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Statement on the Care of the Child with Chronic Lung Disease of Infancy and Childhood

Executive Summary

  I. Introduction, Definitions, and Epidemiology, 356

    A. Introduction, 356

    B. Definitions of Bronchopulmonary Dysplasia, 357

    C. Is the Prevalence of Chronic Lung Disease of Infancy Changing?, 357

    D. Differential Diagnosis, 358

  II. Pathophysiology and Pathogenesis, 358

    A. Respiratory System, 358

    B. Cardiovascular System, 363

    C. Feeding, Nutrition, and Gastrointestinal System, 363

    D. Renal System, 364

    E. Neurologic System and Development, 365

    F. Ophthalmology, 366

    G. Chronic Lung Disease of Infancy as a Multisystem Disease, 366

  III. Evaluation and Diagnostic Studies, 366

    A. Respiratory, 366

    B. Cardiologic, 369

    C. Nutritional, 370

    D. Renal, 370

    E. Neurodevelopmental, 371

    F. Ophthalmologic, 371

  IV. Treatment, 371

    A. Transitioning the Infant with Chronic Lung Disease from Hospital to Home, 371

    B. Specific Interventions, 374

      1. Bronchodilators, 374

      2. Antiinflammatory Drugs, 375

      3. Oxygen Therapy, 376

      4. Airway Problems and Tracheostomy Care, 378

      5. Long-Term Ventilator Care, 379

      6. Diuretics, Afterload Reducers, and Other Cardiac Pharmacology, 379

      7. Nutrition, 379

      8. Development Intervention, 381

      9. Ophthalmology, 381

      10. Well-Child Care, 382

      11. Ethical Issues, 382

  V. Conclusions and Clinical Research Questions, 383

EXECUTIVE SUMMARY

Chronic lung disease of infancy (CLDI) represents the final common pathway of a heterogeneous group of pulmonary disorders that start in the neonatal period. Often the inciting factor is bronchopulmonary dysplasia (BPD), a chronic condition that usually evolves after premature birth and respiratory distress syndrome due to surfactant deficiency. Myriad other conditions can also cause airway and parenchymal inflammation that leads to chronic airflow obstruction, increased work of breathing, and airway hyperreactivity. Usually the inciting factors are not only the underlying disorders, but also the effects of the supportive treatment, including mechanical ventilation, barotrauma, and oxygen toxicity. These aggressive interventions for serious neonatal and infant lung diseases are often responsible for much of the chronic pulmonary abnormalities that follow. There has been an evolution of the etiologies of CLDI as well; most current CLDI is seen in infants born increasingly prematurely, and represents a disorder of intrauterine inflammation and premature extrauterine lung development characterized by alveolar simplification. This is in contrast to the early descriptions of BPD, in which postnatal inflammation and fibrosis due to barotrauma and oxygen toxicity played more of a role.

These early lung disorders have far-reaching consequences that extend into childhood and beyond. In addition, they are often accompanied by precipitating and complicating conditions that are not relegated to the respiratory system; CLDI is truly a multisystem disorder. This statement reviews more recent advances in our understanding of the pathophysiology of CLDI, not only in the respiratory system but also in the multiple organ systems involved in these children. The current approaches to diagnostic evaluation of CLDI and its complications are reviewed, and specific interventions based on understanding pathophysiologic mechanisms are discussed. Throughout, an interdisciplinary approach to the care of these children is emphasized. Finally, future directions for clinical research leading to better understanding and more effective prevention and treatment of CLDI are suggested.

I. INTRODUCTION, DEFINITIONS, AND EPIDEMIOLOGY

A. Introduction
Chronic lung disease of infancy (CLDI) is a heterogeneous group of respiratory diseases of infancy that usually evolves from an acute respiratory disorder experienced by a newborn infant. CLDI most commonly occurs in infants with birth weights less than 1,500 g, and especially in those with birth weights less than 1,000 g and who are treated for respiratory distress syndrome (RDS). However, any disorder that produces an acute lung injury and/or requires treatment with positive-pressure mechanical ventilation and high concentrations of inspired oxygen during the initial weeks of life predisposes the infant to the development of CLDI. Therefore, in addition to RDS, conditions that have resulted in CLDI include pneumonia/sepsis, meconium aspiration pneumonia, pulmonary hypoplasia, persistent pulmonary hypertension, apnea, tracheoesophageal fistula, congenital diaphragmatic hernia, congenital heart disease, and congenital neuromuscular disorders (1, 2).

The terminologies used to describe chronic lung disease arising from neonatal insults are confusing. The terms "bronchopulmonary dysplasia" (BPD) and "chronic lung disease of prematurity" (CLDP) are sometimes used interchangeably to describe chronic respiratory disease following treatment for RDS in preterm infants. A National Institutes of Health (NIH, Bethesda, MD) workshop report suggested that the term "bronchopulmonary dysplasia" be retained in preference to "chronic lung disease," citing the lack of specificity of the latter term (3). However, the term BPD has certain histologic and pathogenetic implications associated with oxygen toxicity and/or barotrauma, which certain lung diseases of prematurity (e.g., Mikity–Wilson syndrome, or chronic pulmonary insufficiency of prematurity) do not necessarily share. Conversely, BPD can occur in infants who were born at term. Furthermore, it has been argued that BPD today (the "new" BPD) is different from the BPD described 30 years ago, as the increased survival rate among more premature infants has meant that barotrauma and oxygen toxicity are acting on increasingly immature and possibly more susceptible lungs. One proposed nosology suggests that both BPD and CLDP are forms of CLDI. When infants with CLDI grow into childhood and adolescence, it is probably more appropriate to call residual pulmonary problems simply chronic lung disease (CLD) (Figure 1) . In any event, the principles of the long-term management of all these disorders are largely similar.

View larger version (18K): [in this window] [in a new window]   Figure 1. Proposed nosology of chronic lung disease of infancy. The term bronchopulmonary dysplasia (BPD) best describes chronic lung disease subsequent to oxygen and/or ventilator therapy for respiratory distress syndrome (RDS) in preterm newborns. Some full-term newborns can have BPD subsequent to mechanical ventilation for other neonatal respiratory conditions. Chronic lung disease of prematurity (CLDP) is sometimes used interchangeably with BPD, but this term is best reserved for other chronic lung diseases of the preterm infant that can arise after an initial period without an oxygen or ventilatory requirement. All these disorders are types of chronic lung disease of infancy (CLDI), which can evolve after infancy into CLD of childhood and adolescence. FT = full-term; RDS = post–respiratory distress syndrome of prematurity.

Most of the suggestions given for diagnostic evaluation and treatment of the child with CLDI are based on review of the more recent literature and the experience of the authors. These are not clinical practice guidelines per se, which are best based on formal evaluation of large, randomized, placebo-controlled, blinded clinical trials, often including metaanalyses. Although such trials, some of which are described in this statement, are available in the neonatology literature, they deal primarily with prenatal and postnatal prevention of BPD. Unfortunately, such large clinical trials dealing with the care of established CLDI and CLD in later childhood have not been performed. Until this is the case, care for these children will have to be based on critical evaluation of the literature and experience.

B. Definitions of Bronchopulmonary Dysplasia
A working definition of BPD is necessary, because it is from BPD that the majority of cases of CLDI arise. Since BPD was first described by Northway and coworkers in 1967 (4), there has been considerable debate about the clinical and functional characteristics (and the age at which to determine these characteristics) that should be used in its definition. In 1979, Bancalari and coworkers (5) proposed three basic criteria to define BPD: (1) supplemental oxygen requirement at 28 days of postnatal life, (2) persistent abnormalities of the chest radiograph, and (3) tachypnea in the presence of rales or retractions. In 1989, the Maternal and Child Health Bureau (6) proposed the following diagnostic criteria for BPD: (1) positive-pressure ventilation during the first 2 weeks of life for a minimum of 3 days, (2) clinical signs of respiratory compromise persisting longer than 28 days of age, (3) requirement for supplemental oxygen for more than 28 days to maintain a Pa_O2 above 50 mm Hg, and (4) chest radiograph with findings characteristic of BPD.

The use of the above-defined criteria has been questioned (7–10). With advances in treatment, many infants who still require oxygen at the age of 28 days either do not require prolonged mechanical ventilation during the newborn period or do not have the characteristic radiographic changes of BPD. It has thus been suggested that simple oxygen requirement at 28 days in infants with birth weights of 1,500 g or less be used as a criterion to define BPD (7, 9).

Shennan and coworkers (8) disputed the definition of BPD based on oxygen need beyond 28 days of age. They reasoned that most BPD observed presently occurs in very low birth weight infants with gestational ages of 30 weeks or less. They thus proposed that the need for supplemental oxygen at 36 weeks postconceptional age would be a more accurate estimate of the pulmonary outcome. Other studies suggest, however, that oxygen dependence at 28 days of life remains a useful definition in predicting subsequent respiratory morbidity (11).

A National Institute of Child Health and Human Development/National Heart, Lung, and Blood Institute/Office of Rare Diseases workshop refined the definition of BPD to reflect differing criteria for infants born at gestational ages of greater or less than 32 weeks. In addition, the new definition reflects differing severities based on oxygen requirements of less than or greater than 30% FI_O2 and/or a need for positive-pressure ventilation (3).

C. Is the Prevalence of Chronic Lung Disease of Infancy Changing?
1. Incidence of BPD.
It is unclear whether the prevalence of CLDI is increasing, decreasing, or staying constant. Changing epidemiology and definitions of the disorder complicate the analysis. The increased survivability of infants with the lowest birth weights, in whom the incidence of BPD is the highest (12–16), would favor an increase in the overall prevalence of CLDI (17, 18). This increased survival can be attributed to the introduction of the widespread use of antenatal steroids in the 1970s as well as the more recent introduction of surfactant replacement therapy, newer modes of mechanical ventilation that reduce barotrauma, better nutritional interventions, and careful monitoring of oxygen therapy. The definition of BPD used may affect the estimation of incidence. Studies using a more stringent definition of BPD (oxygen requirement at 36 weeks postconceptional age rather than at 28 days postnatal age) will suggest lower incidence rates. However, when either definition was used in a study comparing data between 1987 and 1997, the increasing percentage of survivors born at less than 32 weeks postconception in the latter period was reflected in an increased incidence of BPD in those survivors (19). A study estimated 30% of preterm infants with birth weights less than 1,000 g develop BPD (15).

2. "New" BPD versus "old" BPD.
The increasing survival of very low birth weight infants may affect not only the "quantity" but also the "quality" of the subsequent lung disease. The differing pathogenesis of BPD based on postconceptional age at birth is discussed below (Section II.A.1: LUNGS). Rather than a decrease in the incidence of BPD, we may be seeing a rising incidence of "new" BPD as the incidence of "old" BPD declines. It is currently unclear whether the long-term epidemiology and outcomes of children with these different forms of CLDI will differ.

D. Differential Diagnosis
There is a need to be vigilant for other conditions that are unrelated to CLDI but may mimic it to various degrees (Table 1) . Usually the neonatal history will help distinguish CLDI from these conditions. However, it is important to remember that CLDI may also be complicated by these conditions, and the listed diagnostic studies are often useful in ruling out concomitant conditions.

A. Respiratory System
1. Lungs.
The pathogenesis of CLDI is multifactorial. CLDI was originally ascribed to oxygen toxicity (4) and certainly prolonged exposure to high oxygen concentrations has complex biochemical, microscopic, and gross anatomic effects on lung tissues (20). The premature infant has a poorly developed antioxidant system and therefore is at risk of oxygen free radical damage (21). Free radical-mediated oxidation of proteins is demonstrated in tracheal aspirates on Days 1–6 (22) and lipid peroxidation reaches a peak on Day 5 (23). Baro- or volutrauma is also important (24), an inverse relationship being described between hypocarbia and the subsequent development of CLDI (25). Several follow-up studies have demonstrated that the most severe lung function abnormalities are found in children who required neonatal ventilation (26, 27). Pulmonary interstitial emphysema is a result of barotrauma (28) and is associated with a high incidence of CLDI (29). The immature lung is usually exposed concurrently to the dual insults of oxygen toxicity and barotrauma (30). The former, however, at least in the neonatal piglet, causes the more significant physiological, inflammatory, and histologic changes (31). All of the above-described pulmonary insults occur at a time when most preterm infants have a relative adrenocortical insufficiency, which may potentiate the inflammatory effects (32–34).

Although oxygen toxicity and barotrauma are frequently considered to be the major contributors to CLDI, other factors are also important. Many studies have demonstrated an association between patent ductus arteriosus (PDA) and CLDI, particularly in infants of extremely low birth weight (35). Infection, especially if temporally related, potentiates the effect of PDA on CLD risk (36). Late episodes of PDA in association with nosocomial infection are important in the development of CLDI in infants who initially have no or mild respiratory distress (37). Interestingly, however, neither ductal ligation nor prophylactic use of low-dose indomethacin initiated in the first 24 hours has been shown to significantly reduce the incidence of CLDI (38, 39).

The relationship between fluid balance and CLDI is controversial. A delayed diuresis has been suggested to be more common in patients with CLDI (39). In addition, infants with CLDI may receive more fluid in the first days of life (40) and it has been suggested that early sodium supplementation may impact unfavorably on CLDI because patients so treated tend to receive higher levels of parenteral fluids (41). Nevertheless, attempting to promote an early diuresis, either with diuretics (42) or albumin infusion (43), does not improve respiratory status. In addition, the data regarding fluid restriction and CLDI are conflicting (44–46), but could be interpreted as demonstrating that only fluid restriction from birth and maintained throughout the neonatal period is effective (46).

A variety of infections, including cytomegalovirus (47) and Ureaplasma urealyticum (48), have been associated with an increase in CLDI. A review of four cohort studies suggested the latter may be important in infants of birth weight less than 1,250 g (relative risk, 1.91; 95% confidence interval, 1.54–2.37) (49). In addition to the role of postnatal infection, antenatal chorioamnionitis may play a key role in the production of a fetal inflammatory response that may lead to early pulmonary damage as a substrate for the development of CLDI (50–52). The mediators involved in this inflammatory response are discussed below.

Infants who develop CLDI can be characterized as having a respiratory deterioration following an initial response to exogenous surfactant (53). In addition, persisting abnormalities of surfactant have been described in infants who develop CLDI and in animal models of this condition. These include delayed appearance of phosphatidylglycerol (54) and deficiency of surfactant protein A (SP-A) mRNA (55). Compared with gestational age and birth weight-matched control subjects, infants who develop CLDI may be further compromised by having higher levels of SP-A–anti-SP-A antibody immune complexes (56). In addition, activated neutrophils can mediate biochemical alterations in SP-A, as well as detrimental biophysical changes (57). Infants who develop CLDI have high alveolar capillary permeability (58). Serum proteins leak into the airways and inhibit surfactant function. There is a marked rank order of proteins with regard to their potency in impairing surfactant function (59). Analysis of airway specimens has demonstrated that even at 4–7 days, infants who subsequently either die or develop CLDI have lower levels of SP-A and higher protein content than do control subjects (60). Other surfactant function inhibitors are also present in the airways; levels of glycolipids, particularly lactosylceramide and paragloboside, are increased even in the first week (61).

Regardless of the etiologic pathway, which in most infants will be multifactorial (62), there is an early inflammatory response that persists over the first weeks. This topic has been excellently reviewed by Ozdemir and coworkers (63). During the acute phase of lung injury, the insults described above initiate a host response (63). Proinflammatory cytokines (interleukin [IL]-1, IL-6, and soluble intercellular adhesion molecule) are demonstrated in lung lavage fluid as early as Day 1 and reach a peak toward the end of the second week (64, 65). During the first week IL-1ß antigen concentration and IL-1 activity increase 16- and 61-fold, respectively (66). IL-ß plays a central role in the inflammation, inducing release of inflammatory mediators, activating inflammatory cells and up-regulating adhesion molecules on endothelial cells (67). In addition, there are high concentrations of another macrophage-derived cytokine, tumor necrosis factor (TNF)- (68). Both TNF- and IL-1 induce fibroblast collagen production (69) and cause pulmonary fibrosis in animal models. TNF- tends to rise later, the highest levels occurring from Days 14 to 28, when IL-6 activity has decreased (70).

There is also extensive release of chemokines. The chemokine IL-8 induces neutrophil chemotaxis, particularly in combination with either leukotriene B₄ or platelet-activating factor (PAF) (71). IL-8 is increased in the bronchoalveolar lavage fluid of infants who develop CLDI (72). The ß chemokine macrophage inflammatory protein-1, which is chemotactic for monocytes/macrophages, is elevated from birth in lavage supernatants from infants who develop CLDI compared with control subjects (73).

Production of the proinflammatory cytokines TNF-, IL-1ß, and IL-8 is regulated in part by the antiinflammatory cytokine IL-10. Sequential bronchoalveolar lavage samples over the first 96 hours have demonstrated the expression of proinflammatory cytokine mRNA and/or protein to be present, but IL-10 mRNA was undetectable (74). This deficiency in the ability of lung macrophages to express antiinflammatory cytokines may predispose to chronic lung inflammation (74).

Histologic and cytologic studies of infants with CLDI have reported increased numbers of inflammatory cells known to produce lipid mediators such as PAF (75), leukotriene B₄ (76), and complement component C5-derived anaphylatoxin (76). Sulfidopeptide leukotrienes C₄, D₄, and E₄ are 10- to 20-fold higher in infants who develop CLDI compared with control subjects with RDS (77). Preliminary evidence suggests that the cysteinyl leukotrienes are also involved in the sequelae of CLDI (78). These mediators attract and activate polymorphonuclear leukocytes, and break down pulmonary vascular endothelium with subsequent leakage of proteins into small airways (76). The levels of PAF correlate with the severity of CLDI (79). PAF is one of the most potent phospholipid mediators; in nanogram quantities it causes bronchoconstriction and vascular smooth muscle constriction. As a consequence, it has been hypothesized that the elevated levels of these leukotrienes may in part mediate the pulmonary hypertension and bronchospasm seen in infants with CLDI (80).

The increase in vascular permeability also leads to movement of leukocytes, initially macrophages and then neutrophils and subsequently monocytes and lymphocytes (81), from the pulmonary vascular compartment into the interstitial and alveolar spaces (63). Direct contact between the activated cells leads to further production of proinflammatory cytokines and other mediators (63). In addition, the activated neutrophils release reactive oxygen metabolites and elastase (82), which may damage the lung. Immunohistochemical analysis has demonstrated that the inflammatory infiltration is associated with striking loss of endothelial basement membrane and interstitial sulfated glycosaminoglycans (83). Glycosaminoglycans are important in restricting albumin and ion flux, inhibiting fibrosis in fetal animals, and controlling cellular proliferation and differentiation (83). The higher levels of elastase reported in certain studies (64, 84) may be restricted to infants who had pneumonia or required prolonged hyperoxic ventilation (85), but do occur in infants who go on to develop pulmonary interstitial emphysema (86). Raised levels of collagenase and phospholipase A₂ (87) and inactivation of ₁-antiprotease by oxidative modification (88) contribute further to the unfavorable protease–antiprotease balance of infants with CLDI (78). Interestingly, in a rat model of hyperoxic lung damage, supplemental ₁-antitrypsin prevented the reduction in compliance seen in untreated control subjects (89). The inflammatory cells and elastase activity remain elevated until 5 weeks of age (64, 84, 90).

In infants not destined to develop CLDI, after the initial injury there is recovery and resolution of the inflammatory process, usually by the end of the first week (91). The infant with CLDI, however, is exposed to ongoing insults resulting in chronic inflammation with further accumulation of inflammatory cells and production of mediators (63), and may also have an inability to mount an appropriate cortisol response in a setting of ongoing lung injury at the end of the perinatal period (92). The result is lung destruction and fibrosis, the latter being a prominent feature in infants with CLDI. The fibroblast is regulated by cytokines produced by alveolar macrophages, including transforming growth factor-ß and platelet-derived growth factor. TGF-ß, which increases the degradation of the existing extracellular matrix, is increased in bronchoalveolar lavage fluid at 4 days of age in infants who develop CLDI (93).

It has been advanced that the pathogenesis of BPD may be heterogeneous, and that the above-described etiologic pathways may be modified according to the postconceptional age at which the infant is born (94). According to this thinking, insults that take place early in the saccular phase of airspace growth (25–40 weeks postconception) have differing consequences from those occurring in the later saccular or alveolar phase (40 weeks to 2–4 years). Classic "old" BPD, occurring in older preterm infants, is characterized by varying degrees of pulmonary fibrosis involving proximal and distal portions of the airway, necrotizing bronchiolitis, peribronchial smooth muscle hypertrophy, squamous metaplasia, loss of ciliated epithelium and damaged ciliary apparatus, mucous gland hypertrophy with excessive mucus in the airway, vascular changes including smooth muscle hypertrophy and peripheral extension, and alveolar Type I cell injury, all contributing to atelectasis, scarring, and variation in alveolar size and shape. The alveolar destruction, reduced multiplication rate, and scarring contribute to emphysema. This form of BPD is characterized by late inflammation, more severe airway injury, and consequent heterogeneity of alveolar damage and fibrosis. There are regions of atelectasis alternating with emphysema. The alveoli served by the most damaged and obstructed airways are often the most spared, presumably having been protected from barotrauma and oxygen toxicity by the obstruction of the airways subtending them (95).

The increased survival of very preterm infants has led to the development of the "new" BPD, characterized by less severe cellular proliferation and fibrosis, but uniformly arrested alveolar development. Several lines of evidence suggest that early inflammation caused by maternal chorioamnionitis may play a key role in the development of this form of BPD. Epidemiologic studies have shown a positive association between maternal chorioamnionitis and BPD prevalence (despite a negative association with RDS) (52). Chorioamnionitis in the preterm sheep model causes decreased alveolar septation in the fetal lamb (96), an effect that can be traced to endotoxin (97). Other causes of alveolar simplification in the early saccular phase of lung development include mechanical ventilation (98), low PO₂, elevated PO₂, steroids (ante- or postnatal), cytokines, and malnutrition (99, 100).

2. Central and upper airways.
Central airways include those structures amenable to study via direct visualization with a standard pediatric (3.6-mm) fiberoptic bronchoscope: these would include the airways extending from the glottis to lobar or segmental bronchi. Central airway obstruction in the infant with CLDI has been associated with cyanotic or life-threatening episodes ("BPD or CLDI spells"), chronic wheezing unresponsive to bronchodilator therapy, recurrent atelectasis or lobar emphysema, and failure to wean from mechanical ventilation or to tolerate tracheal extubation.

2.1. Glottic and subglottic damage.
Endotracheal intubation has been associated with injury to supraglottic, glottic, subglottic, and tracheal tissues in newborns (101–106). Some degree of epithelial damage after endotracheal intubation is common (102, 103), ranging from focal epithelial necrosis over the arytenoid or cricoid cartilages or vocal cords, to extensive mucosal necrosis of the trachea. Early endoscopy after tracheal extubation overestimates the possibility of long-term damage. Because superficial lesions seen at the time of extubation often resolve without sequelae (105–107), the relationship between acute laryngeal or subglottic damage and development of acquired subglottic stenosis is unclear.

Acquired subglottic stenosis has been reported in 1.7 to 8% of previously intubated neonates studied retrospectively (101, 104, 108, 109), and in 9.8 to 12.8% of infants studied prospectively (107, 110). Clinical manifestations include postextubation stridor, hoarseness, apnea and bradycardia, failure to tolerate extubation, and cyanosis or pallor. Similar presentations can result from vocal cord injuries, glottic or subglottic webs or cysts, laryngomalacia, or extrathoracic tracheomalacia. Fixed lesions of the glottis or subglottis often produce biphasic stridor, whereas dynamic lesions usually cause only inspiratory stridor. Postextubation stridor is a significant marker for the presence of moderate to severe subglottic stenosis (107, 110) or laryngeal injury (105). Apnea can replace the usual sign of stridor in preterm infants, because of their easy fatigability and paradoxical response to hypoxemia (109).

Risk factors for laryngeal injury include intubation for 7 days or more, and three or more intubations (106). These same factors are also associated with acquired subglottic stenosis (107, 110). Efforts at reducing the length of tracheal intubation or avoiding intubation altogether have been associated with prevention of subglottic stenosis (111). No cases of subglottic stenosis were found among 201 premature infants when nasal continuous positive airway pressure (CPAP) was used in place of endotracheal intubation and mechanical ventilation or as an adjunct to shorten the course of endotracheal intubation (111). Although route of intubation is not itself a significant risk factor (107), numbers of reintubations were fewer when infants were intubated nasotracheally compared with orotracheal intubation (109).

Use of inappropriately large endotracheal tubes has also been shown to be an important risk factor for the development of subglottic stenosis (101, 107, 110). A tube size-to-gestational age (in weeks) ratio greater than 0.1 has been correlated with acquired airway obstruction (107, 110). In contrast, selection of appropriate-sized endotracheal tubes has been shown to decrease the incidence of subglottic stenosis as well (107, 112). With careful attention to tube size, no differences in gestational age or birth weight per se have been found between those infants who developed subglottic stenosis and those who did not (104, 107, 110).

Concomitant infection in the setting of mucosal injury has been proposed as a risk factor for subglottic stenosis (113). No data exist, however, to suggest that prophylactic or suppressive antibiotic use prevents or decreases the incidence of this complication. Preliminary data in animals suggest that use of aerosolized dexamethasone immediately after laryngeal injury may protect the airway and prevent subglottic scarring (114). How such antiinflammatory therapy might be used in infants receiving prolonged mechanical ventilation is unclear.

2.2. Tracheal stenosis, bronchial stenosis, or granuloma formation.
Acquired tracheal and bronchial stenosis or granuloma formation has been reported in CLDI infants aged 3 weeks to 17 months (115–118). The incidence of this complication among all infants with CLDI is unknown, as only those with acquired lobar emphysema, persistent lobar atelectasis, or unexplained medical failure have been studied (115–122). Within such groups, however, bronchial stenosis or granuloma formation was reported in 1.2 to 36% of infants studied (115, 122).

Endoscopic findings consist of airway narrowing or occlusion by thickened respiratory mucosa or circumferential nodular or polypoid granulations in the distal trachea, often extending into main bronchi (115–117, 120). Histologically, the masses of granulation tissue are accompanied by squamous metaplasia and ulceration of the overlying epithelium, and fibrosis in the mucosa and submucosa (115, 116).

Stenosis and granulation formation may not be complications of CLDP and CLDI per se but instead may be the result of extended endotracheal intubation and vigorous suctioning techniques. Such speculation is based on the observation that lobar emphysema resolved after removal of granulation tissue (115–117, 122, 123). Similarly, because these lesions tend to occur in the distal trachea and right-sided bronchi, repeated mucosal injury from suction catheters has been implicated as the likely mechanism. Acute mucosal injury to the carina and main bronchi occurs from unrestricted or "deep" suctioning (124, 125). In one nursery, the change in suctioning techniques from deep to shallow resulted in qualitatively less severe airway damage, even though the shallow-suctioned group was younger and received a longer course of mechanical ventilation (126).

Both the design of the suction catheter and the pattern of suctioning have been related to mucosal injury (115, 125, 127, 128). The size of the catheter should be small enough so as not to occlude the artificial airway totally, thus avoiding excessive negative pressure (usually 5–6F in newborns) (128). Catheters with multiple side holes on several planes are less likely to cause invagination of airway mucosa into the catheter than those with single side or end holes (125, 127, 128). Use of negative pressures above 50–80 cm H₂O increases the likelihood of mucosal damage and does not increase efficiency of secretion removal (129). The most important preventative measure, however, is to restrict passage of the suction catheter to the distal tip of the artificial airway, so that the airway mucosa is protected from injury (115, 125, 127, 128, 130).

2.3. Tracheobronchomalacia and acquired tracheomegaly.
Central airway collapse, or tracheobronchomalacia, has been documented in patients with CLDI ranging in age from 9 weeks to 35 months (117, 118, 131–134). Tracheomalacia was found in 45% and bronchomalacia in 34% of 47 infants with CLDI undergoing flexible bronchoscopy (122). As with other central airway lesions, however, the actual incidence of this complication is not known.

Infants with abnormal central airway collapse may be asymptomatic at rest, or demonstrate homophonous wheezing, often unresponsive to bronchodilator therapy. Wheezing becomes prominent with increased expiratory effort, and cyanotic spells ("BPD spells") may result. Acquired tracheobronchomalacia is differentiated clinically from congenital tracheobronchomalacia by a history of airway intubation and mechanical ventilation. Other lesions that cause airway compression, such as vascular rings, hypertensive enlarged pulmonary arteries, and emphysematous lobes, must be ruled out.

Acquired tracheobronchomalacia in CLDI has been attributed to barotrauma, chronic or recurrent infection, and local effects of artificial airways. The immature airway is a highly compliant structure that undergoes progressive stiffening with age (135–138). In various animal models, specific tracheal compliance decreases as much as threefold between the last third of gestation and birth (135, 138). These findings parallel changes in the human neonate (136), and appear to correlate better with changes in cartilage mechanics than with passive properties of tracheal smooth muscle (139, 140). The maturational reduction of compliance results in decreased tracheal collapsibility and resistance to deformation during positive-pressure ventilation. Nevertheless, significant and sustained airway deformation can occur at pressures commonly used in supporting infants with respiratory insufficiency. Doubling of tracheal volume and significant alterations in airway mechanics were described after brief exposure of isolated tracheal segments to a CPAP of 10 cm H₂O or to a peak pressure of 25 cm H₂O (141).

The magnitude of pressure-induced deformation is directly related to the compliance of the airway and inversely related to age. It would seem that strategies aimed at limiting peak pressures or minimizing mean airway pressures, such as rapid small positive-pressure breaths, would help to prevent deformational airway changes. It should be noted, however, that similar alterations in airway mechanics occur after exposure to high-frequency jet ventilation (142). Tracheomegaly acquired after extubation has been described in very preterm neonates (birth weight less than 1,000 g) who required mechanical ventilatory support (143).

3. Cardiorespiratory control during sleep.
3.1. Respiratory and cardiac function during sleep.
Several studies conducted starting in the late 1980s found that infants with CLDI experienced episodes of hypoxemia during sleep despite acceptable awake oxygen saturation (Sa_O2) (144–148). Clinically unsuspected episodes of hypoxemia during sleep were documented by Garg and coworkers (145) in infants with CLDI tested at a mean postconceptional age (PCA) of 41.0 ± 0.8 weeks. Episodes of desaturation with Sa_O2 values of less than 90% were more common during rapid eye movement (REM) sleep than during non-REM sleep. Although abnormal pneumographic findings did not predict abnormal desaturation episodes, time spent with an Sa_O2 under 90% was correlated with airway resistance (145). The possibility that desaturation may be linked to impaired lung mechanics is of special importance, because hypoxic episodes in infants with CLDI may be potentiated by airway obstruction and by an inability to compensate for this abnormality (149). Furthermore, it has been suggested that a decrease in the inspired fraction of O₂ may worsen airway obstruction (150). Therefore, episodes of hypoxemia may of themselves worsen lung mechanic abnormalities in infants with CLDI. On the other hand, high levels of oxygenation have been shown to decrease airway resistance in infants with CLDI (151).

Oxygen supplementation has been shown to be beneficial in infants with CLDI. Early studies found that the pulmonary vascular bed was responsive to oxygen in these patients (152, 153). Sekar and Duke (147) reported that supplemental oxygen improved central respiratory stability in infants with CLDI, leading to decreases in central pauses and in periodic breathing episodes. Unsuspected marginal oxygenation during sleep in infants with CLDI, together with a limitation in pulmonary reserves, may divert energy away from growth. Moyer-Mileur and coworkers (154) showed that infants with CLDI with Sa_O2 values between 88 and 91% during sleep exhibited decreased growth. In contrast, infants with CLDI with Sa_O2 values greater than 92% during prolonged sleep showed better growth.

Hypoxemia during sleep can also occur in older infants and young children with a history of severe CLDI. In a study of CLDI patients aged 3 to 5 years, Loughlin and coworkers found marked, prolonged episodes of desaturation during sleep despite an awake Sa_O2 value greater than 93% (155). The most severe desaturation episodes occurred during REM sleep. The same finding was reported by Gaultier and coworkers, who also noted REM sleep-related increases in transcutaneous partial pressure of CO₂ and thoracoabdominal asynchrony (156).

An abnormal sleep pattern with significantly reduced REM sleep has been reported in infants with CLDI (157, 158). Harris and Sullivan (157) reported sleep fragmentation and decreased REM sleep in six infants with CLDI with baseline O₂ values greater than 90% during sleep. When supplemental oxygen was given, all six infants had an increase in sleep duration due largely to an increase in REM sleep.

The severity of abnormalities in lung mechanics correlated with the degree of thoracoabdominal asynchrony in infants with BPD as defined by Northway and coworkers (4) tested at a mean PCA of 49 ± 3.2 weeks during quiet sleep (159). Thoracoabdominal asynchrony, a well-known phenomenon during REM sleep in infants, is due to loss of rib cage stabilization as a result of inspiratory intercostal muscle inhibition (160, 161). Rome and coworkers investigated whether residual CLDI affects this phenomenon (162). Infants with CLDI studied at a mean PCA of 41 ± 4 weeks experienced more asynchronous chest wall movements than normal preterm infants during both sleep states. The relationship between thoracoabdominal asynchrony and the severity of lung mechanics abnormalities seems to override in large part the effect of sleep states on chest wall movements. In the group of infants with resolving CLDI studied by Rome and coworkers (162), asynchronous chest wall movements throughout sleep were not associated with a significant difference in oxygenation between sleep states. Asynchronous chest wall movements during non-REM and REM sleep were extensively studied in 14 young children (mean age, 32 months; range, 19–46 months) with severe CLDI (163). During non-REM sleep, thoracoabdominal asynchrony included paradoxical abdominal movement during early inspiration in the majority of these patients. Expiratory muscle activity was suggested as a potential mechanism for the paradoxical abdominal movement. The severity of paradoxical abdominal movement was significantly correlated with age between 2 and 4 years of age, suggesting that the change from the circular infant-type thorax with horizontal ribs to the elliptical adult-type thorax with oblique ribs, which occurs around 2 years of age in normal children (164), may result in patterns of thoracoabdominal asynchrony similar to those observed in adults with chronic lung disease. During REM sleep, the typical pattern of thoracoabdominal asynchrony included paradoxical rib cage movement during inspiration in the study of young children with severe CLDI (163).

The influence of sleep on cardiac function in severe CLDI was assessed in five children aged 1.5 to 5 years (165). Left and right ventricular ejection fractions were determined by equilibrium radionuclide ventriculography during the different states of alertness assessed on the basis of neurophysiological criteria. During sleep, marked decreases in both left and right ventricular ejection fractions were seen in the two children with the lowest nocturnal Sa_O2 levels and the most prolonged paradoxical rib cage movements during inspiration. These data suggest that sleep-related hypoxemia may lead to substantial impairment in right ventricular function and to mild impairment in left ventricular function.

One study looked at heart rate variability during sleep in 10 oxygen-dependent patients with severe CLDI aged 7 to 29 months (166). The patients were studied at normal Sa_O2 levels (greater than 95%) and at slightly decreased Sa_O2 levels (90 to 94%). Abnormalities in the autonomic control of heart rate variability suggesting long-term changes in autonomic heart rate control were found. The changes were more marked at slightly decreased Sa_O2 levels than at normal Sa_O2 levels, indicating that even mild hypoxemia occurring repeatedly may adversely affect autonomic heart rate control.

3.2. Sudden infant death syndrome risk in infants with CLDI.
An increased risk of mortality during the first year of life has been documented in infants with CLDI (167, 168). It has been widely cited that infants with CLDI are at high risk for sudden infant death syndrome (SIDS).

An association between CLDI and SIDS was suggested by Werthammer and coworkers in the early 1980s (169). Home pulse oximetry was unavailable and home oxygen therapy was not often used at the time. Werthammer and coworkers found that the incidence of SIDS was increased sevenfold in a group of 54 outpatients with CLDI versus a group of 65 control infants without CLDI. Infants with CLDI had Northway Stage IV radiographic changes (4). Histologic evidence of resolving CLDI was found at autopsy in all the SIDS infants with CLDI. The diagnosis of SIDS was based on the absence of any other cause of death at autopsy. This higher incidence of SIDS in infants with CLDI is at variance with a report by Sauve and Singhal (170). From 1975 through 1982, Sauve and Singhal studied the postdischarge death rate in 179 infants with CLDI and in 112 control subjects. Of the 20 deaths recorded in the study group, only 1 was ascribed to SIDS (170).

During the early 1990s, two studies on the occurrence of apparent life-threatening events (ALTEs) and/or SIDS in infants with CLDI were published (171, 172). Iles and Edmunds monitored 35 infants with chronic lung disease of prematurity defined as oxygen dependency at 28 days of postnatal age and 36 weeks of PCA. There was no control group (172). ALTEs occurred in seven cases, and one infant died unexpectedly. This infant was not receiving supplementary oxygen at the time of death; changes due to chronic lung disease were minimal and were not believed to be a significant factor in the infant's death. Gray and Rogers (171) reported follow-up data from 78 preterm infants of 26 to 33 weeks gestational age, who were discharged after being diagnosed with CLDI on the basis of the clinical criteria of Bancalari and coworkers (5). Twenty infants received home oxygen therapy. The control group comprised 78 infants matched with the study infants by birth weight categories. None of the infants died during follow-up. Seven (8.9%) of the patients versus eight (10.5%) of the control subjects experienced an ALTE. None of the infants receiving home oxygen therapy had an ALTE. These findings suggest that infants with CLDI may not be at increased risk for SIDS if they receive appropriate management including close attention to oxygenation. The treatment of CLDI has changed considerably since the early 1980s, with far greater emphasis being placed on ensuring adequate oxygenation not only at the hospital but also after discharge.

Infants with CLDI who die suddenly probably have clinically unrecognized periods of hypoxemia (145, 169, 173). Abnormal ventilatory and/or arousal responses during sleep may contribute to their death. Garg and coworkers reported abnormal responses to a hypoxic challenge in infants with CLDI with a mean PCA of 41.4 ± 1.3 weeks (174). Twelve infants with CLDI weaned from supplemental oxygen breathed a hypoxic gas mixture (inspired partial pressure of O₂ equal to 80 mm Hg) while asleep. Although 11 infants showed arousal in response to the hypoxic challenge, all the infants required vigorous stimulation and supplemental oxygen after this initial arousal response, suggesting an inability to recover from the hypoxia.

Ventilatory and arousal responses to hypoxia depend on the function of the peripheral chemoreceptors (175). These reset to a higher PO₂ level after birth (176). Hypoxia during the neonatal period has been shown to delay peripheral chemoreceptor resetting in newborn animals (177). Studies have sought to determine whether hypoxemic episodes in infants with CLDI result in altered responsiveness to chemoreceptor stimulation. Peripheral chemoreceptor function can be tested in isolation, using either the hyperoxic test (HT) (178) or the alternating breath test (ABT) (179). The hyperoxic test induces "physiologic chemodenervation" of the peripheral chemoreceptors. The decrease in minute ventilation occurring after a change in the inspired fraction of oxygen from normoxia to hyperoxia is believed to reflect an acute reduction in peripheral chemoreceptor input and, therefore, the strength of the peripheral chemoreceptor drive. The ABT delivers a rapid hypoxic stimulus to the peripheral chemoreceptors by means of breath-by-breath alternations between a low and a normal inspired O₂ fraction. Both tests are reproducible under standardized conditions (180, 181). Calder and coworkers (182) reported a reduced response to the ABT in eight infants with CLDI as compared with age-matched control infants. Katz-Salamon and coworkers designed a more extensive study involving an HT in 25 infants with CLDI and in 35 preterm infants without CLDI (183). All infants were tested during the 40th week postconceptional age. Sixty percent of the infants with CLDI lacked a hyperoxic ventilatory response. The intensity of the hyperoxic response was negatively correlated with the time spent on a ventilator and positively correlated with the time spent without supplemental oxygen. The degree of chemoreceptor activity was closely related to the severity of CLDI, with none of the infants in the most severe CLDI category (Grade III [184]) showing a ventilatory response to hyperoxia. Thus, infants with CLDI may have deficient peripheral chemoreceptor function as a result of repeated and/or prolonged hypoxemia responsible for impaired postnatal peripheral chemoreceptor resetting.

The same group investigated whether peripheral chemoreceptor responsiveness returned to normal during recovery from CLDI (185). Ten preterm infants with chronic lung disease and absence of a response to the HT were divided into subgroups based on disease severity (184). Episodes of desaturation were recorded during sleep despite supplemental oxygen therapy. However, these episodes decreased in number with advancing age. All the infants but two, who were in the category of maximal disease severity, developed a response to the HT within the first 4 months, at a mean postnatal age of 13 weeks (range, 9–16 weeks). The two exceptions developed the response to hyperoxia at a much later postnatal age (6 and 8 months). Thus, the most severely affected infants lacked the HT response at the age of peak occurrence of SIDS. Infants with CLDI who do not have functional peripheral chemoreceptors are unable to mount a protective response against hypoxemia and may be at risk for ALTE and SIDS (186, 187).

Interestingly, whereas development of peripheral chemoreceptor sensitivity to hypoxia seems to be impaired in subjects with CLDI who have had significant repeated or prolonged hypoxemia, the converse may also be true: hyperoxia during early life may attenuate peripheral chemoreceptor function (188–190).

B. Cardiovascular System
1. Cor pulmonale.
The pulmonary hypertension and resulting cor pulmonale that is present in some patients with CLDI is produced by both functional and structural changes in the lung. In addition to acute vasoconstriction caused by alveolar hypoxia, hypercarbia, or acidosis, patients with CLDI have altered pulmonary structure involving the airways and arteries. Most patients with CLDI are born prematurely with birth weight less than 1,000 g, so that altered structure occurs in an immature lung. Although studies of pulmonary structure have been limited to fatal cases (4, 24, 95, 191–201), it is reasonable to assume that similar although less severe anatomic changes occur in patients with milder forms of CLDI. Alveolar development is impaired, with a reduced number of alveoli forming with somatic growth. Because arteries accompany the airways, there is a reduced number of intraacinar arteries; this is true of both "old" and "new" BPD. The reduction in vascular number along with alveolar hypoxia contribute to structural changes in the pulmonary arteries. The arteries that are present frequently are remodeled by medial hypertrophy and abnormal extension of muscle to arteries in the periphery (those accompanying alveolar ducts and alveoli); there can also be endothelial cell injury and intimal proliferation and thickening of the adventitia that reduces the cross-sectional area of the vascular bed and increases wall stiffness. Arteries coursing through scarred regions have further reduction in external diameter. Vascular changes in more recent studies have not been as severe as reported in earlier investigations, possibly because of improved methods of mechanical ventilation (196, 199). There is structural remodeling and an attempt at normal adaptation in childhood with a trend toward decreased medial hypertrophy with age (195).

Studies of the molecular basis for the vascular changes in BPD have examined the role of vascular endothelial growth factor. These studies have suggested that lung vascular endothelial growth factor expression is decreased in BPD, and that impaired vascular endothelial growth factor signaling can contribute to the disordered vascular growth and perhaps diminished alveolarization as well (202–204).

2. Systemic hypertension.
Infants with CLDI can develop systemic hypertension (195, 205–209). There is a higher incidence of this complication in patients with CLDI compared with a group of infants who had only respiratory distress syndrome (208). Between 6 weeks and 1 year of age the upper limits of normal (95th percentile) for blood pressure while awake (not crying or feeding) is 113 mm Hg, and during sleep it is 106 mm Hg (210). The blood pressure should be recorded during the inpatient and outpatient follow-up period. When systemic hypertension occurs in patients with CLDI it is usually detected in the first year of life, with a mean age of diagnosis of 4.8 months (range, 2 weeks to 15 months) (208). In one report 43% of patients developed this finding (208).

Hypotheses to explain the pathogenesis of systemic hypertension have included the potential effect of hypoxia or medications on stimulating the renin–angiotensin or adrenergic system (207, 208). There may also be altered pulmonary endothelial function as evidenced by decreased clearance or net production of norepinephrine by the lung in patients with CLDI (205). Although many of these patients had umbilical artery catheters placed in the neonatal period, the use of such monitoring is not significantly related to the occurrence of hypertension. Patients receiving steroids as part of a therapeutic program to improve pulmonary function can develop systemic hypertension (207, 211); in such a circumstance decreasing the dose, changing the route of administration (nebulized instead of oral), or discontinuation of these agents should be considered. Systemic hypertension is usually transient, lasting a mean of 3.7 months (range, 1 to 10 months) in patients not treated with antihypertensive agents (208). Approximately half the reported patients have required medical therapy, which produced normalization of the blood pressure.

3. Left ventricular hypertrophy.
Patients with CLDI can develop left ventricular hypertrophy (LVH), for often unclear reasons. The incidence of this feature in this patient group is difficult to determine because LVH documented by echocardiography or autopsy is frequently undetected by electrocardiographic screening alone (167, 212). Doppler and M-mode echocardiography have shown that LV posterior wall thickness is directly correlated, and transmitted flow velocities and early diastolic/atrial contraction flow velocity are inversely correlated, with the severity of BPD (213). The contribution of LVH to the clinical course of CLDI has not been settled. If hypertrophy is severe enough, it may cause an elevation in left atrial pressure, thereby potentially contributing to pulmonary edema and the severity of CLDI (212). In one retrospective series, patients with prolonged mechanical ventilation (greater than 60 days) and late unexpected sudden death had a higher incidence of LVH than patients with a similar ventilatory course who survived (167). However, whether LVH represents an independent risk factor is unclear because these patients also had prolonged use of multiple pharmaceutical agents. The pathogenesis of LVH has been attributed to the metabolic effects of chronic hypoxemia, hypercarbia, and acidosis, which can increase cardiac output (207, 212); stimulate the renin–angiotensin system, thereby elevating afterload (95); or produce scarring of the myocardium (198). In addition, the more negative intrathoracic pressure during inspiration in these patients increases left ventricular afterload and can contribute to hypertrophy (214). Although a single identifiable cause is usually not found, patients with LVH should be screened for systemic hypertension or, with the aid of echocardiography, for left-to-right shunting via a patent ductus arteriosus or large systemic-to-pulmonary collateral vessels. Serial echocardiograms are necessary to monitor the degree of hypertrophy and the level of myocardial function.

C. Feeding, Nutrition, and Gastrointestinal System
Infants with CLDI have difficulty maintaining a rate of growth, weight gain, and development similar to that of a healthy infant of the same age. The causes of growth failure and malnutrition in affected infants include concomitant dysfunction of other organ systems (producing congestive heart failure or renal insufficiency in some infants), decreased nutrient intake (which is generally a consequence of fluid restriction, swallowing dysfunction and fatigue during feeding, or dysphagia due to reflux esophagitis), hypoxemia, and increased requirements for energy. Infants with CLDI and tachypnea have poorer growth and increased growth hormone secretion compared with control infants and infants with CLDI and normal respiratory rates (215). In general, there is no significant impairment of nutrient absorption or digestion in these infants unless there is concomitant bowel disease or there has been bowel resection due to necrotizing enterocolitis (216).

1. Energy.
An increase in oxygen consumption is present early in the illness and correlates with severity of disease. This may reflect an increased work of breathing and therefore increased energy expenditure and may lead to energy requirements greater than those of healthy age-matched infants. However, methodologic problems in investigating infants who require supplemental oxygen make the precise determination of energy expenditure in these infants uncertain at this time. Indirect calorimetry, which has been the method by which energy expenditure is measured in these infants, is inaccurate under conditions of increased FI_O2 (217). Nevertheless, investigators have demonstrated increased energy requirements in infants with CLDI and growth failure compared with similar infants who were growing well (218). The energy expended in the work of breathing only partially accounts for the observed increases in oxygen consumption in infants with CLDI and growth failure. Resting metabolic energy requirements are higher in those infants as well and also contribute to their increased energy and nutrient needs (219). Anemia of prematurity may cause increased heart rate, stroke volume, cardiac output, and shortening fraction. Although transfusion can correct these problems, it has not been shown to reduce oxygen consumption, carbon dioxide production, or energy expenditure (220). Frequent infections can increase energy needs. Medications such as caffeine, theophylline, and ß agonists may also increase energy expenditure (221). The decrease in respiratory work effected by these medications may, however, balance the increase in metabolic rate.

2. Water and electrolytes.
Fluid retention may significantly limit or restrict pulmonary function in infants with BPD. In the early phase of the illness, increased levels of renin, angiotensin, and aldosterone have been documented (222). In addition, humidification in the incubator, and through mechanical ventilation to greater than 80% relative humidity, reduces or eliminates the loss of water from evaporation through the respiratory tract, leading to positive free water retention. Water collecting in respiratory tubing and running down into the infant may also be a source of free water (223, 224). The water of oxidation increases with the increased substrate utilization that accompanies the increased energy requirements seen in some of these infants and also contributes to a positive free water balance (219, 225).

3. Vitamins and minerals.
Specific nutrients may play a role in the protection of parenchymal tissue or in the healing of injured tissue. Vitamin A deficiency has been associated with abnormal secretions in the lung, interruption of normal water homeostasis across tracheobronchial epithelium, absence of cilia, and lack of airway distensibility. All of these changes appear to be reversible with vitamin A supplementation. Premature infants as a group have lower serum and cord blood levels of vitamin A (226, 227). Vitamin A levels also appear to decline during the first 4 months of life in infants who are not receiving vitamin A-supplemented diets. This is often the case for infants with BPD (228, 229).

Whereas early reports suggested that vitamin E supplementation may be of benefit in the treatment of BPD, a subsequent study did not confirm any specific benefit for therapeutic amounts of vitamin E (230). Finally, supplementation with inositol, a nonessential nutrient supplied at 80 mg/kg/day for 5 days, increased the survival of a group of infants with respiratory distress syndrome and lowered the subsequent incidence of BPD (231).

Infants with CLDI are at great risk for delayed skeletal mineralization and osteopenia of prematurity. Low body calcium and phosphorus stores are exacerbated by calciuretic effects of chronic diuretic therapy (232).

4. Gastroesophageal reflux.
Small, fragile infants with CLDI are prone to gastroesophageal reflux, which, on occasion, may complicate enteral feeding and worsen an already compromised respiratory system by causing asymptomatic aspiration or triggering bronchospasm (118). Medications such as theophylline and, to a lesser extent, ß agonists may also increase the risk (233). Whereas it is clear that uncontrolled gastroesophageal reflux can complicate the management of established CLDI, the role that gastroesophageal reflux plays in the pathogenesis of BPD lung disease is controversial.

D. Renal System
Multiple variables, including the degree of renal maturation (a function of gestational age and postnatal age), the extent of respiratory compromise, the amount and character of fluid administered, and other nonrenal obligate losses all play major roles in determining the type of changes observed in the body fluids and electrolytes.

When pulmonary insufficiency occurs, several pathophysiologic processes can indirectly or directly modify renal function (234). Direct physical factors related to the pulmonary process, such as increased thoracic pressure accompanying positive-pressure ventilation, that adversely affect cardiac output can limit the excretion of extracellular fluid and sodium. Hormonal factors appear to play a conflicting role in the regulation of salt and water balance under conditions of pulmonary insufficiency. Atrial natriuretic peptide and vasopressin are peptide hormones commonly affected by changes in lung function. Vascular resistance in the pulmonary circuit may remain elevated, resulting in a distended right atrium that, in turn, results in a chronic increase in circulating atrial natriuretic peptide levels (235, 236). Decreased glomerular filtration rate, tubular immaturity, and a generalized decrease in renal blood flow may attenuate the effects of this natriuretic peptide. Vasopressin has also been shown to be persistently elevated in infants with CLDI (237).

Drugs are capable of affecting renal salt and water handling by the premature infant. Furosemide is perhaps the best studied agent employed in the treatment of premature infants with CLDI (238–240). Furosemide clearly has been shown to increase lung compliance and decrease airway resistance in the short term, but these effects do not consistently improve oxygenation (238, 239). The repeated administration of furosemide, however, has been associated with potential side effects, including sodium, chloride, and volume depletion (241). Infants with CLDI who develop hyponatremia and hypochloremia exhibit a higher incidence of hypertension and lower growth rate including that of head circumference (208, 241).

Renal calcifications were first described in premature infants in 1982 (242). The pathogenesis of nephrocalcinosis in very low birth weight infants appears to be multifactorial. The vulnerability of extreme immaturity and the underdevelopment of renal function may be the most important variables. Hypercalciuria is common in the very low birth weight infant, yet not all develop nephrocalcinosis (242). Decreased glomerular filtration rate, low citrate excretion, and frequently an alkaline urine are in part due to the immaturity of renal function of these infants. The development of CLDI frequently requires the administration of diuretics that may cause phosphaturia and magnesium depletion, increasing calcium excretion. Even transient insults to the kidneys, such as hypoxia or hypotension or the use of nephrotoxic drugs, provoke tubular injury.

E. Neurologic System and Development
Children with CLDI are developmentally vulnerable. Prematurity and low birth weight predispose them to all the risks of preterm birth, including infection, poor growth, brain injury, and disorganized behavioral interactions. In addition, they are subject to developmental and behavioral effects of impaired respiratory function.

Studies on the neurodevelopmental outcome of children with CLDI are limited because CLDI rarely exists in isolation. Premature infants and children with CLDI frequently have other medical problems that impact on behavior and development, including intraventricular hemorrhage, sepsis, anemia, apnea, parenteral feeding, ophthalmologic problems, and auditory deficits. Data generated about developmental sequelae must be interpreted cautiously in that the role of each risk factor in influencing outcome may be unclear. In addition, the causes or predisposing risk factors for the prematurity may be important in the assessment of developmental outcome. Maternal age, maternal substance abuse, absence of prenatal care, pregnancy-induced hypertension, maternal infection, or other maternal medical disorders may cause prematurity and resultant CLDI. These conditions may also directly impair fetal brain growth and development during prenatal, perinatal, and postnatal development.

1. Neurodevelopmental outcome.
Developmental outcome studies of children with CLDI in the first 24–30 months of life have shown that CLDI is associated with lower scores for motor and cognitive function compared with premature control children matched for gestational age (243, 244). Most of these studies used the Bayley Scales of Infant Development, which assess psychomotor development and cognitive/mental development (245). This standardized measurement reflects neurologic (especially motor) status and cognitive skills. These studies reveal that at 24 months of age, children with CLDI have a frequency of abnormal neurologic examinations that range from 0 to 38%. The prevalence of cognitive developmental problems ranges from 14 to 80% (170, 246–249). The range of deficits among the studies reflects different definitions of CLDI during the past 20 years, exclusion criteria, and rates of case dropout over time. Socioeconomic variables and different neonatal care practices also account for some of the reported differences. In outcome studies that assessed infants at 2 years of age, it appeared that neurodevelopmental outcome reflected the duration of oxygen supplementation and hence severity of pulmonary illness (8). However, studies that assess developmental outcome into the school age period show a lack of significant correlation between outcome and duration of mechanical ventilation or oxygen therapy. The primary predictor in these late outcome studies has been central nervous system injury, either intraventricular hemorrhage or infection (250).

The studies in early neurodevelopmental outcome suggest that, between 24 and 36 months of age, many children with CLDI who demonstrate abnormal motor or cognitive skills improve dramatically compared with premature control children (250). Studies have extended this observation into the school age period. An assessment of school performance and neurodevelopmental outcome among school age children with CLDI showed that outcome scores were similar to those of premature control subjects without CLDI matched for gestation and birth weight. This finding held with both the older definition of CLDI (supplemental oxygen to a postnatal age of 28 days) and the newer definition (supplemental oxygen until the equivalent of 36 weeks of gestation in preterm infants with a birth gestation of 31 weeks or less) (250–252).

There were no significant differences in neurologic findings at 8 years of age among the children with CLDI and premature control subjects. This included assessments of cerebral palsy, visual impairment, deafness, and severe mental retardation. However, those with CLDI who required oxygen supplementation until the equivalent of 36 weeks of gestation had the highest percentage of multiple disabilities (38%). When school age children with CLDI, but without a major neurologic disability, were compared with term-matched peers on a variety of learning tests, lower scores were seen (Table 2) (250). This observation held for full-scale IQ scores; visual–motor integration; receptive vocabulary; achievement tests in reading, spelling, and arithmetic levels; and hyperactivity. Not surprisingly, premature subjects at 8 years of age, with and without CLDI, performed at lower levels on all these tests compared with full-term control children. The lower scores of children with CLDI thus appeared to be related more to prematurity than to CLDI per se (250, 253).

In the past decade there has been further neurodevelopmental follow-up of children with CLDI that may be more indicative of the "new" BPD. These studies raise concerns regarding both the role of BPD and its treatment with corticosteroids (254–256). While verbal and performance IQ scores do not seem to differ between children who had CLDI and preterm control subjects, children who had CLDI did have a higher prevalence of abnormal "soft" neurologic signs, including visual–spatial defects, impaired gross and fine motor coordination, and integration (243, 244, 253, 257).

2. Behavioral outcome.
Behavior of infants with CLDI has been assessed infrequently. Infants with CLDI have been compared with a control group of premature infants without respiratory disease, using the Preterm Infant Behavior Scale at 8 weeks of age. Infants with CLDI were less socially responsive to animate and inanimate stimuli, were not as cuddly, were more easily upset with sensory stimuli, had less skill in self-quieting, were less consolable, and had higher tone and lower hand-to-mouth ability than control subjects. Infants with CLDI have been characterized as having poorer self-organization and, in general, are not as "robust" as other premature babies (251). These behavioral observations have led to individualized neurobehavioral assessments of premature infants with CLDI. Nursing interventions have been designed to encourage state regulation, preserve energy by sensitive assessment of sleep–wake patterns, planning interventions consistent with the infant's behavioral state, and organizing the physical environment in a manner that supports preservation of energy and social interaction (258).

For a number of conditions associated with prematurity, it has become increasingly apparent that socioeconomic factors play a significant role in developmental outcome studies. Since the pioneering work of Werner, Escalona, and Sameroff and coworkers (259–261), neurodevelopmental outcome studies of premature infants have supported the "double hazard" of biological and social risk. Because many preterm infants with CLDI are born into poverty, social risk factors in this group of babies are significant. A low level of maternal education, low potential income status, and unemployment are major prenatal social risk factors associated with poorer outcomes (250, 262). That these problems do not disappear when the baby leaves the neonatal intensive care unit (NICU) is apparent. In addition, referral to child protective services by a health professional after discharge from the nursery was an additional significant risk factor that influenced long-term development. Most of the referrals were a result of neglect or mild physical abuse (263).

F. Ophthalmology
There is no known direct causal link between retinopathy of prematurity (ROP) and CLDI; however, both disorders share the single most important risk factor, extreme prematurity. For both disorders, the incidence and severity of disease increase as gestation at birth decreases. In animal models, the toxicity of exogenous oxygen can cause disorders resembling CLDI and ROP (264–266). In the later management of these established diseases, maintaining good arterial oxygenation to prevent cor pulmonale in CLDI can potentially conflict with the need to carefully manage arterial oxygen levels when the retina is not fully vascularized.

Vision loss from ROP is a consequence of excessive overgrowth of new vessels in the retina and vitreous cavity of the premature infant. This neovascularization is the recovery phase following an injury to the growing vessels, much as the fibrosis seen in CLDI follows the initial pulmonary injury. In Figure 2 , the proportion of retina vascularized is depicted over time in both the normal infant (upper line) and in the premature infant who is born long before the retinal vessels (that start growing at about 16 weeks of gestation) reach the edge of the retina (ora serrata).

View larger version (22K): [in this window] [in a new window]   Figure 2. Diagram illustrating the progression of retinal vessels from the disk to the ora in the normal in utero fetus (upper line) and in the infant born prematurely who develops retinopathy of prematurity (ROP) (lower line). Normal vascularization begins at about 16 weeks and is completed around term. If initial injury to the growing vessels occurs around the time of premature birth, the rate of vascularization is slowed. The shaded area indicates the timing of active ROP, which can be observed by an ophthalmologist. Reprinted by permission from Ross Laboratories (The micropremie: the next frontier. Report of the 99th Ross Conference on Pediatric Research. Columbus, OH: Ross Laboratories; 1990. pp. 145–153).

G. CLDI as a Multisystem Disease
CLDI is a multisystem disease. It is clear that there are many interactions between the pathophysiology of the various organ systems. Figure 3 summarizes the more important interactions between organ systems that have been reported in the literature and that have been outlined in this section. Figure 3 serves as a useful guide when performing an initial evaluation of the infant with CLDI.

View larger version (32K): [in this window] [in a new window]   Figure 3. Interactions between organ systems in infants with CLDI. Each arrow represents an interaction that has been shown to be of significance in the pathophysiology of CLDI. For details see Section II (PATHOPHYSIOLOGY AND PATHOGENESIS). Pulmonary Cardiac: Hypoxemia leads to pulmonary artery hypertension and possible vascular remodeling, which presents the right ventricle with an increased afterload against which to pump. Left ventricular dysfunction can also occur as a result of (1) decreased left ventricular filling due to rightward septal shift and (2) increased negative pleural pressure during inspiration due to decreased pulmonary compliance and resistance, leading to increased left ventricular transmural pressure. Pulmonary Renal: ; Syndrome of inappropriate antidiuretic hormone secretion (SIADH) in infants with CLDI can reduce renal excretion of water. Pulmonary Neurologic: Chronic hypoxemia can affect neurologic growth and development independent of the effects of prematurity. Pulmonary Musculoskeletal: Abnormal lung mechanics can lead to diaphragmatic remodeling to more fatigue-resistant Type I fibers; respiratory muscle fatigue and chronic respiratory pump failure are seen in severe CLDI. Pulmonary Nutrition: Chronic hypoxemia is one cause of failure to thrive in infants with BPD. Increased work of breathing, decreased efficiency of breathing, and chronic inflammation can all divert calories that otherwise might be used for growth. Pulmonary GI: Pulmonary hyperinflation may affect diaphragmatic configuration and lower esophageal sphincter function, leading to gastroesophageal reflux. Tachypnea can lead to swallowing dysfunction. Central airways Pulmonary: Excessive central airway collapsibility can lead to abnormalities in forced expiratory flow, air trapping, and hypoxemia. Abnormal lung mechanics can in turn affect airway collapsibility by increasing pleural pressure swings to which the airways are exposed. Renal Pulmonary: Decreased renal excretion of water can cause increased lung water, decreased lung compliance, and increased airway resistance. Renal Nutrition: Decreased renal function is associated with failure to thrive. Renal Cardiac: Decreased renal excretion of water can pose an increased preload on the left ventricle. Neurologic-developmental musculoskeletal: Developmental delay commonly affects muscle tone, and motor skills. Neurologic-developmental GI: Swallowing dysfunction has been described in infants with CLDI, probably due to adverse oromotor stimulation combined with central nervous system dyscoordination of the swallow reflex. Neurologic-developmental Pulmonary: Control of breathing may be affected in infants with CLDI, possibly because of a reset respiratory control center secondary to chronic respiratory muscle fatigue. These effects may be more marked during sleep. There may be a predisposition to SIDS. Neurologic-developmental Central airways: Poor control of the upper airway and pharyngeal musculature can lead to upper airway obstruction, especially during sleep. Musculoskeletal Pulmonary: Respiratory muscle weakness and fatigue can lead to chronic respiratory failure. Nutrition Pulmonary: Poor nutrition as a consequence of decreased caloric intake and excessive caloric expenditure can lead to delayed lung, chest wall, and alveolar growth, delaying pulmonary healing. Nutrition Neurologic-developmental: Malnutrition leads to decreased central nervous system growth and skeletal muscle weakness, which in turn adversely impacts gross motor development. Nutrition Musculoskeletal: Malnutrition can cause respiratory muscle weakness and susceptibility to diaphragmatic fatigue. GI Pulmonary: Aspiration due to GE reflux and/or swallowing dysfunction is a common cause for failure of the pulmonary status to improve in infants with CLDI, leading to pulmonary inflammation and bronchospasm. GI Central airways: Aspiration can also lead to central airway inflammation, with subsequent homophonous wheezing, and excessive collapsibility. Cardiac Pulmonary: Left ventricular dysfunction causes increases in lung water, leading to increased airway resistance and decreased lung compliance. Cardiac Central airways: Left atrial enlargement can compress the left main bronchus leading to atelectasis. Airway malacia may develop in the compressed airway segment. Cardiac Renal: Decreased cardiac output causes decreased effective renal blood flow, leading to renal sodium and water retention. Cardiac Nutrition: Heart failure can cause failure to thrive. GE = gastroesophageal; GI = gastrointestinal.

A. Respiratory
1. Pulmonary.
Until more recently, assessment of lung function in infants was performed only rarely. In the past 15 years, however, there have been numerous studies of developmental lung function in normal infants and comparative studies in infants with CLDI.

1.1. Lung volumes.
Lung volumes in infants with CLDI and less than 6 months of age have been reported as both lower (270–272) and higher (273–275) than those of normal control infants. This discrepancy may be due to methodologic differences: studies reporting low values used helium dilution, which can underestimate lung volumes in the presence of airway obstruction, whereas studies reporting increased lung volumes have used body plethysmography. One study directly comparing the two techniques in 36-week postconceptional infants showed that FRC in infants with CLDP was lower than normal when measured by nitrogen washout, but higher than in control subjects when measured by body plethysmography (276).

FRC in infants with CLDI and older than 6 months has been reported as normal (270, 277) or as increased by up to 60% (272). Longitudinal studies have demonstrated a shift from low to relatively high FRC between the ages of 1 and 3 years (278).

In summary, most studies show that lung volumes are low early in infancy and become normal or elevated later in infancy. Methodologic differences probably do not account for this change. Over time, pulmonary fibrosis may become less important relative to airway disease and, therefore, lung volumes may increase disproportionately with growth (2).

1.2. Pulmonary and respiratory system compliance.
Because compliance is dependent on lung volume, the results of most studies are expressed as "specific compliance" (corrected for body weight, lung volume at FRC, or body length). Normal lung compliance is 1.2 to 2.0 ml/cm H₂O per kilogram body weight (270, 278, 279). Studies of infants with CLDI report dynamic specific compliance to be 30 to 50% of control values for infants 2 to 4 months of age (270, 272, 278, 279). Static compliance of the respiratory system in young (10 months postconceptional age) infants with CLDI, determined by the weighted spirometer technique, has been reported as 60% of control values (280). That static and dynamic compliance measurements yield similar values suggests that changes in parenchymal elastic properties alone can explain the low compliance seen in these infants, rather than altered airway properties leading to frequency dependence of c