- Email: [email protected]
Hyaline membrane disease: A discussion
FETAL
AND
MED I CINE
NEONATAL RichardE. Behrman, Editor
Hyaline membrane disease: A discussion The purpose o[ this symposium is to provide some management guidelines [or the pediatrician; these are presented in the context o[ our present understanding o[ the pathophysiology o[ a newborn in[ant with respiratory distress. In our experience Jew o[ these in[ants require artificial ventilation with mechanical ventilators, since this subject has recently received a great amount o[ attention, we have excluded this aspect o[ treatment [rom the commentary. Several pediatricians with a special interest in hyaline membrane disease have been asked to reply to questions which are relevant to understanding the pathogenesis, clinical mani[estations, and usual supportive treatment o[ this inadequately understood disorder. An attempt has been made to preserve the integrity o[ each participant's opinion both when they were in agreement as well as when they disagreed with one another. RICHARD E. BEHRMAN
P e t e r A u l d , A l a n Hodson, a n d R o b e r t Usher, N e w York, N. Y., Seattle, Wash., and Montreal, Quebec, Canada
1. W h a t are some of the most significant clinical a n d laboratory features of hyaline m e m b r a n e disease ( H M D ) a n d how are they related to the pathophysiologic developm e n t of the disease? AULD. I think of respiratory distress in the premature infant as two different clinical syndromes. (1) An acute condition, hyaline membrane disease, characterized by the onset of respiratory difficulty at birth and by increasing severity of symptoms which reach a peak at 48 to 72 hours and then gradually regress over the From the Departments o[ Pediatrics, Cornell University School o[ Medicine, University o[ Washington School o[ Medicine, and Departments of Pediatrics and Obstetrics and Gynecology, McGill University School of Medicine.
first week. Such an infant generally has a birth weight of 1,200 to 2,000 Gm. and is of 30 to 60 weeks' gestation. In severe cases symptoms may persist for many weeks due to pulmonary oxygen toxicity. (2) A "chronic" condition which is less common and occurs exclusively in infants under 1,200 Gm. birth weight and of 28 to 30 weeks' gestation. Most often the infant is in good condition for the first 24 to 36 hours and may not require any oxygen. Then a progressive increase in respiratory difficulty is observed, characterized by increasing cyanosis and apnea. These symptoms are most prominent at 4 to 7 days but continue into the second and third week. Oxygen toxicity may prolong this course. In both of these conditions, atelectasls is the major pathologic entity; hyaline membranes are more frequent in the first group at necropsy. Vol. 80, No. 1, pp. 129-140
I 30
Auld, Hodson, and Usher
Atelectasis and poor pulmonary perfusion result in hypoxia (cyanosis), hypercarbia, and acidosis. Some degree of atelectasis is present in most premature infants, even in those without obvious respiratory symptoms. SIGNIFICANT CLINICAL F E A T U R E S OF H M D A N D THEIR RELATIONSHIP TO PATItOPHYSIOLOGY Decreased chest volume. Most normal infants have a decrease in chest volume in the days after birth due to the release of trapped gas. In infants with HMD and those with the more "chronic" form of respiratory distress, the decrease in chest volume is readily apparent clinically: This can be used as a diagnostic aid. The effect is most clearly appreciated as a concavity in the axillary area. In HMD this decrease in chest volume is related to the progressive development of atelectasis. I n the smallest infants with "chronic" respiratory distress the decrease in chest volume is often associated with the development of apneic spells. Chest retraction. The chest wall of the infant provides poor support for the lungs because it is very compliant. However, diseased lungs have decreased compliance. Retractions occur as the infant attempts to exert an increased negative pressure in response to the low pulmonary compliance. Expiratory grunt. The expiratory grunt which is such a prominent feature in the early stages of HMD is probably due to airway collapse during expiration. Because of the increased pressure needed to ventilate the lungs (decreased compliance), the pressure difference between the inside and outside of the bronchioles is greatest at the beginning of expiration. The supporting structures are deficient and as expiration begins the airways collapse. In order to evacuate the air now trapped distally, the infant must increase the expiratory pressure with a resultant grunt. Cyanosis. Cyanosis is due to venoarterial shunting in the heart (foramen ovale and ductus arteriosus) and in the lungs (perfusion of atelectatic or nonventilated alveoli). Pallor. Pallor is frequently associated with acidosis and may result from poor tissue perfusion due to hypotension. Apnea. Apnea is associated with atelectasis and decreased lung volume. Although it may be an oversimplification to assume cause and
The ]ournal o[ Pediatrics January 1972
effect, some evidence indicates that apnea is due to mechanical factors in the lung that develop from atelectasis. When the at~lectasis decreases apnea often disappears. Apnea may also be a manifestation of injury to the central nervous system. RELATIONSHIP OF L A B O R A T O R Y F E A T U R E S TO PATHOPHYSIOLOGY OF H M D
Chest roentgenogram. The typical chest roentgenogram of HMD shows a reticulargranular appearance and an air bronchogram. These changes are related to atelectasis, and airfilled bronchi stand out in bold relief. In the more "chronic" form of respiratory distress syndrome, the reticular appearance is more prominent than the air hronchogram. This may be a consequence of the increased tendency for terminal bronchioles to collapse in very small infants; they have fewer air-filled structures to form an air bronchogram. Decrease in functional residual capacity. In almost all infants with HMD who have been studied, there is a decrease in the functional residual capacity during the first two days of life. This decrease closely parallels the clinical course; in the most severely ill patients the functional residual capacity may be very low from the outset. Low Po 2. The very low arterial Po 2 in infants with both types of respiratory distress is due to venoarterial shunting, as noted above. Shunting increases progressively in parallel with the decrease in functional residual capacity. During recovery the low Po2 is due to either a diffusion block or abnormal distribution of ventilation as well as to venoarteriat shunting. Increased PeG 2, Increased Pco 2 is due to the development of areas of relative underperfusion in the lung; i.e., perfusion is reduced relative to ventilation. These inequalities may be minimal initially but become progressively more prominent as the clinical condition worsens. Acidosis. Prior to the clinical recognition of HMD, a profound combined respiratory and metabolic acidosis is often present in depressed infants who have required resuscitation in the delivery room. Frequently this acidosis corrects itself spontaneously or may be corrected following assisted ventilation and administration of sodium bicarbonate. If the infant develops hyaline membrane disease, the disease may be characterized by varying degrees of persistence
Volume 80 Number 1
of this acidosis. In addition, with the onset of hyaline membrane disease, respiratory acidosis develops due to a reduction of perfusion of the lung relative to ventilation; this is one of the major laboratory features of the disease toward which therapy must be directed. Metabolic acidosis also occurs as lactic acid accumulates due to poor tissue perfusion and an inability to adequately oxygenate the patient. Hypotension. This may be related to severe acidosis and is corrected by treating the acidosis. However, the possibility that hypovolemia from blood loss or dehydration is producing the hypotension must also be considered. Edema. Peripheral edema is a frequent accompaniment of HMD, but clearly is not due to congestive heart failure. Its origin is unknown; it may be a result of catabolism in a relatively starved and distressed subject, producing an increased solute load that cannot be excreted by an underperfused kidney. Hyperkalemia. Hyperkalemia is secondary to catabolism and does not occur when sufficient calories are provided intravenously. HODSON. The most important clinical features of H M D are: retractions (subcostal, xyphoid, and suprasternaI), tachypnea, flaring of alae nasae, expiratory grunting, and cyanosis. These signs are all related to the pathophysiologic process of progressive focal atelectasis causing a decrease in lung compliance and increased work of breathing. Tachypnea probably represents an attempt to decrease the elastic work load of the lung and to alleviate hypoxia by increasing alveolar ventilation. The retractions and nasal flare are related to the increased intrapleural pressure necessary to inflate partially collapsed alveoli. Expiratory grunting due to closure of the glottis probably elevates expiratory pressure; this prolongs alveolar expansion and improves oxygen exchange. (The application of a positive end expiratory pressure has been shown to increase arterial Po 2 in experimental animals and in infants with HMD.) Cyanosis is related to three pathophysiologic developments. In decreasing order of magnitude these are: (1) There is a moderately large rightto-left vascular shunt. The major site of this shunting has not been clearly established. Intrapulmonary shunting of blood past collapsed alveoli probably accounts for most of this. However, some shunting also probably exists through the ductus arteriosus and the foramen ovale. (2) There is a decreased ventilation/perfusion ratio as measured by alveolar nitrogen gradients. This
Hyaline membrane disease
13 1
is due to poorly ventilated alveoli and results in venous admixture. (3) True alveolar hypoventilation also accounts for a very small part of the hypoxia. The radiologic criteria for diagnosis indicated by Dr. Auld depend upon a good quality film and sufficient evolution of the disease. The roentgenographic pattern represents atelectasis with fluid or congestion in the interstitium and possibly fluid in the alveoli. IJSH~R. My opinion is that this is a disease process involving pulmonary edema, congestion, and atelectasis of unknown etiology. It develops at birth, progresses for 12 to 60 hours, and then may improve spontaneously. It occurs in infants born at least 10 days prematurely and is more frequent and more severe after cesarean section or when the umbilical cord is clamped early. It is greatly exacerbated by exposure of the lungs to high oxygen concentrations. Clinically, the key manifestations result from decreased compliance (retracti*ns, grunting, decreased air entry). The most significant signs of progressive respiratory failure during H M D are the increasing need for oxygen, central nervous system depression, and puhnonary rales. 2. A t w h a t age is the r o e n t g e n o g r a m of the chest likely to be of value in diagnosing hyaline m e m b r a n e disease? AULD. A roentgenogram of the chest is of most value in diagnosing HMD when the functional residual capacity is least, indicating the greatest amount of atelectasis. This is generally at 24 to 48 hours. However, many infants (particularly those most severely ill) will show the typical picture in the first hours after birth. More important than making this diagnosis, the chest roentgenogram is of greatest value in excluding other conditions such as pneumothorax, etc. Thus all distressed infants should have a chest roentgenogram early in the course of their respiratory distress. I don't think that one should jeopardize the condition of the infant by taking serial roentgenograms to watch for the development of the typical picture of HMD. Further roentgenographic studies should be reserved for the evaluation of changes in the clinical course which may herald a complication. Ghest roentgenograms are indicated later if pulmonary oxygen toxicity is st~spected. In the "chronic" form of respiratory distress observed in the smallest infants, the most severe reticular pattern is obvious on day 4 or 5.
132
Auld, Hodson, and Usher
The Journal of Pediatrics January 1972
Table I
Gestation (wk.) 39+ 37-38 35-36 33-34 31-32 29-30 25-28
Incidence of HMD per 100 live births Vaginal Cesarean section (%) (%) 0.04 0.8 5.4 20.5 35.0 64.3 64.9
USI~ER. An initial radiograph is of most value to rule out other specific causes of respiratory distress which can be clearly identified radiologically, such as diaphragmatic hernia, lobar atelectasis or emphysema, or pneumothorax. Roentgenograms are also necessary to diagnose the pneumothuraces which occur secondarily to HMD in 2 to I0 per cent of patients; these usually present at about 48 hours of age as a sudden deterioration in the infant's condition. In infants treated liberally with oxygen, the reticulogranular pattern of respiratory distress syndrome persists or progesses for 72 hours. Patients treated with more restricted oxygen show steady radiologic improvement after the first few hours of life. IIonsoIq. The chest roentgenogram is diagnostic within one hour of birth in severe HMD, within 4 hours in the moderately ill, and within 8 hours in all cases. Every infant with respiratory distress probably should have a chest roentgenogram prior to 3 hours of age to rule out other pulmonary abnormaIities such as pneumothorax. 3. W h a t is the incidence of clinical H M D disease in various populations of infants? AuLo. I have no valid data on the incidence of clinical HMD in various populations. I have been unable to satisfy myself that the numerator of the equation (i.e., number of infants with hyaline membrane disease) can be clearly determined. However, I do not think that that cesarean section, per se, predisposes an infant to HMD. In addition, no infant of a diabetic mother has died of hyaline membrane disease at the New York Hospital in the last 8 years; very few have had the disease. The frequency of HMD is related to prematurlty, not to maternal diabetes or cesarean section. Infants with fetal distress and/or a low Apgar score at birth do not develop HMD with a predictable increased frequency. Almost all infants
1.0 8.4 31.8 53.8 53.8
Risk o[ death [rora HMD per 100 live births Vaginal Cesarean section (%) (%) 0 0 0.3 2.3 8.3
0 1.2 5.9 17.9 23.1
under 1,000 Gm. have some form of respiratory distress syndrome, often of the "chronic" type. HMD is rare in full-term infants. All premature infants should be considered at high risk for developing the full clinical syndrome, which is most often well established in the first 2 to 3 hours of life. UsHeR. It is our experience (Table I) that ttMD develops only in infants who are of gestatlonal ages less than 270 days (38~2 weeks). Cesarean section is associated with a greatly increased incidence of HMD and a higher neonatal mortality rate, irrespective of the indications for the section. Maternal diabetes, per se, plays no role in the incidence of or death from HMD except that many infants of diabetic mothers are delivered prematurely by cesarean section. The over-all incidence of HMD in our neonatal unit ranges from 1 to 2 per cent of all live births, 20 per cent of all low-birth-weight infants, and 35 per cent of low-blrth-weight infants of appropriate weight for gestationaI age. HODSO~. There is no evidence for differences in the incidence of HMD in different racial or ethnic groups independent of their rates of premature births. In our experience perinatal factors other than prematurity and the second born of twins do not have a statistically significant relationship to an increased incidence of HMD. The second born of twins has a 16 per cent higher incidence than the first born. A review of 135 infants at the University of Washington with birth weights less than 1,000 Gm. revealed an incidence of 66 per cent with HMD. The incidence decreased in direct proportion to advancing gestational age. HMD occurs in approximately 50 per cent of the neonatal intensive-care population at University of Washington (50 per cent of this population is derived from referrals of babies born in other hospitals).
Volume 80 Number 1
The incidence of HMD is considerably increased when there is a history of a previous sibling with HMD. 4. H o w do you m a n a g e a n i n f a n t in the delivery room who develops clinical signs of hyaline m e m b r a n e disease b u t does not require t r e a t m e n t for asphyxia or shock. ( U m bilical catheter? I m m e d i a t e alkali t r e a t m e n t versus delay u n t i l the i n f a n t can be treated in the nursery, etc.?) AULD. If a sick infant does not require immediate resuscitation in the delivery room, he is promptly transferred to the nursery. Only the most urgent emergency treatment should be carried out in the delivery room. Further therapy is delayed until adequate assessment of the patient's condition can be made; this includes measurement of blood gases. USHER. Delivery room management is primarily aimed at (1) providing at least one minute of placental transfusion, (2) ensuring adequate ventiiation if the infant is asphyxiated, and (3) reducing cold exposure and minimizing handling of the infant. There is no evidence that early rapid correction with alkali or early elevation of arterial Po2 tensions to adult levels are beneficial; infants with respiratory distress syndrome are, therefore, only given enough oxygen to control cyanosis, are not catheterized, and are not given intravenous fluids in the delivery room. HODSON. Most infants with clinical signs of respiratory distress in the delivery room are not severely compromised unless they have suffered asphyxia at the time of delivery. Therefore, in the absence of asphyxia it is preferable to insert an umbilical arterial catheter, if needed, under the more optimal conditions (sterility and warmth) of the nursery or a treatment room. It is especially important to maintain an appropriate environmental temperature for the infant with respiratory distress; cold stress increases oxygen consumption and the demands on an already burdened respiratory system. There is no evidence that early alkali therapy in the delivery room will affect the course of HMD. 5. W h a t clinical a n d laboratory criteria do you use to decide to initiate t r e a t m e n t with intravenous fluids a n d sodium bicarbonate in a n i n f a n t mildly to moderately ill with hyaline m e m b r a n e disease? HODSON. All infants with mild or moderate illness should receive parenteral fluids. We give
Hyaline membrane disease
133
sodium bicarbonate moderately rapidly to infants with an arterial pH of less than 7.3 due to a metabolic acidosis. The rationale for treatment is related to the untoward effects of acidosis on cardiovascular hemodynamics, especially pulmonary artery vasoconstriction, as shown by Rudolph and Yuan.1 Our recent studies, 7 however, show that the alveolar-arterlal oxygen gradient and hence PAO2 does not change significantly following correction of the pH. This observation suggests that a reduction in pulmonary vascular resistance will not decrease hypoxia due to intrapulmonary shunts. Infants with mild-to-moderate respiratory distress should not be given oral fluids or feedings because of the increased risk of apnea, regurgitation, and aspiration. USHER. All infants with clinical evidence of HMD are treated with a scalp vein intravenous infusion of 10 per cent glucose and up to 15 mEq. per cent sodium bicarbonate, administered at a rate of 65 ml. per kilogram per day from the first half hour of life until the infants are taking an equivalent volume of milk feedings. Sodium bicarbonate is started at concentrations of 15 mEq. per 100 ml. if the capillary (warmed foot blood) or arterial pH is below 7.20, at 10 mEq. per 100 ml. if the pH is between 7.20 and 7.29, and at 5 mEq. per 100 ml. if the pH is between 7.30 and 7.35. No bicarbonate is infused when the pH of arterial or arterialized capillary blood is above 7.35; this seldom occurs within the first hour of life. Subsequently, the concentration of sodium bicarbonate is adjusted in order to achieve and then maintain capillary or arterial pH values of 7.35 to 7.40; most patients with ttMD have pH's in this range from 6 to 12 hours of age onward. The purposes of this intravenous infusion therapy are to provide basal caloric needs and adequate hydration, to correct acidosis, and to decrease catabolism and prevent the development of hyperkalemia and azotemia. The rapid infusion of sodium bicarbonate during the first 3 hours of life was associated with a doubling of the mortality rate from HMD in our unit compared with the deaths which occurred when we employed a regimen of more gradual intravenous infusions. Therefore, we recommend a maximum rate of infusion of intravenous sodium bicabonate equal to 0.4 mEq. pe kilogram per hour. AULD. For all distressed infants we immediately start an intravenous infusion to provide fluid and calories; this also provides a readily avail-
134
Auld, Hodson, and Usher
sodium bicarbonate given if ventilation is ineffective in completely reversing the trend.
Table II
Venous pH
The Journal of Pediatrics January 1972
Administer sodium bicarbonate (l mEq./c.c.)
7.10
~10 c.c.
7.20
<10 c.c.
7.30
< 5 c.c.
7.35 and falling
~ 3 c.c.
able route for the administration of sodium bicarbonate. I do not think that there are good clinical criteria for administering sodium bicarbonate. It is absolutely imperative to monitor pH and Peon; for clinical purposes it is adequate to use free-flowing venous or capillary blood. The aim of sodium bicarbonate therapy is to alter the pH toward normal. Bicarbonate need not be given when the venous blood pH is over 7.30, unless this value reflects a trend of a falling pH (in which case sodium bicarbonate would be given to reverse the trend). Although various formulas have been proposed for the correction of acidosis based on serum bicarbonate concentrations, in my experience they are no better than the empirical approach outlined below. I favor a fairly vigorous and rapid intravenous administration of sodium bicarbonate; when the dosage is decided upon, the bicarbonate is infused over a 5 to 10 minute period according to the schedule shown in Table II. The blood gases should be analyzed for pH, Pca~, actual bicarbonate concentration, and deviation from the normal buffer base content 30 minutes after each dose of sodium bicarbonate. If the venous pH is unchanged, the dose should be repeated. If the pH goes from 7.10 to 7.25, I would observe the infant for another hour and repeat the pH before giving more sodium bicarbonate. Whereas sodium bicarbonate is the treatment of choice for metabolic acidosis, it should not be regarded necessarily as the best therapy for respiratory acidosis. When respiratory acidosis is mild (i.e., Pco~ less than 50 mm. Hg), sodium bicabonate may be used alone and generally the pH will be corrected. However, in cases of moderate and severe respiratory acidosis, sodium bicarbonate should be regarded as an adjunct to assisted ventilation with bag and mask which must be the primary therapy. When confronted with moderate or severe respiratory acidosis, assisted ventilation should be started first and
6. W h e n is tris-hydroxymethyl a m i n o m e t h a n e ( T H A M ) indicated in place of sodium bicarbonate? USlaER. I have not seen an infant benefit fl'om administration of THAM when bicarbonate treatment was ineffective. I no longer use it. HoosoN. THAN[ may be indicated when there is a need for the rapid correction of a marked combined respiratory and metabolic acidosis such as occurs with severe asphyxia. It temporarily buffers CO, as well as noncarbonic acids, and thus may have a more rapid and hence beneficial effect on pulmonary blood flow in the infant suffering from acute asphyxia. Some evidence suggests that myocardial contractility is increased to a greater extent with THAM than with NaHCO~ at comparable degrees of acidosis. In the treatment of metabolic acidosis, NaHCO~ appears to be as effective a buffer as THAM. The rapid intracellular distribution of THAM can result in sudden changes in the pH of fluids in the central nervous system (in an alkaline direction); this may produce apnea. AULD. I give THAM in place of sodium bicarbonate only in two conditions: (1) When the cumulative dose of sodium bicarbonate is leading to hypernatremia, i.e., generally after 30 to 50 c.c. of sodium bicarbonate (I mEq. per cubic centimeter) has been administered and/or the sodium level is over 155 mEq. per liter. (2) When severe respiratory acidosis is not responding to assisted ventilation and sodium bicarbonate (i.e., Pco~ > 85 mm. Hg). Respiratory arrest is an important complication of the administration of THAM. If it is used, assisted ventilation should be readily available. 7. Is there a n indication for oral or gavage fluids a n d sodium bicarbonate i n mildly to moderately ill infants with hyaline m e m b r a n e disease? USHER. Although there have been several reports of the use of the gastrointestinal route to administer glucose and bicarbonate, absorption from this route is uncertain. I would consider the gastrointestinal administration of glucose and bicarbonate only when personnel are not available to start intravenous infusions and transfer to an appropriate neonatal unit is not possible.
Volume 80 Number 1
Gavage feedings of milk should, however, be started as soon as an infant is over the acute phase of his illness and seems active and well enough to tolerate the feedings. They provide a more balanced electrolyte mixture and adequate caloric intake. AULD. There is no indication for oral sodium bicarbonate. Correction of acidosis needs to be given in a more directly controlled fashion than can be accomplished by oral administration. HODSON. The goal of correction of acidosis is an immediate improvement in physiologic and/ or biochemical function; slow correction or maintenance by oral administration probably provides little, if any, benefit. Furthermore, oraI or gavage fluids increase the risks of regurgitation and aspiration which occur more commonly in infants with respiratory distress. 8. W h a t volumes of m a i n t e n a n c e fluids do you use on days 1, 2, a n d 3? W h e n do you add potassium? W h a t do you use as guides in m a k i n g these decisions? AULD. Fluids should be given at the rate of 100 c.e. per kilogram per day for the first 3 days of life. For the first 2 days, we consider the caloric requirements to be the first priority and thus give a solution of 10 per cent gIucose and water, which provides sufficient calories to reduce catabolism. This solution may cause a mild osmotic diuresis with loss of electrolytes; thus maintenance electrolytes (including potassium) are added on the third day and the glucose concentration is reduced to 5 per cent. UsItER. Our goal is to provide adequate fluids to prevent dehydration. In general the caloric intake provided by fluids with 5 to 10 per cent glucose concentration administered during the first 3 days of life to infants with a respiratory distress syndrome is below their maintenance need of 100 calories per kilogram per day; therefore, a i to 2 per cent weight loss per day can be expected due to catabolism from starvation. Fluids are initiated at a rate of 50 to 100 ml. per kilogram per day (the highest rates for the infants under 1,000 Gm. and the lowest rates for those over 2,500 Gm.), and the rate is adjusted according to the weight obtained at intervals of every 12 hours to prevent more than a i to 2 per cent weight loss per day until an adequate caloric intake is achieved. In most infants the original rate is increased 50 per cent during the first 72 hours of life as urinary output increases and more fluids are required to main-
Hyaline membrane disease
135
tain the desired body weight. Edema formation in the presence of a falling weight is not considered an indication to reduce fluid intake in infants with respiratory distress syndrome. Potassium supplementation is not required in most patients because of a tendency for the serum potassium concentration to be elevated during the first 3 days of life. After this time the usual patient is receiving adequate maintenance potassium from milk supplied by gavage feedings. Potassium is added to intravenous fluids of infants with HMD only after the third day of life, if there is no enteric potassium intake, and if the serum potassium concentration is below 4 mEq. per liter. I-IoDsoN. Maintenance fluids of t0 per cent glucose and water are given at a rate of 65 ml. per kilogram per 24 hours during the first day, 75 to 85 ml. per kilogram over the second, and 90 to 100 ml. per kilogram on the third day. Usually sufficient maintenance sodium is administered on day one in the form of sodium bicarbonate for the treatment of acidosis; if an infant has not received NaHCO~ he is given 3 mEq. per kilogram per day. Potassium is usually added on day two, 2 mEq. per kilogram per day. Serum electrolytes are measured on day 2 and potassium is withheld if the serum concentration is above 7 mEq. per liter. 9. W h e n are umbilical vessel versus peripheral venous infusions indicated? AULD. Infusion of fluids through an umbilical vessel is rarely preferred over a peripheral venous infusion. When there is difficulty in beginning a peripheral vein infusion in a severely ill infant, an umbilical vessel infusion may be desirable because of an urgent need to begin therapy. However, the umbilical catheter should be removed as soon as possible. Routine use of umbilical vessels should be avoided because of dangers of infection and thrombosis. End-hole catheters are preferred when umbilical catheters are utilized. HODSON. Peripheral venous infusions, when technically possible, are always preferred to umbilical vessel infusions, unless an umbilical artery has been cannulated for the primary purpose of blood gas sampling. There is little indication for infusion into an umbilical vein since hepatic necrosis may result from sodium bicarbonate or THAM administered via this route. USHER. Umbilical infusions greatly increase the risk of infection, thrombosis, hemorrhage, and accidental fluid overload; they should only be
136
Auld, Hodson, and Usher
used when peripheral infusions are impossible, and for as short a period of time as is possiblc. 10. H o w long do you leave an umbilical catheter i n place? Do you prefer umbilical artery or vein? AULD. We prefer to use an umbilical vein catheter rather than an umbilical artery catheter because it is easier to insert in the proper location. (We also measure Po~ on temporal or radial artery blood samples when arterial blood sampling is necessary.) The umbilical vein catheter must be carefully positioned, and the best location for the tip of the catheter is in the inferior vena cava; this probably minimizes the chance of thrombotic complications. The umbilical venous catheter should be removed as soon as a peripheral vein intravenous infusion can be started. No umbilical venous catheter should be left in place for more than two days. An infant in whom an umbilical venous catheter has been inserted is treated with antibiotics (ampicillin and kanamycin) in an attempt to decrease the hazard of infection. The major dangers in the use of umbilical catheters are: (1) infection and (2) thrombi and liver necrosis due to administration of strong alkali. This latter complication is unusual if only glucose and water is infused. HODSON. We leave an umbilical artery catheter in place as long as there is a need for oxygen. Infants greater than 1,600 Gm. can be managed without inserting a catheter when oxygen concentrations are less than 30 per cent. Generally we do not use umbilical vein catheters, except briefly when it is necessary to treat a severely asphyxiated infant with sodium bicarbonate in the delivery room. USHER. We have had severe infections from indwelling catheters in both umbilical artery and vein and, therefore, we resort to them only when periphreal intravenous infusions are impossible or when arterial blood sampling has a decided advantage over capillary sampling, as in a patient requiring mechanical respirator therapy. My preference is for sampling capillary blood from warmed heels to avoid the trauma of repeated percutaneous arterial punctures, and the risks of infection, thrombosis, and hemorrhage associated with indwelling umbilical artery catheters. Capillary blood acid-base values approximate arterial blood values. Capillary oxygen tensions closely parallel those of arterial
The Journal o[ Pediatrics January 1972
blood in the hypoxemic range (below 40 mm. Hg) and deviate increasingly from arterial blood values in the normoxemic and hyperoxemie ranges. We provide sufficient oxygen to maintain arterial tensions of 40 to 65 mm. Hg, which correspond to warmed heel capillary Po 2 values of 35 to 55 ram. Hg. When sufficient oxygen is given to raise the capillary Po 2 above 65 mm. Hg, arterial values may exceed 150 mm. Hg and allow development of retrolental fibroplasia. In practice we increase ambient oxygen when warmed heel capillary Po 2 falls to 35 to 40 mm. Hg, and reduce ambient oxygen when capillary P% exceeds 45 to 50 mm. Hg. The only exception is when acidosis is severe and the hemoglobin-oxygen dissociation curve is displaced to the right, under which conditions arterial Po 2 may need to be increased to above 60 mm. Hg to provide a minimum of 85 per cent oxygen saturation. 1I. H o w m u c h oxygen should be used in treating a n i n f a n t with hyaline m e m b r a n e disease a n d how long should it be used? If a Po2 m e a s u r e m e n t is unavailable, what criteria would you use to decide u p o n the proper treatment with oxygen? W h e n do you use assisted ventilation? AULD. Oxygen should be used in concentrations necessary to abolish cyanosis or to maintain Po~ between 60 and 80 mm. Hg. Our indications for assisted ventilation are: apnea, inability to oxygenate the patient in 100 per cent oxygen by mask, and respiratory acidosis. Mild respiratory acidosis can usually be treated by the administration of sodium bicarbonate. Severe respiratory acidosis (pH 7.20 and Pco2 50) is an indication for assisted ventilation with a bag and mask. In my opinion, assisted ventilation of neonatal infants is best performed with an anesthesia bag supplied with oxygen (whose concentration can be varied) and a face mask ( ~ liter anesthesia bag and Rovenstine angle). An indwelling gastric tube is also employed to decompress the stomach. The advantages of this method over respirators are: (1) almost anyone can be trained to perform this type of ventilation in five minutes, (2) it avoids endotracheal intubation with the dangers of trauma to the airway, especially in unskilled hands, (3) assisted ventilation can be stopped and started with minimum difficulty, (4) each patient requires individual attention (I think this is the key to suc-
Volume 80 Number 1
cess in assisting ventilation), (5) it is easy to reassess the degree of oxygenation frequently and to make the needed adjustments and, (6) an infant can be ventilated intermittently for 5 or i0 minutes every hour. This can only be accomplished by the bag and mask method. This method does not require more nursing personnel. It is necessary to have more people to treat ill infants but they need not be registered nurses. USHER. Oxygen should be used only in an amount sufficient to eliminate cyanosis. In infants with a relatively normal pH, cyanosls develops at an arterial Po~ below 40 mm. tIg (arterialized capillary blood below 35 mm. Hg). An infant does not benefit from and may be injured by maintaining arterial oxygen tensions at adult levels (80 to 120 mm. Hg). Oxygen should be regarded as an essential, though toxic, drug for anoxic infants; it may cause pulmonary toxicity which is indistinguishable from hyaline membrane disease or it may cause retrolental fibroplasia. Therefore, it should be used only if needed and in the minimal effective dose. In addition to cyanosis, infants suffering from hypoxemia develop a progressive metabolic (lactic) acidosis and may become very lethargic. A depressed, dusky, infant with a metabolic acidosis needs more oxygen no matter how much he is receiving at the time. Fairly accurate control can be obtained by experienced clinical observations of color, tone, etc. HMD can be treated without facilities for blood gas measurement, but whenever possible oxygen therapy should be guided by blood gas measurements. In the absence of laboratory measurements, I would treat cyanosis with just enough oxygen to keep the infant pink (equivalent to arterial Po 2 of 40 mm. Hg). I would also use intravenous infusions of 10 per cent glucose and water with 5 mEq. per 100 ml. bicarbonate for the first 72 hours of life without blood gas monitoring in an infant with HMD. We employ mechanical ventilation with a respirator for apneic spells not responding to bag and mask resuscitation or an arterial or capillary P ~ below 30 mm. Hg when breathing 100 per cent oxygen. HODSON. Oxygen should be used in sufficient concentrations to provide an arterial Po~ of 50 to 80 ram. Hg; this may require concentrations as high as 100 per cent. Despite the well-recognized toxic effects of oxygen on pulmonary tissues, the consequences of O~ damage to the lung are of much less concern than inadequate
Hyaline membrane disease
13 7
tissue (especially brain) levels of oxygen. Therefore, high levels of oxygen are continued as long as necessary to maintain an adequate Po, We have followed approximately 30 infants with radiotogic evidence of chronic pulmonary changes attributable to high oxygen concentrations. Apart from tachypnea during the first 3 months of life, all but one of these infants has become asymptomatie without evidence of recurrent or chronic pulmonary disability. There has been marked radiologic improvement by 2 years of age in all of the infants (with residual parenchymal streaking and possibly fibrosis). If a Po~ measurement is unavailable, oxygen should be administered at a concentration about 5 per cent higher than that at which cyanosis appears. The risk of retrolental fibroplasia increases with immaturity, and in our nursery population arterial oxygen tensions greater than 100 mm. Hg have been associated with cicatricial retinal changes. We have not observed retinal changes in any infants with birth weights greater than 1,600 Gm. This has also been the experience of the collaborative study of oxygen therapy for premature infants. The greatest risks of not being able to measure Po.. are probably limited to those infants weighing less than 1,600 Gm. t2. I f there are no clinical or laboratory signs of sepsis, do you treat infants who have hyaline m e m b r a n e disease with antibiotic agents? AvEr. No antibiotics are given to patients with HMD unless an umbilical catheter is used or they have clinical signs of sepsis. USttER. It is exceedingly difficult to distinguish intrauterine pneumonia from HMD in premature infants. Therefore, we treat with antibiotics all infants who have a clinical syndrome of respiratory distress and prolonged rupture of the membranes, maternal fever, or foul-smelling amniotic fluid; we also examine the placenta for inflammation, and obtain blood and throat cultures, white blood count, C-reactive protein, and a sedimentation rate. Most infants with HMD do not have these conditions which predispose toward infection and are, therefore, not treated with antibiotics. If, however, the condition of an infant with HMD does not improve by 4 days of age (especially if patchy densities develop in the lung) an investigation for infection is undertaken and antibiotic therapy is started. Hovso~. Infants who do not have clinical and
13 8
Auld, Hodson,
laboratory signs of septicemia are not treated with antibiotics in our nursery. It is, therefore, important to observe neonatal infants carefully for subtle signs of infection. For this reason we do not use selwocontrolled incubators which may prevent the early detection of fever, hypothermla, or temperafure instability. This, in turn, requires appropriate careful regulation of the environmental temperature, especially the temperature of the inspired gas within an oxygen hood or a respirator. The chest roentgenogram is helpful in diagnosing pneumonia; neither the reticular pattern nor an air bronchogram should be present in infected areas. Infants with temperature fluctuations of greater than 1~ C. (not due to environmental changes) or with other signs of infection are cultured and treated with ampicillin and kanamycin. 13. A t w h a t level of hematocrit or hemoglobin do you transfuse a sick i n f a n t with hyaline m e m b r a n e disease? USI~ER. With the exception of replacing blood lost from internal (e.g., intracranlal) or external hemorrhage or from excessive blood sampling, transfusions of blood are not used routinely in our unit. I would transfuse an infant with HMD if the hemoglobin concentration were below 10 Gin. per cent, irrespective of cause, but this seldom occurs. Although I am convinced that placental transfusion is of benefit to the infant with HMD, there is no convincing evidence that postnatal blood transfusion is of value as a standard treatment of HMD. AULD. We rarely transfuse an infant with HMD because of an anemia that results from blood sampling. If a sign of acute blood loss develops, i.e., hematocri~ drop of 15 per cent in 24 hours, we transfuse the infant. A slow progressive fall in hematocrit is not treated unless the hematocrit falls below 20 per cent. HoDso~. Infants with a hematocrit value below 35 per cent in the first few hours of life are given albumin to expand their plasma volume. Serial hematocrit determinations are necessary to interpret acute or chronic blood loss. A central arterial blood pressure below 30 mm. Hg in infants weighing less than 1,000 Gin., below 35 ram. Hg in 1,001 to 1,500 Gin. infants, and less than 40 mm. Hg in infants between 1,501 and 2,001 Gm. is also an indication for expansion of the blood volume with plasma, whole blood or albumin. Preliminary evidencea indicates that survival
The Journal of Pediatrics January 1972
rates are improved when infants with low centraI arterial bIood pressures receive plasma volume expanders. All transfusions are given to improve cardiovascular hemodynamics; decreased oxygen carrying capacity of the blood is usually not a concern unless the hematocrit fails below about 18 per cent. 14. W h a t criteria for digitalization do you use in m a n a g i n g these infants? AvLD. The presence of HMD, per se, is not an indication for digltalization of an infant. The studies of Rudolph and associates s were unable to document the presence of congestive heart failure. UsHF,~. Digitalis is almost never used in our unit for the treatment of ItMD. I would consider its use if severe eardiomegaly and hepatomegaly developed during the course of HMD, but this is so unusual that I would first search for another etiologic factor, such as arteriovenous shunting. HoDsorr. Infants with HMD are not digitalized unless there are signs of heart failure, which in almost all circumstances are related to events other than HMD. 15. H o w often do you get a roentgenogram of the chest after a diagnosis is m a d e if the infant's clinical course is u n c h a n g e d ? AULD. If an infant's clinical course is unchanged, I see no reason for further chest roentgenograms. If the initial roentgenogram of the chest is equivocal for HMD and the elinicat course is typical, another study is frequently done for "interest." However, portable roentgenograms disturb the infant and modify his environment and they should be avoided unless there is a sudden change in the patient's condition. HODSON. A chest roentgenogram is obtained every 24 hours if the infant's condition has not deteriorated. Following clinical improvement, roentgenograrns are obtained at 3 to 5 day intervals or until there is radiotogic evidence of resolution. All infants should have chest roentgenograms just prior to discharge to rule out chronic or residual pulmonary changes. This is especially important in infants who received several days of oxygen therapy or who had prolonged tachypnea. USHER. Serial roentgenograms of the chest are of no value in the management of HMD except if the clinical condition deteriorates and for research purposes.
Volume 80 Number 1
16. H o w often should blood be d r a w n for laboratory determinations of acid-base status etc., w h e n the infant's clinical course is u n changed? AULD. Laboratory determinations of the acidbase status of blood are indicated only once or twice per day if the clinical course is unchanged. More frequent determinations of acidb,ase status are important early in the course when attempting to stabilize the patient's condition and treat acidosis. When the clinical course is stable, acidosis is usually well compensated; the Pco~ may be higher than normal but this elevation is of less clinical significance if the pH is normal. USHER. Rapid changes in acid-base balance or oxygenation often occur during the first few hours of life. For this reason I usually obtain capillary blood gas and pH determinations at ~/2 hour, 4 hours, and 8 to 12 hours of age in all patients with HMD. if sodium bicarbonate treatment and oxygen therapy are continued after this point, the determinations are repeated at 6 to 8 hour intervals; otherwise, they are repeated once daily until the distress subsides. HODSON. Arterial blood is drawn as frequently as is necessary to evaluate acute therapy. The Pao_o should be measured within 30 minutes of a change in inspired oxygen concentration. The PAco2 and PAo2 should be measured within 30 minutes of any adjustment in a respirator setting; pH should be assessed within 30 minutes of the administration of alkali since metabolic acidosis may be due to a continuing process. Once the: course is stable, blood gases and pH probably should be measured at 6 to 8 hour intervals in the first 24 hours and at increasing intervals of time thereafter, depending on the severity of the disease. In our experience many sick infants have required 40 to 50 blood gas determinations prior to complete recovery. 17. W h a t is the incidence of central nervous system hemorrhage, heart failure, p u l m o n a r y hemorrhage, secondary sepsis, retrolental fibroplasia, a n d p u l m o n a r y reaction to oxygen i n hyaline m e m b r a n e disease? AULD. Central nervous system hemorrhage is common in infants under 1,200 Gm. with respiratory difficulty but rare in larger infants. In my experience heart failure is not a complication of HMD, and pulmonary hemorrhage is very rare. Secondary sepsis is unusual, and when it
Hyaline membrane disease
139
does occur, it is often related to the use of an indwelling umbilical venous catheter in an infant who is not treated with antibiotics. I have not seen retrolental fibroplasia as a complication of HMD. However, infants who have had the "chronic" form of respiratory distress have developed retrolental fibroplasia; the last case was 5 years ago. Pulmonary reaction to oxygen occurs relatively frequently in the very ill patient; such infams generally require I00 per cent O5 and assisted ventilation for 6 or 7 days. In the "chronic" type of respiratory distress syndrome, involving the smallest and sickest infants, pulmonary oxygen toxicity (Wilson-Mikity syndrome) is common. USHEr. Approximately one third of the infants dying with HMD have an associated intraventrieular hemorrhage, and one half have subarachnoid hemorrhage. Heart failure, pulmonary hemorrhage, and proved secondary sepsis are extremely rare. Retrolental fibroplasia has not occurred in our last 350 patients; all had their eyes examined at the time of discharge. Puhnonary oxygen toxicity is, in my view, so similar in appearance to HMD, itself, that one cannot talk about its "incidence." All infants exposed to supplemental ambient oxygen should be assumed to have sustained additional lung damage from the treatment. Oxygen should be considered a toxic albeit often essential, drug in the management of HMD. HODSON. Central nervous system hemorrhage occurs in 65 per cent of autopsied infants with HMD at the University of Washington. We do not find evidence of heart failure in infants who have only HMD. Sepsis (positive blood culture) occurs in 5 to 7 per cent of infants with HMD. However, in 1969 about 60 per cent of the infants with HMD in our unit were treated with antibiotics at some time during their hospital course for suspicion of or presumptive sepsis. The records of all infants admitted to the Premature Center of the University o f Washington Hospital between 1960 and 1967 were reviewed and infants with birth weights less than 1,300 Gm. had follow-up ophthalmologic examination.~ Six instances of retrolental fibroplasia were detected; 4 of these infants had birth weights less than 1,000 Gm. The incidence of retrolental fibroplasia in survivors of less than 1,300 Gm. at birth was 7.0 per cent. Only one infant above this weight (1,405 Gm.) developed retrolental fibroplasia. Chronic pulmonary changes attributable to
14 0
Auld, Hodson, and Usher
oxygen toxicity are relatively common in infants who have had severe HMD. In a study of 78 infants treated with positive pressure ventilation, 8 of 15 survivors had radiologic evidence of chronic pulmonary "infiltrates.''s 18. W h a t is the prognosis for infants with hyaline m e m b r a n e disease? AULD. Long-term prognosis for all infants with hyaline membrane disease is difficult to determine. The generally favorable outlook is modified somewhat if pulmonary oxygen toxicity occurs. UshEr. The case mortality rate among 196 newborn Caucasian infants with HMD weighing more than 1,000 Gm. treated at our maternity hospital over the past 5 years was 8.3 per cent. As the incidence may vary according to criteria for diagnosis of the disease (our incidence was 14.5 per 1,000 live births), a more pertinent estimate of prognosis is the mortality rate from HMD per 1,000 births over 1,000 Gin., which for this period at our hospital was 0.083 • 14.5 = 1.2 HMD deaths per 1,000 births. The impression gained from our own patients, as well as those followed up in the literature, is that infants surviving HMD have the same intellectuaI and neurologic prognosis as premature infants of similar gestational age who have not developed the syndrome. We have rarely observed marked central nervous system damage in children surviving even severe uncomplicated HMD. HonsoN. The prognosis depends on the degree of prematurity and the severity of the disease. In general, the experience in our nursery has confirmed the prognostic usefulness of the PA02 for estimating the likelihood of survival.6 It is exceedingly difficult to assess the contribution of neonatal intensive care to the survival of infants with HMD. The prognosis for surviving infants appears to be excellent, and this may represent the most important contribution of intensive care. CONCLUSION
BEHRMAN. Although there are now broad areas of agreement about the clinical syndrome and the course of hyaline membrane disease, some differences of opinion persist. The importance of cesarean section as an etiologic factor is still
The Journal of Pediatrics ]anuary 1972
vigorously disputed. The appropriate rate of infusion of sodium bicarbonate to treat a metabolic acidosis and/or a mild to moderate respiratory acidosis is unsettled. There is no question that an initial roentgenogram of the chest is mandatory in order to rule out other diagnoses that require specific medical or surgical treatment, as well as to aid in making the diagnoses of hyaline membrane disease, but there are very different attitudes about the indications for subsequent roentgenograms of the chest if the infant's condition is stable or gradually improving. Unfortunately, our fundamental understanding of hyaline membrane disease is still very limited despite a general consensus about the necessary supportive therapy and the importance of many etiologic factors. If we are to reduce the incidence of this disorder, some of these latter factors (i.e., prematurity) will require social, political and economic decisions to complement those made in the nursery and laboratory. REFERENCES 1. Rudolph, A. M., and Yuan, S.: Response of the pulmonary vasculature to hypoxia and H+ ion concentration changes, J. Clin. Invest. 45: 399, 1966. 2. Goldenberg, V. E., Wiegenstein, L., and Hopkins, B.: Hepatic injury associated with tromethane, J. A. M. A. 205: 81, 1968, 3. Hall, R. T., and Oliver, T. K., Jr.: Aortic blood pressure in infants admitted to a neonatal intensive care unit. Submitted for publication. 4. Kalina, R. E.: Opthalmic examination of children of low birth weight, Am. J. Ophthalmol. 67: 134, 1969. 5. Hehnrath, T. A., Hodson, W. A., and Oliver, T. K., Jr.: Positive pressure ventilation in the newborn infant: T h e use of a face mask, J. PEDIATR.76: 202, 1970. 6. Stahlman, M. T., Battersby, E. J., Shepard, F. M., Blankenship, W. J.: Prognosis in hyaline membrane disease: Use of a linear-diseriminant, N. Engl..]'. Med. 276: 303, 1967. 7. Woodrum, D. E., Hodson, W. A., and Oliver, T. K., Jr.: Serial determinations of alveolar arterial oxygen gradient (AaDO2) in premature infants during the first week of life, Pediatr. Res. 3: 379, 1969. 8. Rudolph, A. M., Drorbaugh, J. E., Auld, P. A. M., Rudolph, A. J., Nadas, A. S., Smith, C. A., and Hubbell, J. P.: Studies on the circulation in the neonatal period. The circulation in the respiratory distress syndrome, Pediatrics 27: 551, 1961.
AND
MED I CINE
NEONATAL RichardE. Behrman, Editor
Hyaline membrane disease: A discussion The purpose o[ this symposium is to provide some management guidelines [or the pediatrician; these are presented in the context o[ our present understanding o[ the pathophysiology o[ a newborn in[ant with respiratory distress. In our experience Jew o[ these in[ants require artificial ventilation with mechanical ventilators, since this subject has recently received a great amount o[ attention, we have excluded this aspect o[ treatment [rom the commentary. Several pediatricians with a special interest in hyaline membrane disease have been asked to reply to questions which are relevant to understanding the pathogenesis, clinical mani[estations, and usual supportive treatment o[ this inadequately understood disorder. An attempt has been made to preserve the integrity o[ each participant's opinion both when they were in agreement as well as when they disagreed with one another. RICHARD E. BEHRMAN
P e t e r A u l d , A l a n Hodson, a n d R o b e r t Usher, N e w York, N. Y., Seattle, Wash., and Montreal, Quebec, Canada
1. W h a t are some of the most significant clinical a n d laboratory features of hyaline m e m b r a n e disease ( H M D ) a n d how are they related to the pathophysiologic developm e n t of the disease? AULD. I think of respiratory distress in the premature infant as two different clinical syndromes. (1) An acute condition, hyaline membrane disease, characterized by the onset of respiratory difficulty at birth and by increasing severity of symptoms which reach a peak at 48 to 72 hours and then gradually regress over the From the Departments o[ Pediatrics, Cornell University School o[ Medicine, University o[ Washington School o[ Medicine, and Departments of Pediatrics and Obstetrics and Gynecology, McGill University School of Medicine.
first week. Such an infant generally has a birth weight of 1,200 to 2,000 Gm. and is of 30 to 60 weeks' gestation. In severe cases symptoms may persist for many weeks due to pulmonary oxygen toxicity. (2) A "chronic" condition which is less common and occurs exclusively in infants under 1,200 Gm. birth weight and of 28 to 30 weeks' gestation. Most often the infant is in good condition for the first 24 to 36 hours and may not require any oxygen. Then a progressive increase in respiratory difficulty is observed, characterized by increasing cyanosis and apnea. These symptoms are most prominent at 4 to 7 days but continue into the second and third week. Oxygen toxicity may prolong this course. In both of these conditions, atelectasls is the major pathologic entity; hyaline membranes are more frequent in the first group at necropsy. Vol. 80, No. 1, pp. 129-140
I 30
Auld, Hodson, and Usher
Atelectasis and poor pulmonary perfusion result in hypoxia (cyanosis), hypercarbia, and acidosis. Some degree of atelectasis is present in most premature infants, even in those without obvious respiratory symptoms. SIGNIFICANT CLINICAL F E A T U R E S OF H M D A N D THEIR RELATIONSHIP TO PATItOPHYSIOLOGY Decreased chest volume. Most normal infants have a decrease in chest volume in the days after birth due to the release of trapped gas. In infants with HMD and those with the more "chronic" form of respiratory distress, the decrease in chest volume is readily apparent clinically: This can be used as a diagnostic aid. The effect is most clearly appreciated as a concavity in the axillary area. In HMD this decrease in chest volume is related to the progressive development of atelectasis. I n the smallest infants with "chronic" respiratory distress the decrease in chest volume is often associated with the development of apneic spells. Chest retraction. The chest wall of the infant provides poor support for the lungs because it is very compliant. However, diseased lungs have decreased compliance. Retractions occur as the infant attempts to exert an increased negative pressure in response to the low pulmonary compliance. Expiratory grunt. The expiratory grunt which is such a prominent feature in the early stages of HMD is probably due to airway collapse during expiration. Because of the increased pressure needed to ventilate the lungs (decreased compliance), the pressure difference between the inside and outside of the bronchioles is greatest at the beginning of expiration. The supporting structures are deficient and as expiration begins the airways collapse. In order to evacuate the air now trapped distally, the infant must increase the expiratory pressure with a resultant grunt. Cyanosis. Cyanosis is due to venoarterial shunting in the heart (foramen ovale and ductus arteriosus) and in the lungs (perfusion of atelectatic or nonventilated alveoli). Pallor. Pallor is frequently associated with acidosis and may result from poor tissue perfusion due to hypotension. Apnea. Apnea is associated with atelectasis and decreased lung volume. Although it may be an oversimplification to assume cause and
The ]ournal o[ Pediatrics January 1972
effect, some evidence indicates that apnea is due to mechanical factors in the lung that develop from atelectasis. When the at~lectasis decreases apnea often disappears. Apnea may also be a manifestation of injury to the central nervous system. RELATIONSHIP OF L A B O R A T O R Y F E A T U R E S TO PATHOPHYSIOLOGY OF H M D
Chest roentgenogram. The typical chest roentgenogram of HMD shows a reticulargranular appearance and an air bronchogram. These changes are related to atelectasis, and airfilled bronchi stand out in bold relief. In the more "chronic" form of respiratory distress syndrome, the reticular appearance is more prominent than the air hronchogram. This may be a consequence of the increased tendency for terminal bronchioles to collapse in very small infants; they have fewer air-filled structures to form an air bronchogram. Decrease in functional residual capacity. In almost all infants with HMD who have been studied, there is a decrease in the functional residual capacity during the first two days of life. This decrease closely parallels the clinical course; in the most severely ill patients the functional residual capacity may be very low from the outset. Low Po 2. The very low arterial Po 2 in infants with both types of respiratory distress is due to venoarterial shunting, as noted above. Shunting increases progressively in parallel with the decrease in functional residual capacity. During recovery the low Po2 is due to either a diffusion block or abnormal distribution of ventilation as well as to venoarteriat shunting. Increased PeG 2, Increased Pco 2 is due to the development of areas of relative underperfusion in the lung; i.e., perfusion is reduced relative to ventilation. These inequalities may be minimal initially but become progressively more prominent as the clinical condition worsens. Acidosis. Prior to the clinical recognition of HMD, a profound combined respiratory and metabolic acidosis is often present in depressed infants who have required resuscitation in the delivery room. Frequently this acidosis corrects itself spontaneously or may be corrected following assisted ventilation and administration of sodium bicarbonate. If the infant develops hyaline membrane disease, the disease may be characterized by varying degrees of persistence
Volume 80 Number 1
of this acidosis. In addition, with the onset of hyaline membrane disease, respiratory acidosis develops due to a reduction of perfusion of the lung relative to ventilation; this is one of the major laboratory features of the disease toward which therapy must be directed. Metabolic acidosis also occurs as lactic acid accumulates due to poor tissue perfusion and an inability to adequately oxygenate the patient. Hypotension. This may be related to severe acidosis and is corrected by treating the acidosis. However, the possibility that hypovolemia from blood loss or dehydration is producing the hypotension must also be considered. Edema. Peripheral edema is a frequent accompaniment of HMD, but clearly is not due to congestive heart failure. Its origin is unknown; it may be a result of catabolism in a relatively starved and distressed subject, producing an increased solute load that cannot be excreted by an underperfused kidney. Hyperkalemia. Hyperkalemia is secondary to catabolism and does not occur when sufficient calories are provided intravenously. HODSON. The most important clinical features of H M D are: retractions (subcostal, xyphoid, and suprasternaI), tachypnea, flaring of alae nasae, expiratory grunting, and cyanosis. These signs are all related to the pathophysiologic process of progressive focal atelectasis causing a decrease in lung compliance and increased work of breathing. Tachypnea probably represents an attempt to decrease the elastic work load of the lung and to alleviate hypoxia by increasing alveolar ventilation. The retractions and nasal flare are related to the increased intrapleural pressure necessary to inflate partially collapsed alveoli. Expiratory grunting due to closure of the glottis probably elevates expiratory pressure; this prolongs alveolar expansion and improves oxygen exchange. (The application of a positive end expiratory pressure has been shown to increase arterial Po 2 in experimental animals and in infants with HMD.) Cyanosis is related to three pathophysiologic developments. In decreasing order of magnitude these are: (1) There is a moderately large rightto-left vascular shunt. The major site of this shunting has not been clearly established. Intrapulmonary shunting of blood past collapsed alveoli probably accounts for most of this. However, some shunting also probably exists through the ductus arteriosus and the foramen ovale. (2) There is a decreased ventilation/perfusion ratio as measured by alveolar nitrogen gradients. This
Hyaline membrane disease
13 1
is due to poorly ventilated alveoli and results in venous admixture. (3) True alveolar hypoventilation also accounts for a very small part of the hypoxia. The radiologic criteria for diagnosis indicated by Dr. Auld depend upon a good quality film and sufficient evolution of the disease. The roentgenographic pattern represents atelectasis with fluid or congestion in the interstitium and possibly fluid in the alveoli. IJSH~R. My opinion is that this is a disease process involving pulmonary edema, congestion, and atelectasis of unknown etiology. It develops at birth, progresses for 12 to 60 hours, and then may improve spontaneously. It occurs in infants born at least 10 days prematurely and is more frequent and more severe after cesarean section or when the umbilical cord is clamped early. It is greatly exacerbated by exposure of the lungs to high oxygen concentrations. Clinically, the key manifestations result from decreased compliance (retracti*ns, grunting, decreased air entry). The most significant signs of progressive respiratory failure during H M D are the increasing need for oxygen, central nervous system depression, and puhnonary rales. 2. A t w h a t age is the r o e n t g e n o g r a m of the chest likely to be of value in diagnosing hyaline m e m b r a n e disease? AULD. A roentgenogram of the chest is of most value in diagnosing HMD when the functional residual capacity is least, indicating the greatest amount of atelectasis. This is generally at 24 to 48 hours. However, many infants (particularly those most severely ill) will show the typical picture in the first hours after birth. More important than making this diagnosis, the chest roentgenogram is of greatest value in excluding other conditions such as pneumothorax, etc. Thus all distressed infants should have a chest roentgenogram early in the course of their respiratory distress. I don't think that one should jeopardize the condition of the infant by taking serial roentgenograms to watch for the development of the typical picture of HMD. Further roentgenographic studies should be reserved for the evaluation of changes in the clinical course which may herald a complication. Ghest roentgenograms are indicated later if pulmonary oxygen toxicity is st~spected. In the "chronic" form of respiratory distress observed in the smallest infants, the most severe reticular pattern is obvious on day 4 or 5.
132
Auld, Hodson, and Usher
The Journal of Pediatrics January 1972
Table I
Gestation (wk.) 39+ 37-38 35-36 33-34 31-32 29-30 25-28
Incidence of HMD per 100 live births Vaginal Cesarean section (%) (%) 0.04 0.8 5.4 20.5 35.0 64.3 64.9
USI~ER. An initial radiograph is of most value to rule out other specific causes of respiratory distress which can be clearly identified radiologically, such as diaphragmatic hernia, lobar atelectasis or emphysema, or pneumothorax. Roentgenograms are also necessary to diagnose the pneumothuraces which occur secondarily to HMD in 2 to I0 per cent of patients; these usually present at about 48 hours of age as a sudden deterioration in the infant's condition. In infants treated liberally with oxygen, the reticulogranular pattern of respiratory distress syndrome persists or progesses for 72 hours. Patients treated with more restricted oxygen show steady radiologic improvement after the first few hours of life. IIonsoIq. The chest roentgenogram is diagnostic within one hour of birth in severe HMD, within 4 hours in the moderately ill, and within 8 hours in all cases. Every infant with respiratory distress probably should have a chest roentgenogram prior to 3 hours of age to rule out other pulmonary abnormaIities such as pneumothorax. 3. W h a t is the incidence of clinical H M D disease in various populations of infants? AuLo. I have no valid data on the incidence of clinical HMD in various populations. I have been unable to satisfy myself that the numerator of the equation (i.e., number of infants with hyaline membrane disease) can be clearly determined. However, I do not think that that cesarean section, per se, predisposes an infant to HMD. In addition, no infant of a diabetic mother has died of hyaline membrane disease at the New York Hospital in the last 8 years; very few have had the disease. The frequency of HMD is related to prematurlty, not to maternal diabetes or cesarean section. Infants with fetal distress and/or a low Apgar score at birth do not develop HMD with a predictable increased frequency. Almost all infants
1.0 8.4 31.8 53.8 53.8
Risk o[ death [rora HMD per 100 live births Vaginal Cesarean section (%) (%) 0 0 0.3 2.3 8.3
0 1.2 5.9 17.9 23.1
under 1,000 Gm. have some form of respiratory distress syndrome, often of the "chronic" type. HMD is rare in full-term infants. All premature infants should be considered at high risk for developing the full clinical syndrome, which is most often well established in the first 2 to 3 hours of life. UsHeR. It is our experience (Table I) that ttMD develops only in infants who are of gestatlonal ages less than 270 days (38~2 weeks). Cesarean section is associated with a greatly increased incidence of HMD and a higher neonatal mortality rate, irrespective of the indications for the section. Maternal diabetes, per se, plays no role in the incidence of or death from HMD except that many infants of diabetic mothers are delivered prematurely by cesarean section. The over-all incidence of HMD in our neonatal unit ranges from 1 to 2 per cent of all live births, 20 per cent of all low-birth-weight infants, and 35 per cent of low-blrth-weight infants of appropriate weight for gestationaI age. HODSO~. There is no evidence for differences in the incidence of HMD in different racial or ethnic groups independent of their rates of premature births. In our experience perinatal factors other than prematurity and the second born of twins do not have a statistically significant relationship to an increased incidence of HMD. The second born of twins has a 16 per cent higher incidence than the first born. A review of 135 infants at the University of Washington with birth weights less than 1,000 Gm. revealed an incidence of 66 per cent with HMD. The incidence decreased in direct proportion to advancing gestational age. HMD occurs in approximately 50 per cent of the neonatal intensive-care population at University of Washington (50 per cent of this population is derived from referrals of babies born in other hospitals).
Volume 80 Number 1
The incidence of HMD is considerably increased when there is a history of a previous sibling with HMD. 4. H o w do you m a n a g e a n i n f a n t in the delivery room who develops clinical signs of hyaline m e m b r a n e disease b u t does not require t r e a t m e n t for asphyxia or shock. ( U m bilical catheter? I m m e d i a t e alkali t r e a t m e n t versus delay u n t i l the i n f a n t can be treated in the nursery, etc.?) AULD. If a sick infant does not require immediate resuscitation in the delivery room, he is promptly transferred to the nursery. Only the most urgent emergency treatment should be carried out in the delivery room. Further therapy is delayed until adequate assessment of the patient's condition can be made; this includes measurement of blood gases. USHER. Delivery room management is primarily aimed at (1) providing at least one minute of placental transfusion, (2) ensuring adequate ventiiation if the infant is asphyxiated, and (3) reducing cold exposure and minimizing handling of the infant. There is no evidence that early rapid correction with alkali or early elevation of arterial Po2 tensions to adult levels are beneficial; infants with respiratory distress syndrome are, therefore, only given enough oxygen to control cyanosis, are not catheterized, and are not given intravenous fluids in the delivery room. HODSON. Most infants with clinical signs of respiratory distress in the delivery room are not severely compromised unless they have suffered asphyxia at the time of delivery. Therefore, in the absence of asphyxia it is preferable to insert an umbilical arterial catheter, if needed, under the more optimal conditions (sterility and warmth) of the nursery or a treatment room. It is especially important to maintain an appropriate environmental temperature for the infant with respiratory distress; cold stress increases oxygen consumption and the demands on an already burdened respiratory system. There is no evidence that early alkali therapy in the delivery room will affect the course of HMD. 5. W h a t clinical a n d laboratory criteria do you use to decide to initiate t r e a t m e n t with intravenous fluids a n d sodium bicarbonate in a n i n f a n t mildly to moderately ill with hyaline m e m b r a n e disease? HODSON. All infants with mild or moderate illness should receive parenteral fluids. We give
Hyaline membrane disease
133
sodium bicarbonate moderately rapidly to infants with an arterial pH of less than 7.3 due to a metabolic acidosis. The rationale for treatment is related to the untoward effects of acidosis on cardiovascular hemodynamics, especially pulmonary artery vasoconstriction, as shown by Rudolph and Yuan.1 Our recent studies, 7 however, show that the alveolar-arterlal oxygen gradient and hence PAO2 does not change significantly following correction of the pH. This observation suggests that a reduction in pulmonary vascular resistance will not decrease hypoxia due to intrapulmonary shunts. Infants with mild-to-moderate respiratory distress should not be given oral fluids or feedings because of the increased risk of apnea, regurgitation, and aspiration. USHER. All infants with clinical evidence of HMD are treated with a scalp vein intravenous infusion of 10 per cent glucose and up to 15 mEq. per cent sodium bicarbonate, administered at a rate of 65 ml. per kilogram per day from the first half hour of life until the infants are taking an equivalent volume of milk feedings. Sodium bicarbonate is started at concentrations of 15 mEq. per 100 ml. if the capillary (warmed foot blood) or arterial pH is below 7.20, at 10 mEq. per 100 ml. if the pH is between 7.20 and 7.29, and at 5 mEq. per 100 ml. if the pH is between 7.30 and 7.35. No bicarbonate is infused when the pH of arterial or arterialized capillary blood is above 7.35; this seldom occurs within the first hour of life. Subsequently, the concentration of sodium bicarbonate is adjusted in order to achieve and then maintain capillary or arterial pH values of 7.35 to 7.40; most patients with ttMD have pH's in this range from 6 to 12 hours of age onward. The purposes of this intravenous infusion therapy are to provide basal caloric needs and adequate hydration, to correct acidosis, and to decrease catabolism and prevent the development of hyperkalemia and azotemia. The rapid infusion of sodium bicarbonate during the first 3 hours of life was associated with a doubling of the mortality rate from HMD in our unit compared with the deaths which occurred when we employed a regimen of more gradual intravenous infusions. Therefore, we recommend a maximum rate of infusion of intravenous sodium bicabonate equal to 0.4 mEq. pe kilogram per hour. AULD. For all distressed infants we immediately start an intravenous infusion to provide fluid and calories; this also provides a readily avail-
134
Auld, Hodson, and Usher
sodium bicarbonate given if ventilation is ineffective in completely reversing the trend.
Table II
Venous pH
The Journal of Pediatrics January 1972
Administer sodium bicarbonate (l mEq./c.c.)
7.10
~10 c.c.
7.20
<10 c.c.
7.30
< 5 c.c.
7.35 and falling
~ 3 c.c.
able route for the administration of sodium bicarbonate. I do not think that there are good clinical criteria for administering sodium bicarbonate. It is absolutely imperative to monitor pH and Peon; for clinical purposes it is adequate to use free-flowing venous or capillary blood. The aim of sodium bicarbonate therapy is to alter the pH toward normal. Bicarbonate need not be given when the venous blood pH is over 7.30, unless this value reflects a trend of a falling pH (in which case sodium bicarbonate would be given to reverse the trend). Although various formulas have been proposed for the correction of acidosis based on serum bicarbonate concentrations, in my experience they are no better than the empirical approach outlined below. I favor a fairly vigorous and rapid intravenous administration of sodium bicarbonate; when the dosage is decided upon, the bicarbonate is infused over a 5 to 10 minute period according to the schedule shown in Table II. The blood gases should be analyzed for pH, Pca~, actual bicarbonate concentration, and deviation from the normal buffer base content 30 minutes after each dose of sodium bicarbonate. If the venous pH is unchanged, the dose should be repeated. If the pH goes from 7.10 to 7.25, I would observe the infant for another hour and repeat the pH before giving more sodium bicarbonate. Whereas sodium bicarbonate is the treatment of choice for metabolic acidosis, it should not be regarded necessarily as the best therapy for respiratory acidosis. When respiratory acidosis is mild (i.e., Pco~ less than 50 mm. Hg), sodium bicabonate may be used alone and generally the pH will be corrected. However, in cases of moderate and severe respiratory acidosis, sodium bicarbonate should be regarded as an adjunct to assisted ventilation with bag and mask which must be the primary therapy. When confronted with moderate or severe respiratory acidosis, assisted ventilation should be started first and
6. W h e n is tris-hydroxymethyl a m i n o m e t h a n e ( T H A M ) indicated in place of sodium bicarbonate? USlaER. I have not seen an infant benefit fl'om administration of THAM when bicarbonate treatment was ineffective. I no longer use it. HoosoN. THAN[ may be indicated when there is a need for the rapid correction of a marked combined respiratory and metabolic acidosis such as occurs with severe asphyxia. It temporarily buffers CO, as well as noncarbonic acids, and thus may have a more rapid and hence beneficial effect on pulmonary blood flow in the infant suffering from acute asphyxia. Some evidence suggests that myocardial contractility is increased to a greater extent with THAM than with NaHCO~ at comparable degrees of acidosis. In the treatment of metabolic acidosis, NaHCO~ appears to be as effective a buffer as THAM. The rapid intracellular distribution of THAM can result in sudden changes in the pH of fluids in the central nervous system (in an alkaline direction); this may produce apnea. AULD. I give THAM in place of sodium bicarbonate only in two conditions: (1) When the cumulative dose of sodium bicarbonate is leading to hypernatremia, i.e., generally after 30 to 50 c.c. of sodium bicarbonate (I mEq. per cubic centimeter) has been administered and/or the sodium level is over 155 mEq. per liter. (2) When severe respiratory acidosis is not responding to assisted ventilation and sodium bicarbonate (i.e., Pco~ > 85 mm. Hg). Respiratory arrest is an important complication of the administration of THAM. If it is used, assisted ventilation should be readily available. 7. Is there a n indication for oral or gavage fluids a n d sodium bicarbonate i n mildly to moderately ill infants with hyaline m e m b r a n e disease? USHER. Although there have been several reports of the use of the gastrointestinal route to administer glucose and bicarbonate, absorption from this route is uncertain. I would consider the gastrointestinal administration of glucose and bicarbonate only when personnel are not available to start intravenous infusions and transfer to an appropriate neonatal unit is not possible.
Volume 80 Number 1
Gavage feedings of milk should, however, be started as soon as an infant is over the acute phase of his illness and seems active and well enough to tolerate the feedings. They provide a more balanced electrolyte mixture and adequate caloric intake. AULD. There is no indication for oral sodium bicarbonate. Correction of acidosis needs to be given in a more directly controlled fashion than can be accomplished by oral administration. HODSON. The goal of correction of acidosis is an immediate improvement in physiologic and/ or biochemical function; slow correction or maintenance by oral administration probably provides little, if any, benefit. Furthermore, oraI or gavage fluids increase the risks of regurgitation and aspiration which occur more commonly in infants with respiratory distress. 8. W h a t volumes of m a i n t e n a n c e fluids do you use on days 1, 2, a n d 3? W h e n do you add potassium? W h a t do you use as guides in m a k i n g these decisions? AULD. Fluids should be given at the rate of 100 c.e. per kilogram per day for the first 3 days of life. For the first 2 days, we consider the caloric requirements to be the first priority and thus give a solution of 10 per cent gIucose and water, which provides sufficient calories to reduce catabolism. This solution may cause a mild osmotic diuresis with loss of electrolytes; thus maintenance electrolytes (including potassium) are added on the third day and the glucose concentration is reduced to 5 per cent. UsItER. Our goal is to provide adequate fluids to prevent dehydration. In general the caloric intake provided by fluids with 5 to 10 per cent glucose concentration administered during the first 3 days of life to infants with a respiratory distress syndrome is below their maintenance need of 100 calories per kilogram per day; therefore, a i to 2 per cent weight loss per day can be expected due to catabolism from starvation. Fluids are initiated at a rate of 50 to 100 ml. per kilogram per day (the highest rates for the infants under 1,000 Gm. and the lowest rates for those over 2,500 Gm.), and the rate is adjusted according to the weight obtained at intervals of every 12 hours to prevent more than a i to 2 per cent weight loss per day until an adequate caloric intake is achieved. In most infants the original rate is increased 50 per cent during the first 72 hours of life as urinary output increases and more fluids are required to main-
Hyaline membrane disease
135
tain the desired body weight. Edema formation in the presence of a falling weight is not considered an indication to reduce fluid intake in infants with respiratory distress syndrome. Potassium supplementation is not required in most patients because of a tendency for the serum potassium concentration to be elevated during the first 3 days of life. After this time the usual patient is receiving adequate maintenance potassium from milk supplied by gavage feedings. Potassium is added to intravenous fluids of infants with HMD only after the third day of life, if there is no enteric potassium intake, and if the serum potassium concentration is below 4 mEq. per liter. I-IoDsoN. Maintenance fluids of t0 per cent glucose and water are given at a rate of 65 ml. per kilogram per 24 hours during the first day, 75 to 85 ml. per kilogram over the second, and 90 to 100 ml. per kilogram on the third day. Usually sufficient maintenance sodium is administered on day one in the form of sodium bicarbonate for the treatment of acidosis; if an infant has not received NaHCO~ he is given 3 mEq. per kilogram per day. Potassium is usually added on day two, 2 mEq. per kilogram per day. Serum electrolytes are measured on day 2 and potassium is withheld if the serum concentration is above 7 mEq. per liter. 9. W h e n are umbilical vessel versus peripheral venous infusions indicated? AULD. Infusion of fluids through an umbilical vessel is rarely preferred over a peripheral venous infusion. When there is difficulty in beginning a peripheral vein infusion in a severely ill infant, an umbilical vessel infusion may be desirable because of an urgent need to begin therapy. However, the umbilical catheter should be removed as soon as possible. Routine use of umbilical vessels should be avoided because of dangers of infection and thrombosis. End-hole catheters are preferred when umbilical catheters are utilized. HODSON. Peripheral venous infusions, when technically possible, are always preferred to umbilical vessel infusions, unless an umbilical artery has been cannulated for the primary purpose of blood gas sampling. There is little indication for infusion into an umbilical vein since hepatic necrosis may result from sodium bicarbonate or THAM administered via this route. USHER. Umbilical infusions greatly increase the risk of infection, thrombosis, hemorrhage, and accidental fluid overload; they should only be
136
Auld, Hodson, and Usher
used when peripheral infusions are impossible, and for as short a period of time as is possiblc. 10. H o w long do you leave an umbilical catheter i n place? Do you prefer umbilical artery or vein? AULD. We prefer to use an umbilical vein catheter rather than an umbilical artery catheter because it is easier to insert in the proper location. (We also measure Po~ on temporal or radial artery blood samples when arterial blood sampling is necessary.) The umbilical vein catheter must be carefully positioned, and the best location for the tip of the catheter is in the inferior vena cava; this probably minimizes the chance of thrombotic complications. The umbilical venous catheter should be removed as soon as a peripheral vein intravenous infusion can be started. No umbilical venous catheter should be left in place for more than two days. An infant in whom an umbilical venous catheter has been inserted is treated with antibiotics (ampicillin and kanamycin) in an attempt to decrease the hazard of infection. The major dangers in the use of umbilical catheters are: (1) infection and (2) thrombi and liver necrosis due to administration of strong alkali. This latter complication is unusual if only glucose and water is infused. HODSON. We leave an umbilical artery catheter in place as long as there is a need for oxygen. Infants greater than 1,600 Gm. can be managed without inserting a catheter when oxygen concentrations are less than 30 per cent. Generally we do not use umbilical vein catheters, except briefly when it is necessary to treat a severely asphyxiated infant with sodium bicarbonate in the delivery room. USHER. We have had severe infections from indwelling catheters in both umbilical artery and vein and, therefore, we resort to them only when periphreal intravenous infusions are impossible or when arterial blood sampling has a decided advantage over capillary sampling, as in a patient requiring mechanical respirator therapy. My preference is for sampling capillary blood from warmed heels to avoid the trauma of repeated percutaneous arterial punctures, and the risks of infection, thrombosis, and hemorrhage associated with indwelling umbilical artery catheters. Capillary blood acid-base values approximate arterial blood values. Capillary oxygen tensions closely parallel those of arterial
The Journal o[ Pediatrics January 1972
blood in the hypoxemic range (below 40 mm. Hg) and deviate increasingly from arterial blood values in the normoxemic and hyperoxemie ranges. We provide sufficient oxygen to maintain arterial tensions of 40 to 65 mm. Hg, which correspond to warmed heel capillary Po 2 values of 35 to 55 ram. Hg. When sufficient oxygen is given to raise the capillary Po 2 above 65 mm. Hg, arterial values may exceed 150 mm. Hg and allow development of retrolental fibroplasia. In practice we increase ambient oxygen when warmed heel capillary Po 2 falls to 35 to 40 mm. Hg, and reduce ambient oxygen when capillary P% exceeds 45 to 50 mm. Hg. The only exception is when acidosis is severe and the hemoglobin-oxygen dissociation curve is displaced to the right, under which conditions arterial Po 2 may need to be increased to above 60 mm. Hg to provide a minimum of 85 per cent oxygen saturation. 1I. H o w m u c h oxygen should be used in treating a n i n f a n t with hyaline m e m b r a n e disease a n d how long should it be used? If a Po2 m e a s u r e m e n t is unavailable, what criteria would you use to decide u p o n the proper treatment with oxygen? W h e n do you use assisted ventilation? AULD. Oxygen should be used in concentrations necessary to abolish cyanosis or to maintain Po~ between 60 and 80 mm. Hg. Our indications for assisted ventilation are: apnea, inability to oxygenate the patient in 100 per cent oxygen by mask, and respiratory acidosis. Mild respiratory acidosis can usually be treated by the administration of sodium bicarbonate. Severe respiratory acidosis (pH 7.20 and Pco2 50) is an indication for assisted ventilation with a bag and mask. In my opinion, assisted ventilation of neonatal infants is best performed with an anesthesia bag supplied with oxygen (whose concentration can be varied) and a face mask ( ~ liter anesthesia bag and Rovenstine angle). An indwelling gastric tube is also employed to decompress the stomach. The advantages of this method over respirators are: (1) almost anyone can be trained to perform this type of ventilation in five minutes, (2) it avoids endotracheal intubation with the dangers of trauma to the airway, especially in unskilled hands, (3) assisted ventilation can be stopped and started with minimum difficulty, (4) each patient requires individual attention (I think this is the key to suc-
Volume 80 Number 1
cess in assisting ventilation), (5) it is easy to reassess the degree of oxygenation frequently and to make the needed adjustments and, (6) an infant can be ventilated intermittently for 5 or i0 minutes every hour. This can only be accomplished by the bag and mask method. This method does not require more nursing personnel. It is necessary to have more people to treat ill infants but they need not be registered nurses. USHER. Oxygen should be used only in an amount sufficient to eliminate cyanosis. In infants with a relatively normal pH, cyanosls develops at an arterial Po~ below 40 mm. tIg (arterialized capillary blood below 35 mm. Hg). An infant does not benefit from and may be injured by maintaining arterial oxygen tensions at adult levels (80 to 120 mm. Hg). Oxygen should be regarded as an essential, though toxic, drug for anoxic infants; it may cause pulmonary toxicity which is indistinguishable from hyaline membrane disease or it may cause retrolental fibroplasia. Therefore, it should be used only if needed and in the minimal effective dose. In addition to cyanosis, infants suffering from hypoxemia develop a progressive metabolic (lactic) acidosis and may become very lethargic. A depressed, dusky, infant with a metabolic acidosis needs more oxygen no matter how much he is receiving at the time. Fairly accurate control can be obtained by experienced clinical observations of color, tone, etc. HMD can be treated without facilities for blood gas measurement, but whenever possible oxygen therapy should be guided by blood gas measurements. In the absence of laboratory measurements, I would treat cyanosis with just enough oxygen to keep the infant pink (equivalent to arterial Po 2 of 40 mm. Hg). I would also use intravenous infusions of 10 per cent glucose and water with 5 mEq. per 100 ml. bicarbonate for the first 72 hours of life without blood gas monitoring in an infant with HMD. We employ mechanical ventilation with a respirator for apneic spells not responding to bag and mask resuscitation or an arterial or capillary P ~ below 30 mm. Hg when breathing 100 per cent oxygen. HODSON. Oxygen should be used in sufficient concentrations to provide an arterial Po~ of 50 to 80 ram. Hg; this may require concentrations as high as 100 per cent. Despite the well-recognized toxic effects of oxygen on pulmonary tissues, the consequences of O~ damage to the lung are of much less concern than inadequate
Hyaline membrane disease
13 7
tissue (especially brain) levels of oxygen. Therefore, high levels of oxygen are continued as long as necessary to maintain an adequate Po, We have followed approximately 30 infants with radiotogic evidence of chronic pulmonary changes attributable to high oxygen concentrations. Apart from tachypnea during the first 3 months of life, all but one of these infants has become asymptomatie without evidence of recurrent or chronic pulmonary disability. There has been marked radiologic improvement by 2 years of age in all of the infants (with residual parenchymal streaking and possibly fibrosis). If a Po~ measurement is unavailable, oxygen should be administered at a concentration about 5 per cent higher than that at which cyanosis appears. The risk of retrolental fibroplasia increases with immaturity, and in our nursery population arterial oxygen tensions greater than 100 mm. Hg have been associated with cicatricial retinal changes. We have not observed retinal changes in any infants with birth weights greater than 1,600 Gm. This has also been the experience of the collaborative study of oxygen therapy for premature infants. The greatest risks of not being able to measure Po.. are probably limited to those infants weighing less than 1,600 Gm. t2. I f there are no clinical or laboratory signs of sepsis, do you treat infants who have hyaline m e m b r a n e disease with antibiotic agents? AvEr. No antibiotics are given to patients with HMD unless an umbilical catheter is used or they have clinical signs of sepsis. USttER. It is exceedingly difficult to distinguish intrauterine pneumonia from HMD in premature infants. Therefore, we treat with antibiotics all infants who have a clinical syndrome of respiratory distress and prolonged rupture of the membranes, maternal fever, or foul-smelling amniotic fluid; we also examine the placenta for inflammation, and obtain blood and throat cultures, white blood count, C-reactive protein, and a sedimentation rate. Most infants with HMD do not have these conditions which predispose toward infection and are, therefore, not treated with antibiotics. If, however, the condition of an infant with HMD does not improve by 4 days of age (especially if patchy densities develop in the lung) an investigation for infection is undertaken and antibiotic therapy is started. Hovso~. Infants who do not have clinical and
13 8
Auld, Hodson,
laboratory signs of septicemia are not treated with antibiotics in our nursery. It is, therefore, important to observe neonatal infants carefully for subtle signs of infection. For this reason we do not use selwocontrolled incubators which may prevent the early detection of fever, hypothermla, or temperafure instability. This, in turn, requires appropriate careful regulation of the environmental temperature, especially the temperature of the inspired gas within an oxygen hood or a respirator. The chest roentgenogram is helpful in diagnosing pneumonia; neither the reticular pattern nor an air bronchogram should be present in infected areas. Infants with temperature fluctuations of greater than 1~ C. (not due to environmental changes) or with other signs of infection are cultured and treated with ampicillin and kanamycin. 13. A t w h a t level of hematocrit or hemoglobin do you transfuse a sick i n f a n t with hyaline m e m b r a n e disease? USI~ER. With the exception of replacing blood lost from internal (e.g., intracranlal) or external hemorrhage or from excessive blood sampling, transfusions of blood are not used routinely in our unit. I would transfuse an infant with HMD if the hemoglobin concentration were below 10 Gin. per cent, irrespective of cause, but this seldom occurs. Although I am convinced that placental transfusion is of benefit to the infant with HMD, there is no convincing evidence that postnatal blood transfusion is of value as a standard treatment of HMD. AULD. We rarely transfuse an infant with HMD because of an anemia that results from blood sampling. If a sign of acute blood loss develops, i.e., hematocri~ drop of 15 per cent in 24 hours, we transfuse the infant. A slow progressive fall in hematocrit is not treated unless the hematocrit falls below 20 per cent. HoDso~. Infants with a hematocrit value below 35 per cent in the first few hours of life are given albumin to expand their plasma volume. Serial hematocrit determinations are necessary to interpret acute or chronic blood loss. A central arterial blood pressure below 30 mm. Hg in infants weighing less than 1,000 Gin., below 35 ram. Hg in 1,001 to 1,500 Gin. infants, and less than 40 mm. Hg in infants between 1,501 and 2,001 Gm. is also an indication for expansion of the blood volume with plasma, whole blood or albumin. Preliminary evidencea indicates that survival
The Journal of Pediatrics January 1972
rates are improved when infants with low centraI arterial bIood pressures receive plasma volume expanders. All transfusions are given to improve cardiovascular hemodynamics; decreased oxygen carrying capacity of the blood is usually not a concern unless the hematocrit fails below about 18 per cent. 14. W h a t criteria for digitalization do you use in m a n a g i n g these infants? AvLD. The presence of HMD, per se, is not an indication for digltalization of an infant. The studies of Rudolph and associates s were unable to document the presence of congestive heart failure. UsHF,~. Digitalis is almost never used in our unit for the treatment of ItMD. I would consider its use if severe eardiomegaly and hepatomegaly developed during the course of HMD, but this is so unusual that I would first search for another etiologic factor, such as arteriovenous shunting. HoDsorr. Infants with HMD are not digitalized unless there are signs of heart failure, which in almost all circumstances are related to events other than HMD. 15. H o w often do you get a roentgenogram of the chest after a diagnosis is m a d e if the infant's clinical course is u n c h a n g e d ? AULD. If an infant's clinical course is unchanged, I see no reason for further chest roentgenograms. If the initial roentgenogram of the chest is equivocal for HMD and the elinicat course is typical, another study is frequently done for "interest." However, portable roentgenograms disturb the infant and modify his environment and they should be avoided unless there is a sudden change in the patient's condition. HODSON. A chest roentgenogram is obtained every 24 hours if the infant's condition has not deteriorated. Following clinical improvement, roentgenograrns are obtained at 3 to 5 day intervals or until there is radiotogic evidence of resolution. All infants should have chest roentgenograms just prior to discharge to rule out chronic or residual pulmonary changes. This is especially important in infants who received several days of oxygen therapy or who had prolonged tachypnea. USHER. Serial roentgenograms of the chest are of no value in the management of HMD except if the clinical condition deteriorates and for research purposes.
Volume 80 Number 1
16. H o w often should blood be d r a w n for laboratory determinations of acid-base status etc., w h e n the infant's clinical course is u n changed? AULD. Laboratory determinations of the acidbase status of blood are indicated only once or twice per day if the clinical course is unchanged. More frequent determinations of acidb,ase status are important early in the course when attempting to stabilize the patient's condition and treat acidosis. When the clinical course is stable, acidosis is usually well compensated; the Pco~ may be higher than normal but this elevation is of less clinical significance if the pH is normal. USHER. Rapid changes in acid-base balance or oxygenation often occur during the first few hours of life. For this reason I usually obtain capillary blood gas and pH determinations at ~/2 hour, 4 hours, and 8 to 12 hours of age in all patients with HMD. if sodium bicarbonate treatment and oxygen therapy are continued after this point, the determinations are repeated at 6 to 8 hour intervals; otherwise, they are repeated once daily until the distress subsides. HODSON. Arterial blood is drawn as frequently as is necessary to evaluate acute therapy. The Pao_o should be measured within 30 minutes of a change in inspired oxygen concentration. The PAco2 and PAo2 should be measured within 30 minutes of any adjustment in a respirator setting; pH should be assessed within 30 minutes of the administration of alkali since metabolic acidosis may be due to a continuing process. Once the: course is stable, blood gases and pH probably should be measured at 6 to 8 hour intervals in the first 24 hours and at increasing intervals of time thereafter, depending on the severity of the disease. In our experience many sick infants have required 40 to 50 blood gas determinations prior to complete recovery. 17. W h a t is the incidence of central nervous system hemorrhage, heart failure, p u l m o n a r y hemorrhage, secondary sepsis, retrolental fibroplasia, a n d p u l m o n a r y reaction to oxygen i n hyaline m e m b r a n e disease? AULD. Central nervous system hemorrhage is common in infants under 1,200 Gm. with respiratory difficulty but rare in larger infants. In my experience heart failure is not a complication of HMD, and pulmonary hemorrhage is very rare. Secondary sepsis is unusual, and when it
Hyaline membrane disease
139
does occur, it is often related to the use of an indwelling umbilical venous catheter in an infant who is not treated with antibiotics. I have not seen retrolental fibroplasia as a complication of HMD. However, infants who have had the "chronic" form of respiratory distress have developed retrolental fibroplasia; the last case was 5 years ago. Pulmonary reaction to oxygen occurs relatively frequently in the very ill patient; such infams generally require I00 per cent O5 and assisted ventilation for 6 or 7 days. In the "chronic" type of respiratory distress syndrome, involving the smallest and sickest infants, pulmonary oxygen toxicity (Wilson-Mikity syndrome) is common. USHEr. Approximately one third of the infants dying with HMD have an associated intraventrieular hemorrhage, and one half have subarachnoid hemorrhage. Heart failure, pulmonary hemorrhage, and proved secondary sepsis are extremely rare. Retrolental fibroplasia has not occurred in our last 350 patients; all had their eyes examined at the time of discharge. Puhnonary oxygen toxicity is, in my view, so similar in appearance to HMD, itself, that one cannot talk about its "incidence." All infants exposed to supplemental ambient oxygen should be assumed to have sustained additional lung damage from the treatment. Oxygen should be considered a toxic albeit often essential, drug in the management of HMD. HODSON. Central nervous system hemorrhage occurs in 65 per cent of autopsied infants with HMD at the University of Washington. We do not find evidence of heart failure in infants who have only HMD. Sepsis (positive blood culture) occurs in 5 to 7 per cent of infants with HMD. However, in 1969 about 60 per cent of the infants with HMD in our unit were treated with antibiotics at some time during their hospital course for suspicion of or presumptive sepsis. The records of all infants admitted to the Premature Center of the University o f Washington Hospital between 1960 and 1967 were reviewed and infants with birth weights less than 1,300 Gm. had follow-up ophthalmologic examination.~ Six instances of retrolental fibroplasia were detected; 4 of these infants had birth weights less than 1,000 Gm. The incidence of retrolental fibroplasia in survivors of less than 1,300 Gm. at birth was 7.0 per cent. Only one infant above this weight (1,405 Gm.) developed retrolental fibroplasia. Chronic pulmonary changes attributable to
14 0
Auld, Hodson, and Usher
oxygen toxicity are relatively common in infants who have had severe HMD. In a study of 78 infants treated with positive pressure ventilation, 8 of 15 survivors had radiologic evidence of chronic pulmonary "infiltrates.''s 18. W h a t is the prognosis for infants with hyaline m e m b r a n e disease? AULD. Long-term prognosis for all infants with hyaline membrane disease is difficult to determine. The generally favorable outlook is modified somewhat if pulmonary oxygen toxicity occurs. UshEr. The case mortality rate among 196 newborn Caucasian infants with HMD weighing more than 1,000 Gm. treated at our maternity hospital over the past 5 years was 8.3 per cent. As the incidence may vary according to criteria for diagnosis of the disease (our incidence was 14.5 per 1,000 live births), a more pertinent estimate of prognosis is the mortality rate from HMD per 1,000 births over 1,000 Gin., which for this period at our hospital was 0.083 • 14.5 = 1.2 HMD deaths per 1,000 births. The impression gained from our own patients, as well as those followed up in the literature, is that infants surviving HMD have the same intellectuaI and neurologic prognosis as premature infants of similar gestational age who have not developed the syndrome. We have rarely observed marked central nervous system damage in children surviving even severe uncomplicated HMD. HonsoN. The prognosis depends on the degree of prematurity and the severity of the disease. In general, the experience in our nursery has confirmed the prognostic usefulness of the PA02 for estimating the likelihood of survival.6 It is exceedingly difficult to assess the contribution of neonatal intensive care to the survival of infants with HMD. The prognosis for surviving infants appears to be excellent, and this may represent the most important contribution of intensive care. CONCLUSION
BEHRMAN. Although there are now broad areas of agreement about the clinical syndrome and the course of hyaline membrane disease, some differences of opinion persist. The importance of cesarean section as an etiologic factor is still
The Journal of Pediatrics ]anuary 1972
vigorously disputed. The appropriate rate of infusion of sodium bicarbonate to treat a metabolic acidosis and/or a mild to moderate respiratory acidosis is unsettled. There is no question that an initial roentgenogram of the chest is mandatory in order to rule out other diagnoses that require specific medical or surgical treatment, as well as to aid in making the diagnoses of hyaline membrane disease, but there are very different attitudes about the indications for subsequent roentgenograms of the chest if the infant's condition is stable or gradually improving. Unfortunately, our fundamental understanding of hyaline membrane disease is still very limited despite a general consensus about the necessary supportive therapy and the importance of many etiologic factors. If we are to reduce the incidence of this disorder, some of these latter factors (i.e., prematurity) will require social, political and economic decisions to complement those made in the nursery and laboratory. REFERENCES 1. Rudolph, A. M., and Yuan, S.: Response of the pulmonary vasculature to hypoxia and H+ ion concentration changes, J. Clin. Invest. 45: 399, 1966. 2. Goldenberg, V. E., Wiegenstein, L., and Hopkins, B.: Hepatic injury associated with tromethane, J. A. M. A. 205: 81, 1968, 3. Hall, R. T., and Oliver, T. K., Jr.: Aortic blood pressure in infants admitted to a neonatal intensive care unit. Submitted for publication. 4. Kalina, R. E.: Opthalmic examination of children of low birth weight, Am. J. Ophthalmol. 67: 134, 1969. 5. Hehnrath, T. A., Hodson, W. A., and Oliver, T. K., Jr.: Positive pressure ventilation in the newborn infant: T h e use of a face mask, J. PEDIATR.76: 202, 1970. 6. Stahlman, M. T., Battersby, E. J., Shepard, F. M., Blankenship, W. J.: Prognosis in hyaline membrane disease: Use of a linear-diseriminant, N. Engl..]'. Med. 276: 303, 1967. 7. Woodrum, D. E., Hodson, W. A., and Oliver, T. K., Jr.: Serial determinations of alveolar arterial oxygen gradient (AaDO2) in premature infants during the first week of life, Pediatr. Res. 3: 379, 1969. 8. Rudolph, A. M., Drorbaugh, J. E., Auld, P. A. M., Rudolph, A. J., Nadas, A. S., Smith, C. A., and Hubbell, J. P.: Studies on the circulation in the neonatal period. The circulation in the respiratory distress syndrome, Pediatrics 27: 551, 1961.