There is often a decrease in the pulmonary microvascular development.

Definition of BPD

BPD has been defined differently in published studies and this makes interpretation of results difficult and accounts for some of the variation in the incidence of BPD reported from different centres. Also the terms chronic lung disease and BPD are often used interchangeably in literature.

The most frequently used definition is that of the 1979 BPD workshop which used continued oxygen dependency at 28 days age along with radiographic changes⁹. Oxygen dependency beyond 28 days has been shown to be independently associated with subsequent respiratory morbidity and positive respiratory symptoms in pre-school years. Others use the term to describe oxygen dependency at 36 weeks post conceptual age which was suggested as a better predictor of long term respiratory outcome¹⁰. Chronic lung disease is associated with prolonged hospitalisation, increased risk of nosocomial infection, poor nutrition and growth, poor feeding skills, and increased risk for rehospitalisation after discharge from neonatal intensive care unit with respiratory illness^11,12.

Duration of oxygen therapy, the criterion used to define chronic lung disease depends on the oxygen saturation monitoring practices which have changed in the last decade. These criteria vary between units which makes comparison of current rates of BPD and oxygen dependence difficult¹³.

In a workshop of the NICHD and National Heart Lung and Blood Institute on chronic lung disease the issues relating to definition of BPD were discussed¹⁴. It was decided that the best name for the disorder is BPD in order to differentiate it from chronic lung disease of later life which can be of multiple etiology. A new consensus definition which categorises the severity of BPD was also proposed. As radiographic changes are difficult to interpret and not usually available at precise ages, these were omitted from the definition. This new proposed definition of BPD is outlined in Table 1Table 1

Consensus definition of BPD: diagnostic criteria¹⁴

Gestational age	< 32 weeks	> 32 weeks

Time point of assessment	36 wk PMA or discharge whichever comes first.	> 28 d but < 56d postnatal age or discharge whichever comes first
	Treatment with oxygen >21%forat least 28 days	Treatment with oxygen > 21% for at least 28 days
	plus	plus
Mild BPD	Breathing room air at 36wk PMA or discharge whichever comes first	Breathing room air by 56 d postnatal age or discharge whichever comes first
Moderate BPD	Need for < 30% oxygen at 36 weeks PMA or discharge whichever comes first	Need for<30% oxygen at 56d postnatal age or discharge whichever comes first
Severe BPD	Need for >30% oxygen and/or positive pressure (PPV or CPAP) at 36 weeks PMA or discharge whichever comes first.	Need for >30% oxygen and/or positive pressure (PPV or CPAP) at 56d postnatal age or discharge whichever comes first

PMA: Post menstrual age, PPV: Positive pressure ventilation, CPAP: Continuous positive airway pressure

Risk factors for development of BPD

Prematurity

Mechanical ventilation with subsequent barotrauma/volutrauma

Oxygen toxicity

Genetic polymorphisms

Patent ductus arteriosus/fluid overload

Poor nutrition

Infection and inflammation

Surfactant deficiency

Clinical risk factors related to the occurrence of lung injury and BPD vary and there are always more than one factor implicated. These include:

Gestation Incidence of BPD is highest in the very preterm infants and the risk increases with decreasing gestation and birth weight. BPD is uncommon in infants more than 30 weeks gestation. This suggests that incomplete development of the lungs plays an important role in the pathogenesis of CLD.

Surfactant deficiency Persistent surfactant abnormalities have been identified in infants who develop BPD including delayed appearance of phosphatidyl glycerol ¹⁵ and deficiency of surfactant proteins.

Oxygen toxicity Oxygen is toxic if used injudiciously¹⁶. Oxygen mediated tissue damage is due to the overproduction of toxic oxygen radicals-superoxide, hydrogen peroxide and perhydroxyl radicals. The preterm infant is particularly vulnerable as the anti-oxidant systems develop during the last trimester and so they have a deficiency of these protective enzymes. Reactive oxygen metabolites can inhibit protein and DNA synthesis, cause lipid peroxidation, oxidize enzymes and decrease surfactant synthesis¹⁷.

Mechanical ventilation¹⁸ The mechanisms of ventilator induced lung injury have been much better characterised in recent years. The lungs of the premature infants are especially susceptible to injury due to the presence of immature alveoli that are surfactant deficient, atelectatic and fluid filled and supported by a highly compliant chest wall. The mechanisms of ventilator induced lung injury can be divided into high ventilatory pressures (barotrauma), high tidal volume delivery (volutrauma) and repeated opening and closing during ventilation of closed atelectatic alveoli (atelectrauma).

Inflammation, infection and biotrauma Infection acquired both postnatallyand prenatally with subsequent inflammatory response plays a major part in the development of BPD. The inflammatory response is also triggered by a variety of other factors including mechanical ventilation¹⁸, free oxygen radicals, increased pulmonary blood flow due to PDA and pulmonary and systemic inflammation.

Ureaplasma urealyticum, Group B streptococcus and gram negative rods have been implicated as causes of chorioamnionitis and prematurity¹⁹. The role of prenatal infections in development of BPD is supported by the increased risk of infants born to mothers who have chorioamnionitis to develop BPD²⁰. Nosocomial infections in infants who receive prolonged ventilation due to poor respiratory effort rather than severe underlying lung disease have been implicated in increasing the risk of development of chronic lung disease. Infants who have colonisation of their airways with Ureapalsma urealyticum at birth have a higher risk of developing BPD although the association is not consistent²¹. Several studies have reported an increase in the concentrations of various inflammatory mediators in the alveolar washes of infants who develop BPD²². These inflammatory mediators are found from very early in life supporting the view that in many instances the inflammatory process starts before birth due to infection of amniotic fluid and fetal lungs.

Genetic polymorphisms Genetics is likely to play a significant role in the development of BPD. It has been shown using gene ablation in animal models that there are 'several morphoregulators of lung development including fibroblast growth factor -10, Bmp-4 and NKx2.1²³. Genetic polymorphisms in the genes controlling lung development may influence the development of BPD. Lescart has shown that Transforming Growth Factor present in the lungs of preterm infants predicts the need for home oxygen supplementation²⁴.

PDA and fluid overload Due to increase in pulmonary blood flow and subsequent increase in interstitial lung fluid, the patent ductus influences lung mechanics and causes increased ventilatory and oxygen requirements. Presence of patent ductus also increases the duration of ventilation. The presence of systemic infections adversely affects ductal closure due to increased concentrations of prostaglandins seen in infections. The presence of PDA has been associated with elevation in the concentration of myeloperoxidase in the alveolar lavage fluid suggesting damage to the pulmonary endothelium and subsequent adhesion and migration of neutrophils to the lung tissue²². There is also evidence that infants who receive higher fluid intakes during the first few days of life have a higher incidence of chronic lung disease²⁵.

Interventions for BPD1. Pharmacological therapyAntenatal steroids and postnatal steroids.

Antenatal gluco-corticoids accelerate the maturation of parenchymal structure, increase surfactant production and lung compliance, reduce vascular permeability and increase lung water clearance. This results in better lung function, improved surfactant production and survival but is not always associated with reduction in BPD.

Crowley reviewed the use of prophylactic corticosteroids for preterm birth for the Cochrane database²⁶. Antenatal administration of corticosteroids to women expected to give preterm births was associated with a significant reduction in mortality (odds ratio 0.60, 95%CI 0.48–0.75), respiratory distress syndrome (odds ratio 0.53, 95% CI 0.44–0.63) and intraventricular haemorrhage. No evidence was seen for the reduction in incidence of chronic lung disease but this is probably due to an increase in the survival rate.

As persistent inflammation is an important factor in the pathogenesis of BPD postnatal glucocorticoids have been used extensively not only to treat BPD but also to treat and prevent it. In total more than 35 randomised controlled trials of postnatal dexamethasone administration have been conducted so far. Three types of trials of postnatal steroids for the treatment of BPD have been identified and appraised by the Cochrane collaboration based on the time the steroids were administered. Early postnatal dexamethasone trials used dexamethasone within the first 96 hours of life, moderately early postnatal dexamethasone between 7–14 days, and delayed dexamethasone in infants more than 3 weeks age. There was a trend towards lower mortality in infants treated with dexamethasone using moderately early administration as well as reduction in BPD. Early and late administration of dexamethasone was associated with earlier extubation and decreased BPD. Although several trials have compared short term measures only a few have looked at the long term outcome of these infants. Of major concern therefore are results of trials that suggest an increased risk of cerebral palsy^27,28.

As with all meta-analyses, the evaluation of steroids for chronic lung disease using this technique suffers from certain drawbacks. These include the evaluation of different populations, use of different steroid dosages and duration of treatment, publication bias with positive results much more likely to be published and with only 25%-50% of the studies being published. The lack of follow up data is also a major drawback^29,30.

At present admininistrationion of glucocorticoids postnatally for prevention of chronic lung disease is not standard clinical practice and its use is restricted to babies who are ventilator dependent for a prolonged period where the risk benefit ratio may favour steroid use.

Caffeine therapy

Methylxanthines reduce the frequency of apnoea of prematurity. The caffeine for apnoea study randomised a large number of preterm babies with birth weight between 500–1200 grams within the first 10 days of life into either the caffeine or placebo arm³¹. Babies receiving caffeine discontinued positive airway pressure on an average a week earlier and survivors had a lower incidence of oxygen dependency at 36 weeks post conceptual age (adjusted odds ratio, 0.63; 95% CI, 0.52 to 0.76; P<0.001). Caffeine use may therefore be associated with lower incidence of BPD. There were concerns that use of caffeine might cause neuro-toxicity to the developing brain but this was not confirmed in this study.

Diuretics

Frusemide, thiazide and spironolactone are commonly used in infants with chronic lung disease. They are given to reduce alveolar and interstitial oedema and thus improve pulmonary mechanics. Reviews of diuretic therapy have only shown short term improvement in pulmonary therapy and oxygen requirements but no long term benefits such as reduction in mortality, duration of ventilation or oxygen use and the evidence base for their use is lacking^32,33.

Beta receptor agonists, anticholinergics and cromolyn sodium

Bronchial hyper-reactivity is a feature of some infants with BPD. Bronchodilators are theoretically useful medications in BPD. There are no RCT's to date assessing important clinical outcomes with the use of these agents and studies have only focussed on short term outcomes such as pulmonary mechanics³⁴. These studies have demonstrated no effects, some benefit or indeed worsening in the clinical status with the use of these agents.

2. Reducing oxygen toxicity-judicious use of oxygen and anti-oxidant therapies.

Hyperoxic lung injury can be reduced in tissue culture and in animal models by the administration of recombinant human superoxide dismutase, an antioxidant enzyme. In a placebo control multicentre trial of the use of this enzyme there was no difference in the primary outcome of death and/or BPD. Infants given the enzyme however had less severe IVH and PVL³⁵. Also at 6 months and 1 year corrected age the infants treated with the enzyme had reduced need for respiratory medication. This therapy needs further evaluation.

In an observational study Tin et al showed that preterm infants were 5 times more likely to develop severe retinopathy of prematurity when oxygen saturations were targeted at 96%-99% as compared to 75%-90%³⁶. Babies in high saturation group also had longer period of ventilation and oxygen supplementation, and more of these babies developed chronic lung disease. This gives support to the notion that targeting higher oxygen saturation may in fact be detrimental to pulmonary outcomes in preterm babies. Support to this notion also comes from two subsequent randomized controlled trials.

The STOP-ROP trial was conducted to see the effect of supplemental oxygen on progression of retinopathy of prematurity³⁷. In this trial preterm infants were randomized to receive conventional oxygen with pulse oximetry targeted at saturations of 89%-94% and the control infants were in the supplemental arm where oxygen supplementation was done to target saturations of 96%-99%. Pneumonia, exacerbations of chronic lung disease occurred in more infants in the supplemental arm. The other study (BOOST trial) has also shown that there is no benefit in maintaining oxygen saturations at 95–98% as compared to 91–94% in terms of growth and neurodevelopment³⁸. The high oxygen saturation group needed more prolonged hospitalization and longer home oxygen therapy.

3. Ventilatory strategies aimed to reduce ventilator induced lung injuryVolume targeted modes of ventilation

Ventilator induced lung injury has been shown to induce lung damage in surfactant deficient animals and can induce the changes of chronic lung disease in experimental animals. The high ventilatory pressures and volume delivery results in damage of the lung tissue and barotaruma and volutrauma are key causes of mechanical ventilation induced lung damage. In adults with ARDS the use of lower tidal volumes was associated with a reduction in mortality. There is emerging evidence from randomised studies that volume targeted modes of ventilation may have advantages over traditional Pressure Limited methods of ventilation including a potential to reduce the incidence of Chronic Lung Disease^39–41.

High frequency ventilation

Initial animal studies showed that HFV had the potential to reduce lung injury and thus reduce chronic lung disease. A number of large randomised studies comparing HFV and Conventional ventilation have been included in a Cochrane review⁴². This review of over 3000 babies has shown that HFV does not improve survival and the effects on the incidence of BPD were not consistent across the trials. At present there is not sufficient evidence to justify elective use of HFV in preterm babies.

Synchronised ventilation

The use of patient synchronised methods of ventilation, have been shown to reduce the duration of ventilation when compared to non synchronised ventilation. However no difference has been shown in the incidence of BPD⁴³.

Permissive hypercapnia

This is based on the assumption that deliberately allowing carbon dioxide tensions to remain at a higher than normal level might reduce the incidence of CLD, as well as reduce other complications and the duration of mechanical ventilation. The results of two prospective, randomized trials do not confirm this. More work will be necessary to determine whether permissive hypercapnia is indeed a lung protective strategy.

Early use of CPAP

Observational studies have shown that treating very preterm babies with CPAP is possible and may reduce the incidence of BPD. A recent meta-analysis looking at prophylactic use of CPAP soon after birth regardless of the respiratory status in infants less than 32 weeks gestation found no evidence that this strategy reduces BPD^44,45.

The COIN trial, presented in abstract form only at this stage, randomised 610 babies born at 25–28 weeks gestation to immediate nasal CPAP without surfactant or ventilation. There was no significant difference in the two groups in terms of mortality, duration of respiratory support, and oxygen treatment. More babies in the CPAP group developed pneumothorax (9% vs 3%)⁴⁶.

4. Control of infection

Measures directed at the control of nosocomial infections and aggressive treatment of any infection can be important. Careful hand washing, sterility of respiratory equipment is important. Tracheal secretions should be collected at regular intervals especially if there is a change in the nature of the secretions. It can be difficult to differentiate between colonisation and infection. Chest radiographs, blood cultures and blood counts may help in this. Selection of antibiotics depends on the sensitivity of the implicated organism.

5 Nutrition

Nutrition has an important role in normal lung development and repair of lung damage. Malnutrition has the potential to worsen BPD by compromising lung growth. Under-nutrition and protein deficiency may increase the vulnerability of the infant to oxidant induced lung damage and impair lung growth and DNA synthesis.

Nutritional management of preterm babies should be addressed from the first day. Parenteral nutrition and early enteral feeding are important. Polyunsaturated fatty acids have been shown to have a protective effect against lung injury in experimental models but failed to be of any benefit in clinical trials⁴⁷. Vitamin A has been shown in a recent trial to have a small but significant effect on the reduction of chronic lung disease⁴⁸. Inositol⁴⁹, selenium and sulphur containing amino acids and Vitamin E have also been studied and may have a role in protection against BPD. The use of these agents is however experimental at this stage.

Summary

Most small premature infants who acquire BPD at present have only a mild initial respiratory course and require ventilatory support mostly for the management of apnea and poor respiratory effort. In contrast to infants with severe BPD, these infants require mechanical ventilation with low pressures and oxygen concentration, and therefore are not exposed to barotrauma and oxygen toxicity. These infants require low or moderate initial concentrations of oxygen for treatment of mild RDS that usually responds favorably to exogenous surfactant. This is often followed by a few days with minimal or no supplemental oxygen need ("honeymoon"). Many of these infants however, have a progressive deterioration in their lung function overtime, wherein their ventilatory and oxygen requirements increase, accompanied by signs of respiratory failure (tachypnoea, retractions, etc). This deterioration is frequently triggered by bacterial or viral infections or heart failure secondary to a PDA. In these patients, the functional and roentgenographic lung changes are usually mild, sometimes showing only diffuse haziness that persists over time, without the more coarse changes of non-uniform inflation and cystic nature that is often observed in the classic severe form of BPD. The main morphologic change in the lungs of these infants is an arrest in alveolar and vascular development that leads to a decreased alveolo-capillary surface.

BPD occurs as a result of a number of factors which injure the lungs and interfere in its normal development after premature birth. There is compelling evidence that support the role of infection and inflammation in the pathogenesis of BPD. Prolonged neutrophil influx and increased cytokine activity in bronchoalveolar lavage fluid have been associated with an increased likelihood of BPD in ventilator-dependent premature infants. Colonization with specific microorganisms, such as Cytomegalovirus and Ureaplasma Urealyticum also have been associated with increased risk for BPD.

There has been very limited progress in preventing or treating BPD and this is largely due to the complex interaction of several factors in its etiopathogenesis. Strategies to minimize it include good obstetric care, antenatal steroids, gentler ventilation beginning in the delivery room, minimizing oxygen toxicity by appropriate oxygen saturation targeting, monitoring of tidal volumes to reduce ventilator induced lung injury, use of caffeine, early extubation to nasal CPAP and ensuring babies receive adequate nutrition.

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