Original Article

Nutrition and Bronchopulmonary Dysplasia

Beth Baisden MD, Oommen P. Mathew MD and Jatinder Bhatia MBBS
Medical Colleage of Georgia - Section of Neonatology, Augusta

Bronchopulmonary Dysplasia (BPD) has changed since the first description of this disease by Northway in 1967 (1). Historically those infants were older than 28 weeks, greater than 1500g, and exposed to high airway pressures and oxygen concentrations to treat Respiratory Distress Syndrome (RDS). The routine use of antenatal steroids, postnatal surfactant, gentler ventilation and better nutrition has led to the survival of much younger, smaller infants. These infants initially have minimal lung disease, but later develop ventilator-induced lung injury and oxygen toxicity due to prolonged oxygen and/or ventilatory support as a result of insufficient respiratory drive, recurrent infections and symptomatic patent ductus arteriosus (PDA).Delays in providing adequate nutrition further confounds the issue. Histopathologic specimens obtained from these very low birth weight (VLBW) infants show non-uniform inflation patterns, impaired alveolar formation, increased elastin, inflammation and edema (2, 3) , hallmarks of the new BPD. Requirement of oxygen for 28 days with X-ray changes (4) or oxygen requirement at 36 weeks post menstrual age (PMA) (5) is defined as BPD. A NICHD consensus conference in 2000 further differentiated the disease into mild, moderate and severe categories in infants < 32 weeks gestation (6).

VLBW infants are born during the late canalicular or early saccular stage of lung development. As a result, alveolarization with secondary septation of the saccules has not yet occurred and the pulmonary vasculature is underdeveloped. In attempting to keep these infants alive, our therapies may cause further injury to immature lungs. For example, mechanical ventilation and oxygen administration in premature baboons and sheep caused a halt in alveolar septation even at low tidal volumes and low FiO₂ (7, 8). Glucocorticoid administration, while enhancing surfactant synthesis, has also been shown in animal models to inhibit septation (9).

The diaphragm is the primary muscle of ventilation in the neonate. It is composed of several types of muscle fibers classified by their myosin heavy chain and the rate at which they hydrolyze ATP. The fibers consist of Type I (slow), Type IIa (intermediate fatigue resistance), Type IIb and IIx(fast, fatiguable) fibers. An analysis of muscle fibers from infants less than 37 weeks gestation show that they have approximately 9.7% slow, fatigue resistant fibers compared to term newborns who have approximately 25% fatigue resistant fibers (10). The number of this type of fiber continues to increase for several months after birth. This could make newborns more susceptible to fatigue before undernutrition is even considered.

In adult rat models, the diaphragm was able to tolerate 90 hours of nutritional deprivation without changes in its contractile properties or proportions of slow and fast fibers or susceptibility to fatigue (11). However, the diaphragm does not escape the effects of prolonged undernutrition. Studies in patients with chronic obstructive pulmonary disease (COPD), cystic fibrosis and anorexia all show that weight loss leads to an overall decrease in muscle mass of the diaphragm (12-14). In rodent models of undernutrition, it appears that the Type IIb and IIx (fast, fatiguable) fibers are affected more severely by lack of nutrients (15, 16). The consequences of decreased muscle mass, and more specifically loss of the fast fibers leads to a loss of force generated by the diaphragm (17, 18).
In neonates, another compounding factor is mechanical ventilation. In animal models, diaphragmatic force is decreased after only 12 hours of mechanical ventilation (19) and fiber muscle atrophy can occur after 24-48 hours on the ventilator.

Undernutrition also affects the lung parenchyma. A 2004 study of adult rats showed that both surfactant and elastin were decreased in nutritionally deprived animals compared to controls (20). This would certainly be an important consideration if it were found to be true in studies of neonates. The focus of this article is on the nutritional aspects of preventing and healing respiratory system injury in infants with BPD.

The addition of certain micronutrients to the diet to prevent or correct lung injury is not new. In theory, antioxidant therapy such as vitamins A and E and selenium should help prevent the lung injury of BPD. This is based on the findings that the preterm infant is deficient in these nutrients because of low reserves and their inability to upregulate the antioxidants in times of stress (21). Retinol, or Vitamin A, supplementation has shown the most promise. Other micronutrients such as Vitamin E, Selenium and Inositol have been tried.

Retinol is involved in epithelial changes in many organs, including the lungs. Before lung septation occurs, large stores of retinal precursors are found in fibroblasts at the sites of future alveolarization (22). Animal studies have shown that the presence of retinoic acid (RA) increased the number of alveoli in newborn rats and mice (23, 24). In an elegant study in mice in which two receptors for RA were deleted, the pups had decreased numbers of alveoli (25).

RA has also been shown to be involved in repair of lung tissue. In an adult animal model of emphysema involving elastase, the addition of RA halted the emphysema-like changes in the lungs (26). These changes are similar to those occurring in BPD. Despite the benefits of glucocorticoids in hastening lung maturity, their use interferes with alveolar development. The administration of RA to premature mice and rats partially reversed the halt in septation induced by the steroids (27).

Many preterm infants have low levels of retinol (<20 micrograms/dl) and retinol binding protein (<2.5 micrograms/dl) (28, 29). Furthermore, those infants that go on to develop BPD have lower levels than those preterm infants that do not develop BPD (30, 31).

The significant findings in animals led to studies in preterm infants. In a randomized, multicenter, placebo controlled, blinded trial of 807 infants there was a 7% decrease in BPD in those who received Vitamin A supplementation (32). A review of the literature prior to this study found 4 smaller, single center studies using different doses where the results were variable (33).

The NICHD trial used 5000 IU/dose of Vitamin A 3 times a week by intramuscular injection which was higher than the dose used in some of the previous smaller studies. Even then 22% of infants in the treatment group did not obtain adequate blood levels. A study in 2003 compared the NICHD dosing regimen to a higher dose regimen and a once a week regimen (34). The authors concluded that the higher dose regimen did not decrease the incidence of BPD compared to the NICHD dose and that the “standard” dose used in the NICHD trial led to better serum levels of Vitamin A than the once a week dose (34). A follow up study of the NICHD babies at 18-22 months of age did not show any better outcome in regards to postdischarge mortality, rehospitalization or post discharge pulmonary disease (35).

Investigations in to the supplementation of Vitamin E have not shown promising results. A trial of high dose vitamin C and E in premature baboons did raise the levels of these antioxidants to normal values, but the incidence of BPD was not decreased by treatment (36). Oral vitamin E was given to preterm human infants as part of a randomized controlled trial with the intention of reducing BPD by 50%, but treatment did not change the incidence of BPD in human subjects either (37).

Selenium is an essential cofactor in the glutathione peroxidase pathway, an important antioxident pathway that neutralizes hydrogen peroxide. Low levels of selenium have been documented in preterm infants and studies in New Zealand and the US have shown significant associations between low levels of selenium, glutathione peroxidase and the development of RDS and BPD (38, 39).

Inositol is found in pneumocytes and is important in surfactant production. A 1992 randomized, double blinded, placebo controlled trial in which 114 infants received inositol in TPN showed that those who received the supplement had a significantly decreased incidence of BPD (40). A 2003 Cocrane review of the literature found 1 additional trial that showed a reduction in BPD with the administration of inositol, but no large multicenter trials have been done and its addition to TPN is not routine in the US (41).

Adequate nutrition is required for any organ to develop, including the lungs. Ong and colleagues in 1998 showed that undernourished school children in a remote section of India had decreased lung function even when normalized for size (42). An important function of the lungs is the active process of inspiration.. It is the amount of pressure required to ventilate the lungs to a certain volume. Expiration is usually a passive process. However, as in BPD, if there is air trapping or pulmonary edema, expiration can become an active process. This requires the respiratory muscles to expend more energy and requires a higher percentage of the cardiac output. The amount of calories required to compensate for this increased energy expenditure appears to be about 15-25 kcal/kg/d by indirect calorimetry (43). A more accurate method using the doubly labeled water technique found infants with BPD had 15-25% more energy needs than controls (44).

How best to meet these increased demands is still a matter of debate. In a study of 60 preterm infants with BPD randomized to 24 cal/oz formula at 180 cc/kg/d compared to a 30 cal/oz formula given at 145 cc/kg /d, the infants receiving the higher calorie/lower volume formula had better intake, but this was felt to be because it was difficult for the infants in the high volume group to tolerate that much formula on a regular basis (45).

Adding fortifiers to alter the caloric density is another option. A 1998 study comparing two similar groups of infants randomized to receive a standard formula or one enriched with protein, calcium, phosphorus or zinc found better length, bone density and lean body mass at three months of age (46). Higher protein intakes of 3-3.6 g/100 kcal appear to be safe and provide better catch-up growth (47, 48). Another option is to increase the fat to carbohydrate ratio in hopes of decreasing the respiratory quotient and CO₂ production. This was found to be true in a two (49) week trial of a high fat formula, but the methods have since been questioned.

Providing adequate calories for infants with BPD is challenging. For one, infants who go on to develop BPD show signs of growth failure even before they reach 36 weeks PMA. DeRegner found that between 2 and 4 weeks of age, those infants that went on to develop BPD grew more slowly than infants of similar size who did not develop BPD (50). In another study, at 6 weeks post term, infants with BPD already had decreased weight, length and fat mass compared to healthy term infants (51). Follow up studies on growth at 1 year and beyond have also shown lower weight, length and head circumference and failure to exhibit catch up growth (51, 52). Adequate calories may not be the whole problem. These infants are prone to frequent infections, recurrent hospitalizations, GE reflux and poor oral motor skills. Of note, a Cochrane review of the adult literature found that nutritional supplements for stable COPD did not help the lung function (53).

Medications used to treat BPD also interfere with nutrition. Corticosteroids do help an infant wean from mechanical ventilation, but its administration can cause growth failure even after they are stopped (54). The mechanism of action of the corticosteroids appears to be related to its ability to inhibit growth hormone-insulin like growth factor 1 (GH-IGF 1) (55). The result is that fat is accumulated, but protein accretion and lean body mass are decreased. Diuretics such as furosimide can cause loss of essential electrolytes for growth such as sodium, potassium and calcium through increased renal excretion.

BPD is a multifactorial disease. It is the third most common chronic lung disease in children and as more and more, smaller premature infants survive, BPD will continue to be a common problem. Given that poor growth is common among infants with BPD in the hospital and especially, after hospital discharge (56), optimization of growth should be the goal. Although adequate nutrition is not the be all and end all in repairing lung injury, supplementation with protein, Vitamin A and possibly Inositol show promise in ameliorating the injury and promoting healing. Further research in this area is obviously needed.

References

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