Since 1970, hyaline membrane disease has changed from an illness with a 70% mortality and a high morbidity among its survivors to an illness with a 70% or higher chance of survival. This article will survey some of the recent developments which permitted this achievement, as well as briefly discuss some promising approaches to therapy which have not yet proven their worth in largescale studies.
PREDICTION AND PREVENTION
Physicians are most successful in dealing with illnesses which never develop. Some recent advances in obstetrical perinatology have reduced the likelihood that pediatricians will have to deal with severely distressed infants with respiratory disease.
Accurate dating of a specific pregnancy is an important means of preventing respiratory distress.1 In women with medical complications of pregnancy, such as essential hypertension or diabetes, or obstetrical complications, such as malpresentation or previous caesarean section, a scheduled delivery before the onset of labor is occasionally necessary. Estimates of the size of a fetus based on abdominal examination may be in error by as much as 500 grams, especially as term is approached. The menstrual history may also be in error by one to two weeks, especially if the pregnant woman has recently been taking birth control pills or suffers from menstrual irregularity. This range of error - 500 grams/ seven to 14 days - can be the difference between an infant of 36 weeks gestation with perhaps a three to five percent risk of hyaline membrane disease and a 38 to 39 week infant with a risk of respiratory distress in the range of 0.2% to 0.5% or less. The advent of sonographic scanning, performed serially in monthly intervals in high-risk women, has provided an accurate means of dating these pregnancies and therefore has been effective in reducing the risk of delivering a large but immature infant. When accurate dating is combined with intrauterine assessments of pulmonary maturity, such as the L:S ratio, "foam" test, or FELMA test, elective delivery of an infant with respiratory distress can be avoided almost completely, except when medically necessary because of severe medical complications of either the fetus or mother.2'3
Drugs have also been used to reduce the incidence of prematurity and respiratory distress. Tocolytic agents, such as alcohol and ritodrine (Yutopar), have been used to prevent premature labor.4 While these drugs are successful in preventing many premature deliveries if started sufficiently early, they are not unassociated with risks to mother and fetus. When unsuccessful, the alcohol levels associated with its use result in an increased incidence of neonatal depression and respiratory distress.5 Beta-mimetic tocolytic agents have been associated with maternal pulmonary edema when used in conjunction with glucocorticoids.4 Although glucocorticoids do carry this risk when used with ritodrine, they have reduced the likelihood of respiratory distress in premature infants delivered between 28 and 34 weeks.6 They also appear to be relatively free of neonatal complications. If delivery can be delayed 24 hours, glucocorticoids may be expected to play an increasingly important role in the prevention of respiratory distress due to hyaline membrane disease.
The characteristic x-ray findings and clinical picture of hyaline membrane disease are well known. The recognition that neonatal infection with group B beta-hemolytic streptococcus can mimic this condition has led to new concepts of diagnosis and therapy for infants who develop respiratory distress in the neonatal period.6 Group B beta-hemolytic streptococcal infection has two major presentations. In the "late onset" form, sepsis and meningitis are the major presentations. The "early onset" form presents both as sepsis and as respiratory distress. In fact, one may speculate that the respiratory distress associated with early onset disease is analagous to adult respiratory distress syndrome (ARDS), with a secondary loss of the ability to produce surfactant following overwhelming infection. The clinical signs of respiratory distress secondary to streptococcal infection resemble those of infants with hyaline membrane disease: cyanosis in room air, grunting, retractions, nasal flaring, tachypnea, and shock. Early onset streptococcal infection with respiratory distress has been reported to differ radiographically from hyaline membrane disease in that the infection may present with a less uniform pattern, resembling infiltrates. However a uniform, ground-glass lung, accompanied by air bronchograms may appear in streptococcal infection. Similarly, it has been reported that infected infants may be ventilated at lower pressures, or that other laboratory signs of infection, such as leukopenia or leukocytosis, or elevated sedimentation rate, may be used to differentiate infection from hyaline membrane disease. Unfortunately these tests are nonspecific. Denial of anitbiotic therapy to an infant with respiratory distress possibly due to streptococcal infection could have a fatal outcome. Therefore it has become common practice, and it is the policy of the Neonatal Intensive Care Unit of the New York Hospital-Cornell Medical Center, to perform an evaluation for infection, including a blood culture and spinal tap, on all infants presenting with respiratory distress, and to begin antibiotics as soon as possible after obtaining cultures. The antibiotic treatment generally consists of a penicillin (aqueous penicillin or ampicillin) and an aminoglycoside (gentamicin, kanamycin). These are continued until the cultures are as negative, generally 72 to 96 hours, and are modified if positive cultures are obtained. Since infants with streptococcal infection may become infected in utero and present with fetal distress, the same routine of cultures and antibiotic therapy applies to infants with respiratory distress following resuscitation or meconium aspiration. The widespread use of antibiotics for infants with respiratory distress carries with it the risk of establishing a resistant microbial flora within the intensive care nursery. This should not be used as a reason to deny antibiotic treatment to an infant who may need it. It does require careful surveillance of the microbial flora within the intensive care unit, especially in the case of hospital -acquired infections.
The second important diagnostic advance in the treatment of infants with respiratory distress has been the recognition of the role of the patent ductus arteriosus.7 During fetal life, the ductus arteriosus provides a channel for relatively well-oxygenated blood to go from the pulmonary artery to the aorta. Thus it is a right-to-left shunt, maintained in part by the high pulmonary vascular resistance associated with the hypoxemic fetal state. After birth, pulmonary vascular resistance falls. If the duct remains patent, it may then become a left-to-right shunt. In infants with hyaline membrane disease, particularly those under 1200 grams, this aortico-pulmonary shunt can pose serious problems. Fortunately, non-invasive means to evaluate the significance of this shunt are at hand. By means of echocardiography, the location and size of the ductus can be estimated. This is particularly of value in small infants who may become ventilatordependent, since it is theorized that the additional blood shunted into the lungs via the ductus arteriosus may impair pulmonary mechanics and prevent prompt weaning from assisted ventilation. Early documentation of the significance of the ductal shunt is important, since medical closure of the duct with indomethacin is most effective in younger infants. Therapy will be discussed ina later section.
The recognition that vascular shunts may contribute to the severity of respiratory distress has led to the recognition of the persistent fetal circulation/ persistent pulmonary hypertension (PFC/ PPH) syndrome.8 As indicated earlier, the fetal pulmonary vascular resistance is high in association with low fetal oxygen tensions. In some infants, pulmonary vascular resistance does not fall after birth. This results in shunting of blood from the venous circulation into the arterial circulation via the foramen ovale or the ductus arteriosus. When the ductal right-to-left shunt is significant, arterial blood sampled below the level of the duct has a significantly lower arterial oxygen tension than that sampled in temporal or right radial arteries, which arise from the aorta before the duct. However, if the duct is closed and the major rightto-left shunt is the foramen ovale, there may be little or no difference between "pre-ductal" and post-ductal" blood PaOi. At present, PFC/ PPH may be diagnosed in an infant with no demonstrable cardiac lesion (other than a patent foramen ovale or a patent ductus arteriosus) who requires substantial concentrations of oxygen (over 80%) to maintain clinically adequate arterial oxygen tensions. Echocardiography is a most useful diagnostic tool in the evaluation of the infant with severe hypoxemia and respiratory distress. First, by ruling out significant structural cardiac disease, congenital heart disease may be ruled out. Secondly, a positive diagnosis of PFC/ PPH can be made by injecting saline into the inferior vena cava under echocardiographic surveillance. Microcavitation results from the injection of saline, and the echocardiographic image created by this injection resembles a contrast x-ray image. By demonstrating shunts through the foramen ovale and ductus arteriosus, a positive diagnosis of PFC/ PPH can be made and appropriate therapy instituted.
The advances in diagnosis outlined above have resulted in improvements in the treatment of infants with respiratory distress. In addition, several promising methods of dealing with the metabolic and mechanical abnormalities in lung function arising from hyaline membrane disease have also been evaluated in recent years.
As indicated earlier, streptococcal infection is an important specific cause of respiratory distress. Current treatment of infants with RDS includes institution of antibiotics at an early stage. Current recommendations are the use of a penicillin or analogue (aqueous penicillin 1,000,000 µ/k/day q 12 hours or ampicillin 100 mg/ kg/ day q 12 hours or kanamycin 15 mg/ kg/ day q 12 hours). The choice of these antibiotics is dictated by the likelihood that any respiratory distress present at birth will be due either to streptococci, sensitive to penicillin or ampicillin, or E. coli, sensitive to an aminoglycoside. The choice between gentamicin and kanamycin must be dictated by local patterns of microbial sensitivity to these antibiotics. If a positive culture is obtained, the drug regimen must be modified according to the sensitivities of the agent recovered. Treatment is continued for 72 to 96 hours while cultures are pending, and may be discontinued at that time if cultures are negative and there is no other indication that the infant may be infected.
Treatment of the patent ductus arteriosus has been somewhat controversial.7'9"11 Some physicians have been reluctant to submit an infant to surgery or indomethacin therapy for a problem which may resolve spontaneously. While the risks of these treatments are low, they are not negligible, especially for the smallest infants. Surgery on an infant with respiratory distress requires a skilled surgical team and the ability to monitor a critically ill premature infant throughout surgery and anesthesia. Indomethacin, a prostaglandins synthetase inhibitor, has been associated with gastric irritation, decreased platelet function, and decreased renal output. At present, controlled studies indicate that early closure of the ductus arteriosus (earlier than six months) results in a reduced incidence of bronchopulmonary dysplasia and mortality at six months of age when compared to a group of infants whose ducts were closed later. However, many centers still manage the problem of the ductus arteriosus with fluid restriction, diuretics, and digitalization, submitting an infant to indomethacin or surgery only after these modalities have failed. Unfortunately, delay in closure of the duct means that pharmacological attempts at closure are less likely to be successful, and any delay in a ventilator-dependent infant increases the likelihood of developing bronchopulmonary dysplasia. Therefore, it would seem prudent to consider pharmacological closure of the clinically significant ductus arteriosus in the infant under 1 200 grams at birth duringthe first week of life with indomethacin (0.2 mg/ kg every eight hours for 24 hours). Initial restriction of fluids to 60 to 80 cc/ kg/ day may also be a useful means of preventing the development of a significant patent ductus arteriosus.
PFC/ PPH is also a controversial topic.1""14 Isoproterenol and tolazoline are both available as pulmonary vasodilators, but both have disadvantages. Isoproterenol causes tachycardia, and may therefore not be of use in infants with heart rates significantly over 160 beats per minute. Tolazoline may cause gastrointestinal bleeding, but its most significant undesirable effect is that of systemic vasodilation in addition to pulmonary vasodilation. The dose necessary to produce an improvement in systemic arterial oxygen tensions may also be a dose which produces hypotension. Thus its use requires continuous monitoring of systemic blood pressure, and may also require treatment with a pressor agent, such as dopamine. Both of these agents should therefore be administered in such a way as to ensure that maximal levels are delivered to the lung. Systemic administration via the inferior vena cava is inappropriate. Ideally, a pulmonary arterial catheter should be the route of administration, since the condition of PFC/ PPH excludes blood from the pulmonary circulation and diverts venous return through the ductus arteriosus or foramen ovale. If this route is not available, administration of the drug through the scalp vein seems to be a more effective route than administration at other sites. This may be because blood returning to the heart via the superior vena cava is more likely to enter the pulmonary circulation than blood from other channels. The greatest published experience of drug therapy in this condition has been with tolazoline. The initial dose is 2 mg/ kg IV in IO minutes, with a maintenance of I to 2 mg/ kg per hour IV.
Monitoring systemic venous pressure and arterial blood gases will provide the necessary information for determination of the use of pressor agents, such as dopamine. The use of alkali nization (arterial Pco2 25 to 30, arterial pH 7.5 or over) is also controversial. However most studies report the best outcomes with arterial pHs maintained at this level. Whether these results are due to improved drug action at higher pH, better pulmonary blood flow in the alkalotic and well-oxygenated patient, or simply due to the fact that patients who can be made alkalotic may have less severe disease is not yet clear from published studies. At present, hyperventilation, pulmonary vasodilation, systemic pressors when necessary, and muscle relaxants as an adjuvant to assisted ventilation form the basis for the treatment of PFC/ PPH in newborn infants.
Muscle relaxants have played an increasing role in assisted ventilation of newborn infants with refractory hypoxemia or hypercapnia.15 Until recently these agents have not traditionally been used in pediatric therapy. The present agent of choice is pancuronium (Pavulon). It is given intravenously in an amount sufficient to abolish spontaneous respiratory activity. The goal of therapy is to abolish spontaneous respirations in the patient receiving treatment and permit full benefit from the mechanical ventilator. Muscle relaxants permit ventilation of patients at lower transpulmonary pressures, and may therefore reduce the risk of pneumothorax. Because they abolish the respiratory activity of the patient, they may only be used when mechanical ventilation has already been established. Careful followup of arterial blood gases after initiation of therapy is essential, since the loss of the patient's spontaneous ventilation may result in a deterioration in arterial blood gases and require further adjustment of ventilator settings. Usually, however, the patient initially shows an improvement within a few hours. Pancuronium may be given in a dose of 0.03 to 0.04 mg/ kg intravenously. It has an onset of action within seconds, and may be repeated whenever necessary to prevent spontaneous respiratory activity. Usual indications for its use include inability to oxygenate a spontaneously breathing patient on mechanical ventilation with an F1O2 of 80% or greater, or inability to correct a respiratory acidosis in a spontaneously breathing patient. Undesirable effects, such as hypertension and tachycardia, have been reported in adults, but not infants.
The effects of pancuronium can be reversed with atropine and prostigmine. Because muscle activity is abolished, some neonatologists routinely administer phénobarbital to infants receiving pancuronium in order to prevent convulsions which could not be observed because of the use of this paralyzing agent. In general, pancuronium has proven to be a useful adjunct in the therapy of the severely ill infant with hyaline membrane disease or another form of neonatal respiratory distress.
Since 1970, new methods of assisted ventilation have improved the survival of infants with hyaline membrane disease. The major advance that has been made in the therapy of HMD is the technique of CPAP (continuous positive airway pressure).16 Alveoli lacking surfactant lack stability and tend to collapse. This is reflected in the low functional residual capacity of infants with HMD, and produces the typical radiographic appearance of ground-glass lungs with air bronchograms. Until surfactant can be produced in adequate amounts, CPAP has been successfully used to support the alveoli of patients with HMD. Most apparati for producing CPAP permit the patient to breathe spontaneously while receiving therapy. Assisted ventilation can simultaneously be given along with continuous distending alveolar pressure, and this is the most frequently used technique at present. The usual level of CPAP is approximately 5 cm of water. The indication for the use of CPAP is hypoxemia, since CPAP simply distends collapsed alveoli and does not provide additional alveolar ventilation. However, collapsed lungs are more difficult to ventilate. When distended with CPAP the patient's own spontaneous respirations may become more effective. The enlarged lung volume resulting from the use of CPA P also dilutes the alveolar CO2. These two factors account for the reduction in arterial CO2 levels seen in some patients receiving CPAP without the addition of assisted ventilation. The main complication from the use of CPAP is pneumothorax. This must be sought for in any patient experiencing a sudden deterioration while receiving CPAP treatment. Excessive levels of CPAP may also result in impairment of cardiac output, presumably from cardiac compression, although increased pulmonary vascular resistance may also play a role. Some investigators also feel that elevated airway pressures, reflected in the venous system, can also result in intracranial hemorrhage. In spite of these potential problems, CPAP has formed a cornerstone of the ventilator treatment of infants requiring respiratory assistance.
The use of the pressure-cycled ventilator has been another major advance in the treatment of HMD. The first ventilators applied in the treatment of HMD in the 1960s were adaptations of existing adult ventilators. These machines were pressure-cycled, in that the respiratory cycle ended when a preset pressure had been reached. Unfortunately, these machines could not follow the rapid breathing patterns of newborn infants and at the same time deliver adequate tidal volumes for the stiff lungs of infants with HMD. Rapid tidal volumes required high flow rates, which, in turn, required high pressures. The Bourns LS 1 04 was a successful attempt at producing a neonatal ventilator capable of high respiratory frequencies which matched the infant's own tachypnea, and at the same time was capable of producing the high pressures and flow rates necessary to generate adequate tidal volumes. This machine was volume-cycled. As compared with previous pressure-cycled machines, the volume-cycled respirator stopped generating a breath when a preset volume was reached. If the lungs became stiff because of the progression of the illness, the machine simply generated a higher pressure. If a high respiratory frequency was required, an even greater pressure was generated to produce the same tidal volume. Although this machine was successful at ventilating many infants, it also produced the problems of pneumothorax and bronchopulmonary dysplasia. The high pressures resulted in frequent cases of pneumothorax, while the pressure and oxygen levels necessitated by the stiff lungs of infants with respiratory distress resulted in pressure-oxygen injury to the lungs analogous to the "respirator lung" syndrome seen in adults or older children.
In an effort to replace this therapy, Reynolds and his colleagues developed the system of ventilation at "reversed" I: E ratios.17 Normally, inspiration is shorter than expiration, on the average of 1:2 to 1:4 in healthy individuals. Reynolds and his colleagues recognized that adequate volumes of air could be delivered with each breath at lower pressures if the I:E ratio of 1:1 or 2:1 was adopted. This, in fact, has proven to be the case, and the newer infant ventilators (Bourns BP200, BabyBird, etc.) are examples of ventilators which are pressure-cycled/ time-cycled machines. In these machines, the operator sets the cycling pressure, rate, and I: E ratio in order to achieve clinically satisfactory blood gases. Larger tidal volumes may be achieved, for instance, by increasing the cycling pressure. Hypoxemia, which requires greater distending pressure for its treatment, may be relieved by raising the mean airway pressure (either by raising the peak pressure, the level of CPAP, or prolonging the inspiratory phase). Because these ventilators produce "square" respiratory waveforms, as opposed to the "peaked" respiratory waveforms of earlier pressurecycled ventilators, they are capable of producing normal arterial blood gases at relatively lower mean airway pressures. This has resulted in a reduced incidence of pneumothorax, and probably in a lower rate of chronic lung changes, such as bronchopulmonary dysplasia.
High-frequency oscillatory ventilation (HFOV) and "jet" ventilation are new developments looming on the therapeutic horizon. Both methods require establishment of a mean airway pressure somewhat higher than that used with presently available commercial ventilators, on the order of 10 cm to 20 cm H20. With the establishment of this airway pressure, a rapid jet of air at a frequency of 120 to 150/ minute, or an oscillation which may go as high as 600/ minute (10 Hz) is produced. Both methods have been successfully used in experimental animals, adult patients, and for short periods in infants with severe HMD. With further study, their use in the treatment of neonatal respiratory distress may become important, if significant undesirable effects on pulmonary function and cardiac physiology do not appear.18"20
It would seem logical that replacement of the missing substance in HMD would be the basis of all therapy. After all, replacement of insulin in diabetics, thyroid hormone in hypothyroid patients, or vitamin C in scorbutics has been commonplace for many years.
Nevertheless, initial trials with surfactants in the therapy of infants with HMD were disappointing. Perhaps the earlier investigators were unable to overcome the difficulties of administration of surfactant in such a way that effective amounts reached the alveoli. Perhaps the preparation they used was lacking in various important components. With improved knowledge of the chemical composition of surfactants, as well as better methods of depositing these substances in the lungs of neonates, trials of "natural" and "artificial" surfactants in infants with HMD have begun.21'22 Natural surfactant, obtained from animal lungs, has the presumed advantage of containing all clinically significant surfactants, even those which clinicians do not yet know about. Its disadvantage is the one of possible sensitization of the recipient to an animal protein. The artificial surfactant contains chemically pure substances in mixtures resembling those found in normal human infants. Its disadvantage is that there may be components of natural surfactants whose functional significance outweighs their apparent chemical importance. Early trials of both these substances in animals have been encouraging, and preliminary work by some investigators on small groups of human infants with HMD has been similarly encouraging. However the initial human trials have been small, and the possibility of acute or remote side effects is not yet known. As experience with these substances grows, their role in the prevention and treatment of HMD will become clear.
PREVENTION OF COMPLICATIONS
Bronchopulmonary dysplasia is an important longterm complication of HMD. This is probably due to a combination of pressure and high levels of inspired oxygen. Methods of treatment which minimize the pressure needed to ventilate infants with HMD and lower the total exposure to oxygen would probably be of importance in reducing the incidence of the debilitating and potentially fatal condition. In fact, the pressurecycled, time-cycled system of ventilation has probably had a significant role in reducing the total incidence of bronchopulmonary dysplasia, since this type of ventilator minimizes both pressure and oxygen exposure. Vitamin E, which may protect against free radical formation from oxygen, may have some effect in preventing bronchopulmonary dysplasia, although early studies indicating this effect have not been confirmed.23'24
Vitamin E has also been proposed as a means of preventing the retinopathy of prematurity, retrolental fibroplasia (RLF). Present knowledge of this blinding illness indicates that oxygen levels may play a major role in its production. Transcutaneous monitoring of oxygen has been of value in preventing excessive oxygen levels between arterial blood sampling. The ability to successfully care for very low birthweight infants has continued to produce infants who survive with RLF. Present studies confirm that vitamin E reduces the incidence of severe (grade III) RLF when administered orally in a dose of 100 mg ( 100 international units) of vitamin E per kilogram. It is of interest that this dose reduced the incidence of severe disease only, and did not affect the appearance of grades I and II. Nevertheless, there appear to be no negative studies concerning the use of vitamin E and RLF. It would therefore appear prudent, in - light of current knowledge, to administer vitamin E in recommended doses to very low birthweight infants who are at greatest risk for developing RLF.25
Survival of infants with HMD has improved remarkably in the last decade. This has resulted from improved methods of diagnosis, which enables clinicians to recognize infection, the patent ductus, and the presence of pulmonary hypertension complicating HMD; from improved methods of ventilation, which result in a lower incidence of acute and chronic complications; and from a reduced incidence of pulmonary and extrapulmonary complications, such as bronchopulmonary dysplasia and retrolental fibroplasia. These advances arise from a deep understanding of pulmonary and metabolic physiology of the newborn infant with respiratory distress. Only an approach firmly rooted in an understanding of physiology, pharmacology, and biochemistry can be completely successful in the therapy of these infants.
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