Chronic Pulmonary Disease following Neonatal Respiratory Failure Broce G. Nickerson, M.D.
Infants with respiratory failure in the &rst weeks of life may develop a chronic pulmonary condition called bronchopulmonary dysplasia. 'Ibeir lungs have areas of atelectasis and areas of air trapping from variable obstruction of the airways. 'Ibese infants may be dependent on supplemental oxygen or a ventilator and may require hospitalization for months, and have symptoms of airway obstruction which last for years. 'Ibey require meticulous medical
management to avoid a number of common complications such as patent ductus arteriosus, cor pulmonale, tracheal stenosis, recurrent aspiration, and death. 'Ibe condition of most infants improves over the &rst two years. Preliminary studies suggest that their exercise and pulmonary function is usually close to normal by school-age. 'Ibe long-term implications for the increasing number of children with this disease who will soon reach adulthood are still unknown.
Bronchopulmonary dysplasia (BPD) was described in 1967 by Northway, Rosan, and Porter. 1 They described a series of roentgenographic changes in premature infants who survived hyaline membrane disease with respiratory failure. Since then, the term has been used to refer to a clinical syndrome of chronic pulmonary disease fOllowing respiratory failure due to many causes. • In the chronic phase the clinical features and roentgenograms of premature infants whose illness started with hyaline membrane disease, and those of more mature infants whose initial pulmonary disease was meconium aspiration or neonatal pneumonia, may be indistinguishable. Some authors prefer the term, chronic pulmonary disease fOllowing neonatal respiratory failure. This is a more accurate but cumbersome term, since respiratory failure is the common feature of the syndrome regardless of the initial cause; however, fur brevity and to reflect common usage, we will use the term, BPD, in this article. Bronchopulmonary dysplasia occurs in between 15 and 38 percent of infants under 1,500 g who require mechanical ventilation fur hyaline membrane disease. s.T A much smaller percentage of larger infants develop BPD. Despite many advances in neonatal intensive care, the most recent series from Northway's group at StanfOrd' still fOund that 20 percent of infants weighing less than 1,500 g developed radiographic changes of BPD. Because of small numbers, diffel'-
ences in survival of the smallest infants at highest risk to develop BPD, and the fact that milder degrees of chronic pulmonary disease may not be recognized until after discharge, claims that BPD has been eliminated should be viewed with skepticism. Prevention of BPD and neonatal pulmonary disease by improvements in prenatal and obstetric care is beyond the scope of this article.
•From the Pediatric Pulmonary Center, Children's Hospital Medical Center, Oakland, Cali£ ManUICript received September 7; accep~ed September 1.2. .Reprint n~gJIB#I: Dr. Nlcbnon, ChUdreni Hospital, 511t and Grooe, Odland 94609 128
The etiology of BPD is multifactorial. Most authors believe that BPD is an iatrogenic disease caused primarily by oxygen toxicity and barotrauma from mechanical ventilation. In addition, there is evidence suggesting that premature birth, fluid overload, patent ductus arteriosus, damage caused by severe pulmonary disease, and familial predisposition fur asthma play additional roles. OxYGEN TOXICITY
Bronchopulmonary dysplasia has been correlated with either short-term exposure to a fractional concentration of oxygen in the inspired gas (Flo.} of greater than 0. 80 or more prolonged exposure to lower oxygen concentrations in infants with hyaline membrane disease;5 however, some infants have developed BPD fOllowing mechanical ventilation fur apnea without exposure to supplemental oxygen. Experiments with animals, and tissue cultures have studied the mechanism of pulmonary oxygen toxicity. "'13 These and other studies fOund damage to the endothelial cells of the pulmonary capillaries by superoxide radicals produced by polymorphonuclear cells. Endothelial damage is Bronchopulmonary Dy8plata (Stuoe G. Nlclcer8on)
fOllowed by leakage of fluid into the interstitial spaces. Later, and with more exposure to oxygen, there is gross hemorrhage into the interstitial spaces and damage to the epithelial cells lining the airways. Still later, the interstitial edema is replaced by fibrosis, and squamous metaplasia of the bronchiolar and bronchial epithelium is round. These pathologic changes in the animal model of oxygen toxicity are similar to but do not exactly match the pathologic changes of BPD in humans. BAROTRAUMA
Bronchopulmonary dysplasia is also related to barotrauma. In a postmortem series, 'Iaghizadeh and Reynolds14 related BPD to peak inspiratory pressures greater than 35 em H10. Moylan et al18•18 also round an association between pneumothorax and BPD. Since pneumothoraces are related to overdistention of areas of the lungs, this is also a pressure-related phenomenon. Reynolds and 'Iaghizadeh• reported a dramatic decrease in the incidence of BPD fOllowing a change in ventilator regimens from high inspiratory pressures to lower peak inspiratory pressures with longer inspiratory times. Other groups17 have round a similar decrease in the incidence of BPD when lower inspiratory pressures were used. Recognition of the inspiratory pressure has been a importance oflimi~ng significant advance in prevention of BPD; however, some caution must be exercised. Pressures adequate to inflate the lungs should be used in order to avoid inadequate gas exchange and prevent the necessity fur higher oxygen concentrations or prolonged ventilation. 18 In some infants with very noncompliant lungs, the use ofhigh pressures is necessary fur survival. The exact mechanisms of pulmonary barotrauma are less well studied than oxygen toxicity. Dissection of air into the pulmonary lymphatic vessels may obstruct the drainage of interstitial fluid, preventing resolution of edema. 111 The recent development of primate models of respiratory distress syndromelliO shows promise fur greater future understanding of this phenomenon. Preliminary studies using high-frequency ventilation suggest that it may cause a different form of barotrauma. PATENT Ducrus ARrEruosus
Gay et al11 noted a high incidence of bronchopulmonary dysplasia among infants who had ligation of a patent ductus arteriosus. A number of subsequent seriesllll-14 have noted this same association between congestive heart failure due to left-to-right shunting through the patent ductus arteriosus and development of BPD. The increased Fio1 and ventilator settings necessary to support the infant through the pulmonary complications of a patent ductus arteriosus result in increased oxygen toxicity and barotrauma. Also, increased pulmonary blood flow
may cause additional pulmonary damage. Improvements in echocardiographic diagnosis, medical closure of the ductus arteriosus with the prostaglandin inhibitor, indomethacin, and early ligation in cases offailure of medical treatment have recently led to significant improvements in the care of infants with patent ducti. FLUIDS
Bronchopulmonary dysplasia may also be related to fluid overload in the first few days of life. Brown et al13 round that infants who developed BPD had received significantly more fluid during the first five days of life than infants who did not develop BPD. These investigators13 suggested that fluid overload might potentiate the other factors and increase the risk of BPD. Fluid overload is also associated with congestive heart failure in infants with patent ductus arteriosus. 111 Fluid status can be very delicate in the tiniest infants at most risk fur BPD. Infants weighing less than 1,000 g have huge insensible fluid losses through their skin due to the large ratio of surface area to body mass, the porosity of their skin, and the use of radiant warmers or phototherapy. Fluid balance is also complicated by frequent intolerance of enteral feedings, the necessity of delivering adequate nutrition while avoiding hypei'tonic solutions, and the technical difficulties of keeping intravenous catheters in small vessels. PREMATURITY
Premature delivery alone may have a significant effect on pulmonary development. Coates et al111 showed that premature infants who did not receive mechanical ventilation and did not have BPD had decreased function of their small airways when they were six to ten years old. These authors 18 postulated that prematurity alone resulted in differences in development of the small airways. Thus, premature infants might be particularly susceptible to additional damage to the small airways from oxygen, ventilator pressure, fluid, and circulatory overload. PuLMONARY DAMAGE FROM REsPIRATORY DISEASE
There are several studies which relate a long-term decrease in the function of the small airways to prior pulmonary diseases such as croup, bronchiolitis, and pneumonia early in life. 17.;n Acute respiratory failure may be fOllowed by chronic pulmonary disease in other situations. Follow-up studies of adults who survived respiratory failure have demonstrated persistent abnormalities of pulmonary volumes, gas exchange, and diffusing capacity. 311-34 From this evidence, one might expect that any pulmonary disease s~ere enough to cause respiratory failure in newborns might result in some long-term pulmonary damage regardless of the treatment. FAMILY HISlORY OF ASTHMA
Finally, each infant has an inherent predisposition CHEST I 87 I 4 I APRIL, 19815
fOr pulmonary disease which is present prior to birth. Male gender is associated with increased incidence and severity of most pediatric pulmonary diseases, 311 including hyaline membrane disease and BPD. In addition, Nickerson and 'Iilussigll showed that infants who developed BPD had first-degree or second-degree relatives with asthma severe enough to require hospitalization more commonly than controls. These investigators~~ speculated that the lungs of infants with a genetic predisposition fOr asthma were less tolerant of the insults of premature birth, pulmonary disease, oxygen, pressure, and 8uids. In summary, the recognition that oxygen toxicity, barotrauma, patent ductus arteriosus, and excessive 8uid administration are risk factors fOr BPD has resulted in more cautious management of all of these; however, BPD is still common because of a marked increase in overall survival of the smallest and sickest babies who are most predisposed to BPD. NATURAL HISTORY
The natural history of BPD and some of its common treatments and complications are summarized in 'Thble 1. The first three phases correspond to Northway's first three stages based on roentgenographic findings. I have divided stage 4 of Northway's classification into fOur subdivisions based on the clinical course, in order to include important events in the natural history of infants with BPD.
1bcolytic drugs are often used in efforts to stop premature labor. Frequently, a cesarean section is done to prevent birth asphyxia and trauma to the brain. Many infants with BPD have suffered from prenatal asphyxia due to the problems precipitating premature delivery. Depending on the skill and experience of the staff resuscitating the infant, there may be a period of postnatal asphyxia as well. The infant generally requires intubation and ventilation in the first hours of life. Ifthe birth occurs in a community hospital, the infant requires transport to a medical center with an intensive care nursery. Most infants are evaluated fur sepsis and treated with penicillins and aminoglycocides. Most infants receive multiple transfusions of blood products. Neuromuscular blockade may be used ifthe respiratory failure is not controlled by mechanical ventilation and supplemental oxygen, or if the infant is strong enough to fight the ventilator. 'IYPically, the infant suffers the usual course of hyaline membrane disease with decreasing pulmonary compliance and increasing oxygen requirements and alveolararterial oxygen gradient over the first three days. In the first few days, there are scant tracheal secretions with few cells. 311 The roentgenogram shows a groundglass appearance with diffuse atelectasis and air bronchograms.
Stage 2: Patent Ductus Arteriosus
In the second stage of BPD, the clinical course is frequently dominated by a patent ductus arteriosus. Stage 1 of BPD as described by Northway is indisInstead of the usual course of hyaline membrane disease with improving respiratory status, after tinguishable from hyaline membrane disease. It indiuresis begins on about the third day, 37•311 the infant eludes the first three days of life. 'IYPically, an infant continues to have high oxygen and pressure requirewho willdevelop BPD is hom two to fOur months early. Sometimes, prenatal treatment with steroids is used to ments. Roentgenograms show a "white-out" appelll'try to increase release of pulmonary surfactant. ance. As the pulmonary vascular resistance begins to 'Illble 1-Nt.dural Hidory, 7mJtmenla, and Complictlliona tfBPD
Stage 1: Hyaline Membrane Disea8e
Stage 1. Hyaline membrane
Asphyxia; pneumothorax Congestive heart fiUlure Feeding intolerance; growth fililure
2. Patent ductus arteriosus 3. 'Iransition
4-10 days 10-30 days
Failure to improve Wheezing; elevated CO.; cyanotic spells; bubbly
4a. Chronic pulmonary
.Oxygen dependent; elevated wheezing; cyanotic spells; retractions; sputum production; hyperinflation; atelectasis
4b. Hospital discharge
4c. Home care
Wheezing; oxygen dependent Wheezing
Wheezing with infection
'Ireatment Oxygen; mechanical ventilation; antibiotics; blood products Diuretics; indomethacin; surgery Hyperalimentation; diuretics; bronchodilators
Aspiration; tracheal stenosis; viral infection; cor pulmonale; poor growth; liunily; sudden death; osteopenia Social problems
Oxygen; diuretics; sympathomimetics; theophylline; calories; social support; vitamin D; calcium; sprint weaning
Sudden death; respiratory infection; cor pulmonale
Diuretics; oxygen; apnea monitor
Unknown Bnlnchopulmonar Dyeplala (Btuce G. Molcnon)
fall, blood increasingly shunts left to right through the patent ductus arteriosus, flooding the lungs. A systolic murmur can often be heard. Diastolic blood pressure falls, and pulses become bounding. Cardiac size increases,. but it is usually difficult to distinguish the cardiac borders roentgenographically at this stage because of pulmonary infiltrates and atelectasis. The left atrium becomes dilated due to increased blood flow through it. The course is often complicated by pulmonary interstitial emphysema or a pneumothorax. Patent ductus arteriosus may be treated with diuretics, indomethacin, or surgical ligation. When the ductus is closed, it is often possible to begin weaning from high Flo1 and ventilator pressures. Not all infants who develop BPD have a patent ductus arteriosus. There was hope that early treatment with vitamin E, an antioxidant, might decrease the incidence and severity ofBPD;u however, subsequent studies39 •40 did not confirm the initial report. Nevertheless, many premature infimts are given vitamin E because it decreases the severity of retinopathy of prematurity.
Stage 3: 1ransition The transitional phase between one week and one month of age corresponds to Northways radiographic stage 3. The infant's condition improves slowly, but there is a failure to wean from the ventilator or oxygen in the first month oflife. The chest roentgenogram may have a diffuse bubbly appearance, with small areas of atelectasis and small areas of overdistention; however, this appearance is not always seen. 41 The infant may begin to have episodic wheezing and cyanosis as the level of carbon· dioxide rises. Often, the infant will develop other significant complications in this period; fur example, feedings may not be tolerated because of necrotizing enterocolitis. The infant may aspirate, and parenteral hyperalimentation may be needed fur nutrition. Excessive infusion of lipid solutions may further compromise pulmonary function, 41 which may be suggested by tracheal aspirates containing pulmonary macrophages laden with fat. 43 Therapy with diuretics or bronchodilators is often started at this time, and their use is discussed in the next section. Often, these infimts require reintubation as they become more active and dislodge the endotracheal tube.
Stage 4a: Chronic Pulmonary Disease; Complications
By one month of age, a clear distinction between infimts who have BPD and those who do not can generally be made. Infants without BPD generally are able to be weaned from supplemental oxygen and ventilator support in the first month of age. Infants with BPD almost always require supplemental oxygen and often mechanical ventilation beyond one month. The roentgenogram typically shows hyperinflation, and there may be areas of atelectasis. Cardiac size may
be increased. Often infants with BPD have copious endotracheal secretions with neutrophils. 44 They have chronic compensated retention of carbon dioxide. Some infants with BPD develop intractable respiratory failure. Their pulmonary function fails to improve, and the continued high ventilator pressure and high Flo1 add to the pulmonary damage. These infimts may die from their pulmonary disease or other complications. A common problem is recurrent sudden episodes of severe cyanosis. During these episodes, there is often wheezing, and it is difficult to ventilate the infimts lungs, even using an anesthesia bag and high inspiratory pressures. These episodes are widely recognized by clinicians, but their pathophysiology and optimal treatment are an important clinical problem that has not been well studied. These infimts commonly have feeding difficulties. These may be due to bulbar dysfunction causing aspiration with swallowing, gastroesophageal reflux, or rumination. 45 Recognition of recurrent aspiration can sometimes lead to a dramatic improvement after institution of appropriate medical or surgical therapy. 411 Infants with aspiration because of bulbar dysfunction may benefit from bypassing the swallowing mechanism temporarily by nasogastric or gastrostomy feedirigs. Infants with recurrent aspiration due to gastroesophageal reflux may benefit from high-dose therapy with meclopramide, with the dosage titrated by pH probe. More commonly, a fundoplication by an experienced pediatric surgeon is required. The condition of infimts with rumination often improves when a loving consistent caretaker is provided. Growth failure is common. These infimts often require between 130 and 150 calories/kg/day (30 to 50 percent greater than normal infants) to achieve normal rates of growth. Weinstein and Oh47 have shown that infimts with BPD have an increased metabolic rate and oxygen consumption; however, the widely held notion that this is due to mechanical work of breathing does not fit calculations of the actual work done by the ventilatory muscles. 45 The source of the increased caloric needs of infants with BPD . remains to be elucidated. Extubation is often complicated by the development of inspiratory stridor, secondary to tracheal scarring. 'fracheal stenosis may progress over a period of weeks after extubation as the collagen in circumferential scar tissue contracts. 'fracheal stenosis is probably more related to tracheal trauma, the size of the endotracheal tube, and the presence of infection in the trachea than to the duration of intubation. 411 •110 In infants who are dependent on a ventilator fur more than six months, a tracheostomy can greatly facilitate their care, allow greater mobility, and decrease discomfOrt; however, the frequency of severe complications of tracheostomies in young infimts must be recognized. CHEST I 87 I 4 I APRIL, 1985
Another more subtle risk is inadequate oxygenation. Infimts who are chronically hypoxemic are at high risk to develop cor pulmonale because of pulmonary vasoconstriction. There can be findings of left ventricular enlargement, as well as the more common right ventricular hypertrophy. 51.1111 Measurement of arterial oxygenation can be difficult at this stage. The umbilical artery can no longer be used as a source of arterial blood. In a chronically sick infant the other peripheral arteries frequently have been punctured and cannulated many times and have become sclerosed. In addition, as the infant becomes familiar with the pain of an arterial puncture, crying may cause the arterial oxygen pressure to change precipitously. 'Ihmscutaneous oxygen levels are often used, but they can also be inaccurate in infants who have pulmonary hypertension and consequent slowing of cutaneous capillary blood flow. 83 New approaches, such as pulse oximeters, may offer significant advantages to infants in this age group. Often, concern about pulmonary and ophthalmic oxygen toxicity and an eagerness to discontinue supplemental oxygen result in an urgency to wean the infants from oxygen too soon. This can result in poor growth and the development of pulmonary hypertension. If cor pulmonale with heart failure ensues, usually following a viral infection, the infant is likely to require oxygen, diuretics, intensive nutritional therapy, and perhaps mechanical ventilation for several months. Therefore, judicious use of oxygen in the hospital and at home is crucial to the optimal management of infants with BPD. Another frequent complication is osteopenia. 54 Most of the calcium in the bones of a newborn infant is deposited in the last two months ofgestation. Typically, infants with BPD are born prematurely, prior to this calcium deposition. In addition, solutions for parenteral alimentation, which are low in calcium and vitamin D, and the use of diuretics which are potent calciurics, can result in osteopenia of ricketts. Some infants even develop multiple fractures of the ribs and long bones from severe osteopenia. Therapy. Diuretics improve pulmonary function in infants with BPD, as shown by the plethysmographic studies of Kao et al. 55 Intravenous therapy with furosemide resulted in a dramatic improvement in dynamic compliance, specific airway conductance, and airway resistance; however, six hours later, these infimts had returned to baseline. Oral therapy with furosemide is less effective because it is poorly absorbed in infants of this age. 88 We have found twice daily oral therapy with chlorothiazide in dosages of 15 to 25 mglkg of body weight per dose to be more predictably effective than oral therapy with furosemide. Recently, Kao et al57 documented improvements in pulmonary function using oral therapy with chlorothiazide and spironolactone.
Because normal infants do not have peribronchial smooth muscle, pediatricians have been reluctant to use bronchodilator drugs in infants of this age group; however, the study by Bonikos et al• showed that infants who die of BPD have hypertrophied peribronchial smooth muscle even at a young age. The physiologic importance of this was confirmed when Kao et al1111 found that isoproterenol by inhalation improved pulmonary function in infants with BPD. Compared to intravenous therapy with furosemide, Kao et al1111 showed that isoproteronol had a more rapid onset of action with demonstrable improvement in pulmonary function by 30 minutes; however, the effect was not as great as that offurosemide, and it did not last as long. The use of methylxanthines is somewhat more controversial. Recent data show methylxanthines improve the function of ventilatory muscles110 and central ventilatory drive, m in addition to relaxing bronchial smooth muscle, causing a mild diuresis, and stimulating ciliary motility; howevei; the frequent side effects of vomiting and the necessity of using a low dosage makes its use more difficult. Nassif et al81 showed that infants less than one year of age require a much lower dosage than older children. A modification of their formula which we use to calculate a conservative dosage is eight plus the age in months equals the daily dosage in milligrams per kilogram. This is a conservative formula and the dosage should be adjusted according to levels in the blood. Once feedings are successfully established and adequate calories can be given to achieve growth, the infant can then generally be weaned from the ventilator. 83 In my experience, weaning is best done as soon as possible. This means tolerating high arterial carbon dioxide levels as long as metabolic compensation results in normal arterial pH. Because infants with compensated high levels of carbon dioxide can excrete more carbon dioxide for the same alveolar ventilation, they can sometimes be safely weaned from the ventilator earlier, thus minimizing the degree of ventilator trauma. There are a few infimts who are particularly difficult to extubate. Often, these infants experience a cycle of slow progress followed by substantial setbacks requiring higher ventilator rate, pressure, and Flo1 • In these infants the crucial problem may be fatigue of ventilatory muscles. Infants who have undergone mechanical ventilation for long periods of time may be at risk for poor ventilatory muscular endurance because of deconditioning. These infants may be successfully weaned ifa program of ventilatory muscular endurance training is used. Using this technique, we have been able to wean infants who have been refractory to weaning by other methods and have required mechanical ventilation for over one year. 'IYPically, we use full
mechanical support sufficient to depress respiratory drive, interrupted by short periods of significantly lower ventilator settings which we call sprints. These sprints are extended in duration until the infant begins to show signs of stress, and then complete ventilation is reinstituted. As the infant gains endurance, the duration of the sprint is lengthened until the infant can tolerate long periods without the ventilator. We believe that this program is effective because it conditions the ventilatory muscles to endure the work of breathing, but this hypothesis requires study.
Stage 4b: Discharge from the Hospital Once the infant is extubated, the transition to care at home becomes the important issue. The condition of these infants is often quite unstable, with frequent changes in their respiratory status. They may have episodes of severe wheezing and wide swings in their oxygen requirements. Many have chronic production of sputum. Supplemental oxygen at home, long-term administration of medications, special formulas, and special equipment make learning to care for the infant a formidable task for the parents. Frequently, the infants' families have been emotionally traumatized by the events of the previous several months. Effective bonding of mother to infant is prevented by the mandates of critical care. Parents feel unwelcome in the intensive care nursery characterized by unfamiliar protocols such as surgical scrubs, masks and gowns, crowding, and busy highly stressed staff who use technical jargon. Parents perceive that their infant is deformed by multiple catheters and monitoring devices. The parents may need to travel long distances to visit their infant in a regional intensive care unit. The financial burdens of this disease, often in excess of $100,000, add to the preexisting stresses in the family. · Not infrequently, an infant with severe BPD is medically ready for discharge before his family is ready to take on the considerable burden of caring for him. More attention should be paid to the social problems of the families of infants with BPD.
Stage 4c: Care at Home Dramatic improvement is generally observed after discharge from the hospital. Weight increases more rapidly. Social and development skills also suddenly increase. These improvements may be due to the infants better medical condition or to the improved social environment provided by a loving family, instead of nurses and other health care workers who change every eight hours. Nevertheless, infants at this stage face several more significant risks. Werthammer et alec found 11 percent of infants discharged from the Harvard Medical School nurseries with a diagnosis of BPD in 1978 and 1979 died later with a postmortem diagnosis of sudden
infant death syndrome. It is unknown whether these infants die from the same pathologic process as the majority of infants who die of sudden infant death syndrome who have been previously healthy. Nevertheless, infants with BPD are at risk to die unexpectedly. Our practice is to recommend a home monitor and training in cardiopulmonary resuscitation for the caretakers prior to discharge of an infant with significant BPD requiring diuretics and supplemental oxygen at home. Until the risk factors ·are better delineated, this will be a controversial subject. Infants with BPD are also at risk of developing respiratory failure with viral infections. Respiratory syncytial virus is the most common agent in winter months; however, influenza virus, adenovirus, parainfluenza virus, cytomegalovirus, and other agents may be responsible. Typically, respiratory infections will be followed by wheezing, tachypnea retractions, and feeding intolerance. Hospitalization is often required. If cor pulmonale, tracheal stenosis, aspiration, or respiratory failure complicate the clinical course, rehospitalization may last weeks or months. Ifthere are no further complications, these infants generally take several weeks to recover. Many clinicians feel infants with BPD are more likely to tolerate respiratory infections without requiring hospitalization ifthey are taking diuretics, but this has not been studied. Recently, systemic systolic hypertension has been reported as a late complication in infants with BPD. 811 The etiology and long-term prognosis for this complication are not yet known. There is a high incidence of hernias and middle-ear disease in infants with BPD. Elective surgery on an infant with BPD should be planned very carefully. The infant should be in optimum medical condition prior to surgery. Anesthesiologists should avoid excessive administration of fluids. Preparation should be made for intensive postoperative monitoring of respiratory status, and measures should be taken to optimize pulmonary toilet in order to counteract the deleterious effects of general anesthesia on clearance of pulmonary secretions. Often, it is best to delay the surgery, although this is not always possible.
Stage 4d: Resolution? The last stage is the stage of resolution. It usually begins after the first year of life and after the first winter. By this time, infants with BPD are catching up to normal infants in growth parameters. They are still prone to wheezing with respiratory infections. They may develop wheezing with significant exercise. Clinical experience suggests that they respond to bronchodilator drugs more than diuretics, but this has not been studied. Studies of pulmonary function show evidence of air trapping and decreased function of the small airways. Generally, the neurologic prognosis is CHEST I 87 I 4 I APRIL, 1.986
good if the central nervous system has not been compromised by intraventricular hemorrhage or asphyxia; however, there may be a significant incidence of hearing loss and attention deficits in school in these infants. Since the oldest survivors with this disease are less than 20 years old, it is not known what the long-term course will be. There are only a few follow-up studies in the literature which include sensitive tests of pulmonary function. Heldt et al118 studied the exercise performance of 31 school-age children who had required mechanical ventilation and were unable to detect abnormalities in the group's data. They found three individuals who had elevated concentrations of carbon dioxide during exercise. Smyth et al117 studied nine children with BPD when they were seven to nine years old. They had relatively mild BPD by current standards, since none was ventilated for longer than two weeks. Nevertheless, most of these children had recurrent respiratory symptoms and significantly abnormal spirometric data, pulmonary volumes, and bronchial hyperreactivity. Coates et al111 found similar results and even found evidence of disease of the small airways in premature infants who were not ventilated. There is evidence that milder pulmonary insults in childhood, such as bronchitis, may be precursors of chronic obstructive pulmonary disease in adults. Infimts with BPD have much more severe and prolonged pulmonary disease. Therefore, as adults, individuals with BPD may be prone to develop chronic obstructive pulmonary disease. In summary, the chronic pulmonary disease called BPD is a common sequel to premature delivery and neonatal respiratory failure. There is evidence that the etiology is related to both the pulmonary disease and its treatment with oxygen and mechanical ventilation. Avoiding the complications ofpatent ductus arteriosus, cor pulmonale, tracheal stenosis, recurrent aspiration, malnutrition, and death requires meticulous management. Diuretics are useful in the treatment of BPD. Survivors of BPD may carry long-term pulmonary sequelae into adulthood. ACKNOWLEDGMENT: I thank Mr. Brian Linde, Mr. Douglas Nickerson, Ms. Elizabeth Nickerson, and Doctors Nancy Lewis, Herman Li_pow, John McQuitty, Arthur D'Harlingue, Gabriella Molnaa; and !Cram fOr critiCal reading of the manuscript. I am indebted to rs Lynn 'llwssig, Richard Lemen, Thomas Keens, David Warburton, Arnold Platzke~; John McQuitty, Herman Lipow, Byron Aold, Charles Scott, and LilYKao fOr con~ts and observations about BPD. I thank Ms. Patricia Melody fOr her patient preparation of the manuscript.
REFERENCES 1 Northway WH, Rosan RC, Porter DY. Pulmonary disease fOllowing respiratory therapy fOr hyaline membrane disease: bronchopulmonary dysplasia. N Eng) J Med 1967; 276:357-68 2 Northway WH. Observations on bronchopulmonary dysplasia. J PedJatr 1979; 95:815-18 3 Johnson JD, Malachowski NC, Grobstein R, Welsch D, Daily
6 7 8 9 10 11 12
21 22 23 24 25
WJR, Sunshine P. Prognosis of children surviving with the aid of mechanical ventilation In the newborn period. J Pediatr 1974; 84:272-76 Reynolds EOR, 'J8gbizadeh A. Improved prognosis of infimts mechanically ventilated fOr hyaline membrane disease. Arch Dis Child 1974; 49:505-15 Edwards DK, Dyer WM, Northway WH. '1\velve years experience with bronchopulmonary dysplasia. Pediatrics 1977; 159: 839-46 Wung fi: Koons AH, Driscoll JM, James LS. Changing incidence ofbronchopulmonary dysplasia. J Pediatr 1979; 95:845-51 'lboley WH. Epidemiology of bronchopulmonary dysplasia. J Pediatr 1979; 95:851-55 Smith DW, Stevenson DK, Sunshine P, Northway W, Ariagno RL. Predominance of bronchopulmonary dysplasia (BPD) in infimts <1,500 gm at birth. Am Bev Respfr Dis 1983; 127:212 deLemos R, WolfsdonJ, Nachman R, Block AJ, Leiby G, Willdnson HA, et al. Lung Injury from oxygen In lambs: the role of arti6cial ventilation. Anesthesiology 1969; 30:609-17 Miller WW, \\Wdhausen JA, Rashkind WJ. Comparison of oxygen poisoning of the lungs In cyanotic and acyanotic dogs. N Eng) J Med 1970; 282:943-47 Chvapil M, Peng YM. Oxygen and lung fibrosis. Arch Environ Health 1975; 30:528-32 Deneke SM, Fanburg BL. Normobaric oxygen toxicity of the lung. N Eng) J Med 1980; 303:76-86 Merritt TA. Oxygen exposure in the newborn guinea pig lung lavage cell populations, chemotactic and elastase response: a possible relationship to neonatal bronchopulmonary dysplasia. Pediatr Res 1982; 16:798-805 18gbtzadeh A, Reynolds EOR. Pathogenesis ofbronchopulmonary dysplasia fOllowing hyaline membrane disease. Am J Pathol 1976; 82:241 Moylan FMB, \\Wirer AM, Kramer SS, 'lbdres ID, Shannon DC. The relationship of bronchopulmonary dysplasia to the oocul'rence of alveolar rupture during positive pressure ventilation. Crit Care Med 1978; 6:140-42 Moylan FMB, \\Wirer A, Kramer SS, 'lbdres ID, Shannon DC. Alveolar rupture as an independent predictor of bronchopulmonary dysplasia. Crit Care Med 1978; 6:10-3 Rhodes PG, Graves GR, Patel DM, Campbell SB, Blumenthal BI. Minimizing pneumothoru and bronchopulmonary dysplasia In ventilated infimts with hyaline membrane disease. J Pediatr 1983; 103:634-37 Berg TJ, Pagtakhan RD, Langston C, Chernick V. Bronchopulmonary dysplasia and lung rupture In hyaline membrane disease: influence of continuous distending pressure. Pediatrics 1975; 55:51-4 Stahlman MT. Clinical description of bronchopulmonary dysplasia. J Pediatr 1979; 95:829-34 Coalson JJ, Kuehl TJ, Ackerman NB, Escobedo MB, Stoddard RA, Minnick LA, et al. Air leak syndrome in premature baboons on high frequency ventilation (HFV). Am Bev Respfr Dis 1983; 127:211 Gay JH, Daily WJR, Meyer BHP. Ligation of the patent ductus arteriosus In premature infimts: report of45 cases. J Pediatr Surg 1973; 8:677-83 Nickerson BF, 'Dwssfe LM. Family history of asthma in infimts with bronchopulmonary dysplasia. Pediatrics 1980; 65:1140-44 Brown ER, Stark A, Sosenko I, Lawson EE, Avery ME. Bronchopulmonary dysplasia: possible relationship to pulmonary edema. J Pediatr 1978; 92:982-84 Ehrenkranz RA, Bonta BW, Ablow RC, Warshaw JB. Amelioration of bronchopulmonary dysplasia after vitamin E administration. N Eng) J Med 1978; 299:564-69 Bell EF, Warburton D, Stonestreet BS, Oh W. Effect of fluid administration on the development of symptomatic patent
ductus arteriosus and congestiw heart fiailure in premature infants. N Engl J Med 1980; 302:598-604. 26 Coates AL, Bergsteinsson H, Desmond K. Outerbridge EW. Beaudry PH. Long-term pulmonary sequelae ofpremature birth with and without idiopathic respiratory distress syndrome. J Pediatr 1917; 90:611-18 'l:'l'llwssig LM. Clinical and physiologic evidence lOr the persistence ofpulmcmary abnormalities after respiratory illnesses in infancy and childhood. Pediatr Bes 1917; 11:216-18 28 BUI'I'OWI B, Knudson BJ, Lebowitz MD. The relationship of childhood respiratory illness to adult obstructive airway diseue. Am Bev Bespir Dis 1917; 115:751-80 29 Kattan M, ICeens TC, lApierre JG, Levison H, Bryan C, Reilly BJ. Pulmonary function abnormalities in symptom-free children after bronchiolitis. Pediatrics 1917; 159:683-88 30 Sims DG, Downham MAPS, Gardner PS, Webb JICG, Weightman D. Study of'8-year-old children with a history of respiratory syncytial virus bronchiolitis in infancy. Br Med J 1978; 1:11-4 31 LougblinGM,'IlwssigLM. Pulmonaryfimctioninchildrenwith a history of'laryngotracheobroncbitis. J Pediatr 1979; 94:385-69 32 Yabav J, I.Jeberman P, Molho M. Pulmonary fimction IOllowing the adult respiratory distress syndrome. Chest 1978; 74:247-50 33 Elliott CG, Morris AH, Cenglz M. Pulmonary fUnction and ezercise ps 8IChange in surviwn of adult respiratory distress syndrome. Am Bev Bespir Dis 1981; 123:492-95 34 Churg A. Golden J, FJjpe1 S, Hogg JC. Bronchopulmonary clyspluia in the adult. Am Bev Respir Dis 1983; 1'1:1:117-20 35 Glezen WP, Denny Fw. Epidemiology ofacute low8r respiratory diseue in children. N Engl J Med 1973; 288:498-505 38 Merritt TA, Stuard ID, Pucx:ia J, Wood B, Edwards DIC, Finkelstein J, et al. Newham tncheal aspirate cytology: classiftcation during respiratory distress syndrome and bronchopulmonary dyspluJa. J Pediatr 1981; 98:949-58 37 Spitzer AR, F01: WW. Deliwria-Papadopoulos M. Maximum diuresis:& factor in predicting recovery from respiratory distress syndrome and the development of'bronchopulmonary dysplasia. J Pediatr 1981; 98:476-79 38 HeafDP, BelJk J, Spitzer AR, Gewitz MH, Fos WW. Changes in pulmcmary function during the diuretic phase of respiratory distress syndrome. J Pediatr 1982; 101:1()3..()7 39 Ehrenlaanz RA, Ablow RC, \\Vshaw JB. Prevention of bronchopulmonary clyspluia with vitamin E administration during the acute stages of respiratory distress syndrome. J Pediatr 1979; 95:873-78 40 Saldanha RL, Capeda EE, Poland RL. The e8'ect of vitamin E prophyluis on the incidence and sewrity of bronchopulmonary dysplasia. J Pediatr 1982; 101:89-93 41 'lboley WH. Epidemiology of bronchopulmonary dysplasia. J Pediatr 1979; 95:851-515 42 Daluns BB, Halpin TC. Pulmonary arterial lipid deposit in newborn infants receiving intravenous lipid infusion. Pediatrics 1980; 97:800-015 43 Reca1de AL, Niclcenon BG, Veps M, Scott CB, Landing BH, \\Wburton D. I.Jpid-laden macrophages in tracheal aspirates of newbom infants receiving intravenous lipid infusions: a cytologic ltudy. Pediatr Patholl984; 2:25-34 44 Ogden BE, Murphy S, Saunden GC, Johnson JD. Lung lavage ofnewboms with respiratory distress syndrome. Chest 1983; 83: 331S-33S 45 Sheagren TC, Mangurten HH, Brea F, Lutostanld S. Rumination: a new complication of neonatal intensiw care. Pediatrics 1980; 88:551-515 48 Lew C, ICeens 'I; O'Neal M, Ramos A. Platzker A, Nickenon B, et al. Gastroesopbagea reftux prewnts recovery from bronchopulmonary dysplasia. Clio Res 1981; 29:149A
47 Weinstein MR, Oh W. Oxygen consumption in infants with bronchopulmonary dysplasia. J Pediatr 1981; 99:958-80 48 \\VIfion MR, Bhutani VIC, Shaller TH, Bowen Fw. Mechanics and energetics of breathing helium in infants with bronchopulmonary dysplasia. J Pediatr 1984; 104:752-57 49 Rasche RFH, Kuhns LR. Histopathologic changes in airway mucosa of infants after endotracheal intubation. Pediatrics 1972; 50:632-37 50 Mann DG, Kirchner JA. Bronchopulmonary dysplasia (or subglottic stenosis?} Laryngoscope 1982; 92:976-79 51 Melnick G, Pickoft' AS, Ferrer PL, Peyser J, Bancalari E, Gelband H. Normal pulmonary vascular resistance and left ventricular hypertrophy in young infants with bronchopulmonary dysplasia: an echocardiographic and pathologic study. Pediatrics 1980; 88:589-98 52 Berman W. Yabek S, Dillon 'I; Buntein R, Corlew S. Evaluation of infants with bronchopulmonary dysplasia using cardiac catheterization. Pediatrics 1982; 70:708-12 53 Home ES, Storie EK. Carlo WA, Martin RJ. I.Jmitations of transcutaneous Po. and Pea. monitoring in infants with bronchopulmonary dysplasia. Pediatrics 1984; 74:217-20 54 Venkataraman PS, Han BK, Tsang RC, Daugherty CC. Secondary hyperparathyroidism and bone diseue in infants receiving long-term furosemide therapy. Am J Dis Child 1983; 137:1158-81 55 Kao LC, Warburton D, Sargent CW. Platzker ACG, Keens TC. Furosemide acutely decreases airways resistance in chronic bronchopulmonary dysplasia. J Pediatr 1983; 103:624-29 58 Petenon RG, Simmons MA, Rumack BH, Levine RL, Brooks JG. Pharmacology of furosemide in the premature newborn infant J Pediatr 1980; 97:139-43 57 Kao LC, \\Wburton D, Cheng MH, Cedeno C, Platzker CG, ICeens TC. Efl'ect of oral diuretics on pulmonary mechanics in infants with chronic bronchopulmonary dysplasia: results of a double-blind crossover sequential trial. Pediatrics 1984; 74:37-44 58 Bonikos DS, Bensch KG, Northway WH, Edwards DK. Bronchopulmonary dysplasia: the pulmonary pathologic sequel of necrotizing bronchiolitis and pulmonary fibrosis. Hum Pathol 1978; 7:843-66 159 Kao LC, Warburton D, Platzker ACG, Keens TC. Efl'ect of isoproterenol inhalation on airway resistance in chronic bronchopulmonary dysplasia. Pediatrics 1984; 73:509-13 60 Aubier M, de'ltoyer AD, Sampson M, Macklem P1; ~C. Aminophylline improves diaphragmatic contnlctility. N Engl J Med 1982; 3015:240-46 81 Harris MC, Baumgart S, Rooklin AR, Fox WW. Successful utubation of' infants with respiratory distress syndrome using aminophylline. J Pediatr 1983; 103:303-05 8i Nassif EG, Weinberger MM, Shannon D, et al. Theophylline disposition in infancy. J Pediatr 1981; 98:1158-61 83 Morray JP, F01: WW. Kettrick RG, Downes JJ. Clinical correlates of successful weaning from mechanical wntilation in sewre bronchopulmonary dysplasia. Crit Care 1981; 9:815-18 84 Werthammer J, Brown ER, Neft'RK. 'IIIeusch W. Sudden infant death syndrome in infants with bronchopulmonary dysplasia. Pediatrics 1982; 69:301..0. 85 Abunan SH, \\Wady BA, Lum GA. Koops BL. Systemic hypertension in infants with bronchopulmonary dysplasia. J Pediatr 1984; 104:928-31 88 Heldt GP, McDroy MB, Hansen TN, 'lboley WH. Exercise periOrmance of the surviwn of hyaline membrane diseue. J Pediatr 1960; 98:995-99 87 Smyth JA, 'Dibachnilc E, Duncan WJ, Heilly BJ, Levison H. Pulmonary fUnction in bronchial hyperreactivity in long-term survivors of bronchopulmonary dyspluia. Pediatrics 1981; 88:338-40
CHEST I 87 I 4 I APRL, 1a