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Respiratory failure in a full-term infant
CLINICAL-PATHOLOGICAL CONFERENCE*
JayBernstein, Edltor
Respiratory failure in a full-term infant John R. Esterly, M.D., and Arthur O. Stein, M.D. CHICAOOj I L L .
T H E P A T I E N T was a newborn Negro male infant, delivered at 39 weeks' gestation of a 25-year-old, gravlda 6 para 5 mother. The mother's health had been good except for a urinary tract infection during the pregnancy. The birth weights of her previous infants were 6 pounds 9 ounces, 8 pounds 12 ounces, 7 pounds 14 ounces, 7 pounds, and 9 pounds, respectively. She was admitted to The Chicago Lying-In Hospital in false labor at 37 weeks' gestation. Urinalysis showed 2+ albuminuria. She had 1+ ankle edema. Blood pressure was 110/70 ram. Hg; previously recorded blood pressures had been normal, and there had been neither albuminuria nor glycosuria. She was readmitted in active labor 2 weeks later. She gave a history of being febrile for the previous 4 days. She was treated immediately with ampicillin intravenously, and subsequently with cephalothin. The temperature became normal on the third hospital day. KlebsieIla pneumoniae and Staphylococcus albus were cultured from a catheterized specimen of the urine. Urinalysis shortly thereafter revealed approximately 10 red and 8 to 12 white blood cells per highpower microscopic field. She had also complained of an upper respiratory infection and cough, and on admission her breath sounds were described as "coarse." The blood pressure was 130/75 mm. Hg. The fetal
From The Chicago Lying-In Hospital and
University o[ Chicago. *Sponsored by the Pediatric Pathology Club. Vol. 77, No. 3, pp. 508-514
heart rate was 180 beats per minute immediately prior to delivery. The first stage of labor lasted 2 hours and the second stage 28 minutes. Meconium-stained fluid was noted during labor, and at delivery the amniotic fluid was deeply stained. T h e infant's presentation was cephalic; delivery was spontaneous. The birth weight was 4,110 grams. Two minutes elapsed before sustained respiration was initiated by simple resuscitative measures, including endotracheal intubation and oxygen by mask. The Apgar score at one minute was 4 (heart 2, respiratory effort 1, color 1); at five minutes it was 6 (heart 2, respiratory effort 1, muscle tone 1, reflex irritability 1, color 1). T h e infant was covered with meconiumstained material which was not malodorous. T h e initial pediatric examination revealed a distressed male infant with a pulse rate of 140 per minute and a respiratory rate of 54 per minute. His facies was described as that of an infant of a diabetic mother. The skin was tinged green. Generalized cyanosis was present; heart sounds were normal. The breath sounds were coarse, with bilateral moist inspiratory r~les; there was grunting with respirations. The neurologic examination revealed fair muscle tone, fair Moro and grasp reflexes, and poor suck. Viscous green material was aspirated from the stomach. T h e cord hemoglobin concentration was 15 Gm. per 100 ml. Initial blood chemical values were pH 6.84; sodium 136 mEq. per liter; potassium 4.8 mEq. per liter; chloride
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87 mEq per liter; carbon dioxide 12 mEq. per liter; blood urea nitrogen 9 rag. per 100 ml.; glucose 165 mg. per 100 ml. T h e presumptive diagnosis was meconium aspiration with significant respiratory distress. Penicillin and kanamycin were given immediately. Sodium bicarbonate (150 mEq. per liter) in 10 per cent dextrose was administered via an indwelling umbilical catheter at the rate of 65 ml. per kilogram of body weight per 24 hours. The infant was kept in an Isolette, with humidified oxygen supplied to maintain a concentration of 40 per cent. At 4 ~ hours of age the infant continued to look sick, with persistent grunting respiration and flaring of the alae nasae. A soft systolic m u r m u r was noted at the base of the heart. Breath sounds were described as good, with scattered moist rSles. By t3 hours the liver edge was palpable 1.5 cm. below the right costal margin, and at 15 hours of age markedly decreased respiratory efforts were noted. Blood chemical values at that time were p H 7.39; sodium 130 mEq. per liter; potassium 3.3 mEq. per liter; chloride 90 mEq. per liter; carbon dioxide 22 mEq. per liter; and glucose 72 mg. per 100 ml. T h e infant died rather suddenly at 1 6 ~ hours of age, T h e record of vital signs is noteworthy. Body temperatures (rectal) had ranged from 36.4 to 37 ~ C. The pulse rate, recorded at approximately hourly intervals preceding death, had been relatively steady: 140, 132, 140, 160, 164, 146, 152, and 146 beats per minute. Approximately an hour before death the pulse was 154. Terminally he became apneic, and the pulse dropped to 64. Corresponding respiratory rates were somewhat rapid, recorded at 60, 60, 64, 72, 74, 84, 66, 72, and 76 respirations per minute. CLINICAL DISCUSSION DR. H~cK.* The roentgenogram at 3 hours of age shows pulmonary consolidation with suggestion of an air bronchogram, especially on the *Larry L. Heck, M.D., Assistant Resident, Department of Radiology.
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right side. The peripheral lung fields have a fine, granular pattern that is not entirely typical of hyaline membrane disease, but it is compatible with this diagnosis. Linear densities near the hilar region, such as may occur with aspiration pneumonia, are not present; the appearance of an air bronchogram extending to the pleura is a finding against any type of pure aspiration pneumonia. Pulmonary lymphangiectasis or hemorrhage cannot be excluded. DR. STEIN.* The management of this infant was sound. With the history of maternal infection and ingestion of meconium-stained fluid, it was appropriate to begin antibiotic therapy immediately after delivery. The prompt administration of alkalinizing intravenous fluids was also proper, as confirmed by his response. As we examine this case, we should first be suspicious of maternal diabetes mellitus, because of the infant's size, his facial appearance, and the birth weights of two previous siblings. Unfortunately, a glucose tolerance test during pregnancy or in the immediate postpartum period was not done. There is an increased incidence of the respiratory distress syndrome among the offspring of diabetic mothers. In infants of mothers with gestationaI diabetes, the risk may also be high. Second, we must consider the evidence for toxemia of pregnancy and urinary tract disease. Mild toxemia may be characterized by albuminuria, peripheral edema, and slightIy elevated blood pressure. The albuminuria and the mild hypertension during labor were possibly secondary to pyelonephritis, which has clinical features in common with toxemia. Pyelonephritis, which was documented to be present in this case, may predispose to fetal infection. There is a 14 per cent perinatal mortality rate with untreated maternal bacteriuria. 1, 2 Prematurely born infants are at greatest risk. Toxemia often precedes placental abruption and fetal death, but mild toxemia does not seem to be associated with increased infant mortality. The third factor affecting the infant was intrauterine asphyxia. Fetal distress is strongly suggested by the increased fetal pulse rate (although this may have been secondary to the actual labor) and b y the passage of meconium. Meconjure was aspirated from the infant's stomach. Delayed onset of spontaneous respiration, with cyanosis and confirmed acidosis, support the ira*Arthur O. Stein, M.D., Assistant Pro[essor, Department of PediatriCS.
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pression and further suggest depression of the central nervous system, Next, we should consider the differential diagnosis of neonatal respiratory distress. The major causes relate to the cardiovascular, respiratory, neuromuscular, and central nervous systems. With only a faint murmur, normal heart size, and no signs of congestive failure, it is unlikely that congenital heart disease was significant. Likewise, because good respiratory efforts followed the initial depressed state, it is unlikely that a neuromuscular disorder was contributory. The infant clearly had pulmonary disease, as demonstrated clinically and by roentgenography. There were some patchy densities in the lung fields in addition to a granular pattern. These densities are compatible with aspiration and resultant pneumonia. The diffuse granularity of the peripheral lung field and air hronchogram may be evidence for the respiratory distress syndrome, although the findings could represent only poor alveolar expansion. The Apgar scores and acidosis are also consistent with the respiratory distress syndrome. The typical course of the idiopathic respiratory distress syndrome, when the outcome is fatal, is characterized by progressively increasing pulse and respiratory rates. 3 The infant experienced a dramatically abrupt change in his clinical state immediately before death. I believe, therefore, that disturbed function of the central nervous system was a factor in the respiratory diffculty. The Apgar score reflects neurologic depression at birth. After a few hours, muscle tone had improved and Moro and grasp reflexes were elicited, but the suck remained weak. The last suggests persistent dysfunction at a level higher than the spinal cord. The infant's course is consistent with early hypoxia, followed by edema and possible parenchymal bleeding in the brain. The uneventful delivery provides an argument somewhat against massive intracranial hemorrhage. The stability of the vital signs before the terminal apneic event is less consistent with progresive impairment of ventilation than with acute changes in the medullary respiratory center. Early neural dysfunction might also have led to poor expansion of the lungs, a form of primary atelectasis. In summary, this infant was born of a woman who was probably prediabetic, and who had acute pyelonephritis. He suffered from intrauterine asphyxia and was depressed at the time of delivery. He probably aspirated meconium and developed pneumonia. He may have developed the respiratory distress syndrome. None of these,
The Journal of Pediatrics September 1970
however, adequately explain the precipitous deterioration. For this reason, I believe that the mechanism of death was related to antenatal neurologic damage.
Dr. Stein's diagnoses Brain d a m a g e secondary to i n t r a u t e r i n e asphyxia A s p i r a t i o n of m e c o n i u m with p n e u m o n i a Possible m a t e r n a l diabetes mellitus PATHOLOGICAL
FINDINGS
DR. ESTERLY.~ For reasons that will become apparent, it is appropriate to begin the discussion of the postmortem findings in this infant with the more or less objective evidence that confirms the ctinical gestational age of 39 weeks. The birth weight (4,110 grams) and length (55 cm.) were within the range for full-term infants. ~ The most frequent error in calculating the expected date of confinement derives from an incorrect interpretation of a menstrual irregularity and results in a difference of 4 weeks. It is important, therefore, to recognize that these values were well beyond the second standard deviation for the means of infants born at 35 weeks, and that there was no evidence of prolonged gestation. The degree of histologlc maturity was also compatible with that of a full-term infant. The most reliable evidence, however, was provided by the footprints, which showed the moderately complex skin folds of a term or near-term infant (Fig. 1). s The significant alterations found at autopsy were limited to the lungs. There was no evidence of hemorrhage into the body cavities or in the central nervous system, and histologic examination of the brain and spinal cord revealed no abnormalities. The placenta weighed 555 Gm. The fetal surface was meconium stained. The lungs were congested, heavy, and apparently airless. The cut surface was firm and granular. Petechial hemorrhages, presumably due to anoxia, were present on the pleurat and cut surfaces. Hyaline membrane disease, hemorrhage, aspiration, and pneumonia are the most frequent causes of neonatal respiratory deaths. Multiple lesions are often found in the lungs of autopsied newborn infants, 6 but the present case is somewhat unusual because each of these lesions was found. ~John R. Esterly, M.D., Assistant Professor, Dep~rtrnents of Pathology and Obstetrics and Gynecology.
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Fig. 1. The infant's footprints, made shortly after delivery, demonstrate creases of the complexity and distribution of an infant of 39 to 40 weeks of gestation.
Fig. 2. Many areas of the lung are distended by aspirated debris, including squames, vernix, and meconlum. The material is present in peripheral airways as well as larger bronchi. (Hematoxylin and eosin, x156.)
Fig. 3. In other parts of the lung, there are wellformed eosinophilic hyaline membranes in terminal and respiratory bronchioles, and the peripheral lung is collapsed. Membranes are not present in the areas of lung containing aspirated material. (Hematoxylin and eosin. •
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With a history of meconinm-stained amnionic fluid, it is not surprising that both aspirated vernix and meconium were present in the lung (Fig. 2). In several peripheral loci there were acute inflammatory exudates. It is not possible to determine whether this was an early stage of a bacterial pneumonia or represented a response to the irritant action of the aspirate. In either case, it seems unlikely that pneumonia played a significant role in the infant's death. There were also several areas of pulmonary hemorrhage in an interstitial (subpleural and perivascular) distribution. Hemorrhage in the neonatal lung is associated with several clinical and morphologic factors that are indicative of perinatal anoxia, but the etiology and significance of even massive puhnonary hemorrhage are obscure. The incidence of neonatal pulmonary hemorrhage declines with increasing gestational age, but its frequency as an autopsy finding is greatest in full-term deaths. ~ The finding of hyaline membrane disease was unexpected, and it was almost certainly the most important pulmonary abnormality. Its presence in gestationally mature infants has been disputed s and is at best infrequent. 9 In this infant the membranes were well formed and present throughout both lungs. Most of the membranes were localized to respiratory bronchioles (Fig. 3) with air trapping in the proximal airways and patchy atelectasis in the peripheral lung (Swiss cheese atelectasis). This pattern of membrane localization and atelectasis is identical to that seen in premature infants with the respiratory distress syndrome. In the sections of pancreas, islet tissue was scanty rather than hyperplastic. Careful examination of the placenta revealed occasional cytotrophoblastic cells. These were, perhaps, present in greater number than might be expected in a term placenta; they are variably prominent in placentas of diabetic patients. As has been stated, glycosuria had been absent during pregnancy, and diabetes was not suspected. A subsequent (16 weeks post partum) glucose tolerance test was somewhat abnormal: fasting blood sugar, 96 my. per 100 ml.; 30 minutes, 148 mg. per 100 ml.; 1 hour, 92 my. per 100 ml.; 2 hours, 104 mg. per 100 ml.; 3 hours, 61 mg. per 100 ml.; all urine samples negative for glucose. Does an abnormality in "maternal glucose metabolism help explain the respiratory distress syndrome in this case? Unfortunately, I think that no conclusive answer to this question can be given. The limited data on pregnancy with
The Journal of Pediatrics September 1970
gestational diabetes suggest that the complications for the infant are similar, but less frequent and less severe, than those of infants born to mothers with insulin-dependent diabetes,z~ Comparison with the latter, however, is not helpful, since the mortality rate of full-term infants of overtly diabetic mothers is largely due to intrauterine death. Furthermore, there is some doubt that the explanation for hyaline membrane disease in the infant of the diabetic mother is different from that in other infants. 11 In summary, we have a full-term infant who had both historical and morphologic evidence of acute antenatal anoxia. Hyaline membrane disease was the most important postmortem finding. The factors contributing to this condition are obscure in spite of the retrospective evidence of abnormal maternal glucose metabolism.
Pathological diagnoses H y a l i n e m e m b r a n e disease in a full-term infant A s p i r a t i o n of a m n i o n i c sac contents, focal p n e u m o n i a a n d focal p u l m o n a r y h e m o r rhage GENERAL
DISCUSSION
DR. ZUSPAN.e I would like to confine my remarks to points that relate to the pregnancy, labor, and delivery. The question that we need to try to answer is: What during the pregnancy, labor, or delivery might have contributed to the outcome of this pregnancy? A 25-year-old woman who is a gravida 6, para 5 is an individual with an active reproductive life, and statistically we could predict increasing difficulty in the outcome of subsequent pregnancies. When admitted in false labor at 37 weeks, she had a normal blood pressure, minimal edema, and 2+ albuminuria. The albuminuria, in retrospect, probably indicated the presence of a chronic urinary tract infection. Had the diagnosis been made at this point, the intrauterine distress might have been decreased, since a febrile reaction in a pregnant patient invariably results in fetal stress due to hyperthermia and possibly to other toxic bacterial or metabolic products. Fetal tachycardia is one of the last clinical indications of anoxia, and the fetal heart rate of 180 beats per minute indicated that the fetus had a low reserve for stress. The birth weight of over 4 kilograms should have alerted ~Predrlck P. Zuspan, M.D., Professor and Chairman, Department of Obstetrics and Gynecology.
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us to rule out gestational diabetes in the immediate postpartum period, but I question whether a maternal prediabetie state would account for the asphyxia manifested by meconinmstained amniotlc fluid. DR. WRmRT. ~ In spite of the pulmonary lesions that have been shown, it is clear that this infant clinically had a significant neurologic deficit. I wonder if this might not have been reflected in very minor, or even undetectable, alterations? DR. ST~IN. This infant's clinical course highlights the complicated pathogenesis of t h e respiratory distress syndrome of the newborn. There is no dispute that the infant had hyaline membrane disease, among other disorders. I believe, however, that the mechanism of death was within the central nervous system, affected by preterminal changes in oxygenation, or other biochemical disturbances, at the brainstem level. As Dr. Wright has suggested, precipitous changes of these types might not cause visible morphologic changes within the brain. One may postulate distinct, sequential events. The first was the asphyxia at the time of delivery, which predisposed to the development of the respiratory distress syndrome. If the immediate cause of the infant's death had been pulmonary parenchymal disease, the clinical course should have reflected progressive mechanical impairment of gas exchange. Increasing tachypnea, worsening chest retractions, and accelerating tachycardia are findings indicating that a relatively well-oxygenated respiratory center was "driving" a handicapped pulmonary system. This infant, however, did not demonstrate evidence of increasing respiratory impairment; rather, his muscular efforts decreased dramatically and abruptly, indicating failure of the controlling center. He was depressed initially, but had improved significantly; complete recovery from the initial insult to the central nervous system might have been possible. Preterminally, undefined events, possibly related to inadequate oxygenation of the brainstem, led to rapid decompensation in the respiratory center. I would be concerned if we were t o dismiss neurologic disease because we lack morphologic evidence. In retrospect, in cases like these, electroencephalography might be interesting. DR. ESTERLY. These comments emphasize ~F. ItoweR Wright, M.D-, Professor, Department of Pediatrics.
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both the limitations of morphologic examination and how much we have yet to learn about the pathogenesis of the respiratory distress syndrome. Histologic examination of the central nervous system was limited to 6 routine sections. Since the brain in this case was not fixed by perfusion, it is possible that minor autolytic changes may, in fact, represent the residua of antenatal anoxia. However, no lesions were present that could be clearly distinguished from postmortem changes. Bleeding into the brain or meninges was n o t present, but these lesions are uncommon in full-term infants. If we accept the suggestion of antenatal damage to the central nervous system and the finding of hyaline membrane disease, we might consider that the two are etiologically related. Either or both may have been initiated by intrauterine asphyxia and stress. An antenatal origin of the respiratory distress syndrome has been a controversial subject, perhaps reflecting the techniques available for its detection. Membrane formation does not occur without an interval of air breathing, but Gruenwald's data on poor pulmonary stability in some stillborn infants support the hypothesis1~, 1~ of antenatal factors. Nevertheless, the relatively abrupt respiratory failure stressed by Dr. Stein remains unexplained. For this reason, it appears that two factors were important in the death of this infant. One was the brain damage, which for purposes of this conference, at least, can be documented only by history. The other was the uncommon combination of pulmonary lesions, including hyaline membrane disease, in a full-term infant. Until an hour or so before death, the patient's condition remained stable. This course suggests that the pulmonary lesions were not necessarily the lethal ones, although they were the only significant morphologic findings. REFERENCES 1. Kass, E. H.: Bacterluria and pyelonephrltis of pregnancy, Trans. A. Am. Physicians 72: 257, 1959. 2. Kass, E. H.: Pyel'onephritis and bacteriuria: A major problem in preventive medicine, Ann. Int. Med. 56: 46, 1962. 3. Miller, H. C., Behrle, F. C., and Smull, N. W.: Respiratory activity and function in newborn infants dying with pulmonary hyaline membranes, Pediatrics 22: 665, 1958. 4. Gruenwald, P.: Growth of the human fetus. I. Normal growth and its variation, Am. J. Obst. & Gynec. 94: 1112, 1966.
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5. Usher, R., McLean, F., and Scott, K. E.: Judgment of the fetal age. If. Clinical significance of gestational age and an objective method for its assessment, Pediat. Glin. North America 13:835, 1966. 6. Landing, B. H.: Pulmonary lesions of newborn infants, Pediatrics 19: 217, 1957. 7. gsterly, J. R., and Oppenheimer, E. H.: Massive pulmonary hemorrhage in the newborn. I. Pathology considerations, J. PI~DIAT. 69: 3, 1966. 8. Usher, R., McLean, F., and Maughan, C. B.: Respiratory distress in infants delivered by cesarean section, Am. J. Obst. & Gynec. 88: 806, 1964. 9. Esterly, J. R., Langegger, F., and Gruen-
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I0. 11. 12. 13.
wald, P.: Hyaline membranes in full-size infants, Virchows Arch. Path. Anat. 341: 259, 1966. Warner, R. A., and Cornblath, M.: Infants of gestafional diabetic mothers, Amer. J. Dis. Child. 117: 678, 1969. Faxquhar, J. W.; Metabolic changes in the infant of the diabetic mother, Pedlar. Clin. North. America 12: 743, 1965. Gruenwald, P.: Prenatal origin of the respiratory distress (hyaline membrane) syndrome of premature infants, Lancet 1: 230, 1960. Gruenwald, P.: The course of the respiratory distress syndrome of newborn infants, Acta pediat. 53: 470, 1964.
JayBernstein, Edltor
Respiratory failure in a full-term infant John R. Esterly, M.D., and Arthur O. Stein, M.D. CHICAOOj I L L .
T H E P A T I E N T was a newborn Negro male infant, delivered at 39 weeks' gestation of a 25-year-old, gravlda 6 para 5 mother. The mother's health had been good except for a urinary tract infection during the pregnancy. The birth weights of her previous infants were 6 pounds 9 ounces, 8 pounds 12 ounces, 7 pounds 14 ounces, 7 pounds, and 9 pounds, respectively. She was admitted to The Chicago Lying-In Hospital in false labor at 37 weeks' gestation. Urinalysis showed 2+ albuminuria. She had 1+ ankle edema. Blood pressure was 110/70 ram. Hg; previously recorded blood pressures had been normal, and there had been neither albuminuria nor glycosuria. She was readmitted in active labor 2 weeks later. She gave a history of being febrile for the previous 4 days. She was treated immediately with ampicillin intravenously, and subsequently with cephalothin. The temperature became normal on the third hospital day. KlebsieIla pneumoniae and Staphylococcus albus were cultured from a catheterized specimen of the urine. Urinalysis shortly thereafter revealed approximately 10 red and 8 to 12 white blood cells per highpower microscopic field. She had also complained of an upper respiratory infection and cough, and on admission her breath sounds were described as "coarse." The blood pressure was 130/75 mm. Hg. The fetal
From The Chicago Lying-In Hospital and
University o[ Chicago. *Sponsored by the Pediatric Pathology Club. Vol. 77, No. 3, pp. 508-514
heart rate was 180 beats per minute immediately prior to delivery. The first stage of labor lasted 2 hours and the second stage 28 minutes. Meconium-stained fluid was noted during labor, and at delivery the amniotic fluid was deeply stained. T h e infant's presentation was cephalic; delivery was spontaneous. The birth weight was 4,110 grams. Two minutes elapsed before sustained respiration was initiated by simple resuscitative measures, including endotracheal intubation and oxygen by mask. The Apgar score at one minute was 4 (heart 2, respiratory effort 1, color 1); at five minutes it was 6 (heart 2, respiratory effort 1, muscle tone 1, reflex irritability 1, color 1). T h e infant was covered with meconiumstained material which was not malodorous. T h e initial pediatric examination revealed a distressed male infant with a pulse rate of 140 per minute and a respiratory rate of 54 per minute. His facies was described as that of an infant of a diabetic mother. The skin was tinged green. Generalized cyanosis was present; heart sounds were normal. The breath sounds were coarse, with bilateral moist inspiratory r~les; there was grunting with respirations. The neurologic examination revealed fair muscle tone, fair Moro and grasp reflexes, and poor suck. Viscous green material was aspirated from the stomach. T h e cord hemoglobin concentration was 15 Gm. per 100 ml. Initial blood chemical values were pH 6.84; sodium 136 mEq. per liter; potassium 4.8 mEq. per liter; chloride
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87 mEq per liter; carbon dioxide 12 mEq. per liter; blood urea nitrogen 9 rag. per 100 ml.; glucose 165 mg. per 100 ml. T h e presumptive diagnosis was meconium aspiration with significant respiratory distress. Penicillin and kanamycin were given immediately. Sodium bicarbonate (150 mEq. per liter) in 10 per cent dextrose was administered via an indwelling umbilical catheter at the rate of 65 ml. per kilogram of body weight per 24 hours. The infant was kept in an Isolette, with humidified oxygen supplied to maintain a concentration of 40 per cent. At 4 ~ hours of age the infant continued to look sick, with persistent grunting respiration and flaring of the alae nasae. A soft systolic m u r m u r was noted at the base of the heart. Breath sounds were described as good, with scattered moist rSles. By t3 hours the liver edge was palpable 1.5 cm. below the right costal margin, and at 15 hours of age markedly decreased respiratory efforts were noted. Blood chemical values at that time were p H 7.39; sodium 130 mEq. per liter; potassium 3.3 mEq. per liter; chloride 90 mEq. per liter; carbon dioxide 22 mEq. per liter; and glucose 72 mg. per 100 ml. T h e infant died rather suddenly at 1 6 ~ hours of age, T h e record of vital signs is noteworthy. Body temperatures (rectal) had ranged from 36.4 to 37 ~ C. The pulse rate, recorded at approximately hourly intervals preceding death, had been relatively steady: 140, 132, 140, 160, 164, 146, 152, and 146 beats per minute. Approximately an hour before death the pulse was 154. Terminally he became apneic, and the pulse dropped to 64. Corresponding respiratory rates were somewhat rapid, recorded at 60, 60, 64, 72, 74, 84, 66, 72, and 76 respirations per minute. CLINICAL DISCUSSION DR. H~cK.* The roentgenogram at 3 hours of age shows pulmonary consolidation with suggestion of an air bronchogram, especially on the *Larry L. Heck, M.D., Assistant Resident, Department of Radiology.
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509
right side. The peripheral lung fields have a fine, granular pattern that is not entirely typical of hyaline membrane disease, but it is compatible with this diagnosis. Linear densities near the hilar region, such as may occur with aspiration pneumonia, are not present; the appearance of an air bronchogram extending to the pleura is a finding against any type of pure aspiration pneumonia. Pulmonary lymphangiectasis or hemorrhage cannot be excluded. DR. STEIN.* The management of this infant was sound. With the history of maternal infection and ingestion of meconium-stained fluid, it was appropriate to begin antibiotic therapy immediately after delivery. The prompt administration of alkalinizing intravenous fluids was also proper, as confirmed by his response. As we examine this case, we should first be suspicious of maternal diabetes mellitus, because of the infant's size, his facial appearance, and the birth weights of two previous siblings. Unfortunately, a glucose tolerance test during pregnancy or in the immediate postpartum period was not done. There is an increased incidence of the respiratory distress syndrome among the offspring of diabetic mothers. In infants of mothers with gestationaI diabetes, the risk may also be high. Second, we must consider the evidence for toxemia of pregnancy and urinary tract disease. Mild toxemia may be characterized by albuminuria, peripheral edema, and slightIy elevated blood pressure. The albuminuria and the mild hypertension during labor were possibly secondary to pyelonephritis, which has clinical features in common with toxemia. Pyelonephritis, which was documented to be present in this case, may predispose to fetal infection. There is a 14 per cent perinatal mortality rate with untreated maternal bacteriuria. 1, 2 Prematurely born infants are at greatest risk. Toxemia often precedes placental abruption and fetal death, but mild toxemia does not seem to be associated with increased infant mortality. The third factor affecting the infant was intrauterine asphyxia. Fetal distress is strongly suggested by the increased fetal pulse rate (although this may have been secondary to the actual labor) and b y the passage of meconium. Meconjure was aspirated from the infant's stomach. Delayed onset of spontaneous respiration, with cyanosis and confirmed acidosis, support the ira*Arthur O. Stein, M.D., Assistant Pro[essor, Department of PediatriCS.
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pression and further suggest depression of the central nervous system, Next, we should consider the differential diagnosis of neonatal respiratory distress. The major causes relate to the cardiovascular, respiratory, neuromuscular, and central nervous systems. With only a faint murmur, normal heart size, and no signs of congestive failure, it is unlikely that congenital heart disease was significant. Likewise, because good respiratory efforts followed the initial depressed state, it is unlikely that a neuromuscular disorder was contributory. The infant clearly had pulmonary disease, as demonstrated clinically and by roentgenography. There were some patchy densities in the lung fields in addition to a granular pattern. These densities are compatible with aspiration and resultant pneumonia. The diffuse granularity of the peripheral lung field and air hronchogram may be evidence for the respiratory distress syndrome, although the findings could represent only poor alveolar expansion. The Apgar scores and acidosis are also consistent with the respiratory distress syndrome. The typical course of the idiopathic respiratory distress syndrome, when the outcome is fatal, is characterized by progressively increasing pulse and respiratory rates. 3 The infant experienced a dramatically abrupt change in his clinical state immediately before death. I believe, therefore, that disturbed function of the central nervous system was a factor in the respiratory diffculty. The Apgar score reflects neurologic depression at birth. After a few hours, muscle tone had improved and Moro and grasp reflexes were elicited, but the suck remained weak. The last suggests persistent dysfunction at a level higher than the spinal cord. The infant's course is consistent with early hypoxia, followed by edema and possible parenchymal bleeding in the brain. The uneventful delivery provides an argument somewhat against massive intracranial hemorrhage. The stability of the vital signs before the terminal apneic event is less consistent with progresive impairment of ventilation than with acute changes in the medullary respiratory center. Early neural dysfunction might also have led to poor expansion of the lungs, a form of primary atelectasis. In summary, this infant was born of a woman who was probably prediabetic, and who had acute pyelonephritis. He suffered from intrauterine asphyxia and was depressed at the time of delivery. He probably aspirated meconium and developed pneumonia. He may have developed the respiratory distress syndrome. None of these,
The Journal of Pediatrics September 1970
however, adequately explain the precipitous deterioration. For this reason, I believe that the mechanism of death was related to antenatal neurologic damage.
Dr. Stein's diagnoses Brain d a m a g e secondary to i n t r a u t e r i n e asphyxia A s p i r a t i o n of m e c o n i u m with p n e u m o n i a Possible m a t e r n a l diabetes mellitus PATHOLOGICAL
FINDINGS
DR. ESTERLY.~ For reasons that will become apparent, it is appropriate to begin the discussion of the postmortem findings in this infant with the more or less objective evidence that confirms the ctinical gestational age of 39 weeks. The birth weight (4,110 grams) and length (55 cm.) were within the range for full-term infants. ~ The most frequent error in calculating the expected date of confinement derives from an incorrect interpretation of a menstrual irregularity and results in a difference of 4 weeks. It is important, therefore, to recognize that these values were well beyond the second standard deviation for the means of infants born at 35 weeks, and that there was no evidence of prolonged gestation. The degree of histologlc maturity was also compatible with that of a full-term infant. The most reliable evidence, however, was provided by the footprints, which showed the moderately complex skin folds of a term or near-term infant (Fig. 1). s The significant alterations found at autopsy were limited to the lungs. There was no evidence of hemorrhage into the body cavities or in the central nervous system, and histologic examination of the brain and spinal cord revealed no abnormalities. The placenta weighed 555 Gm. The fetal surface was meconium stained. The lungs were congested, heavy, and apparently airless. The cut surface was firm and granular. Petechial hemorrhages, presumably due to anoxia, were present on the pleurat and cut surfaces. Hyaline membrane disease, hemorrhage, aspiration, and pneumonia are the most frequent causes of neonatal respiratory deaths. Multiple lesions are often found in the lungs of autopsied newborn infants, 6 but the present case is somewhat unusual because each of these lesions was found. ~John R. Esterly, M.D., Assistant Professor, Dep~rtrnents of Pathology and Obstetrics and Gynecology.
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5 11
Fig. 1. The infant's footprints, made shortly after delivery, demonstrate creases of the complexity and distribution of an infant of 39 to 40 weeks of gestation.
Fig. 2. Many areas of the lung are distended by aspirated debris, including squames, vernix, and meconlum. The material is present in peripheral airways as well as larger bronchi. (Hematoxylin and eosin, x156.)
Fig. 3. In other parts of the lung, there are wellformed eosinophilic hyaline membranes in terminal and respiratory bronchioles, and the peripheral lung is collapsed. Membranes are not present in the areas of lung containing aspirated material. (Hematoxylin and eosin. •
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Clinical-pathological con[erence
With a history of meconinm-stained amnionic fluid, it is not surprising that both aspirated vernix and meconium were present in the lung (Fig. 2). In several peripheral loci there were acute inflammatory exudates. It is not possible to determine whether this was an early stage of a bacterial pneumonia or represented a response to the irritant action of the aspirate. In either case, it seems unlikely that pneumonia played a significant role in the infant's death. There were also several areas of pulmonary hemorrhage in an interstitial (subpleural and perivascular) distribution. Hemorrhage in the neonatal lung is associated with several clinical and morphologic factors that are indicative of perinatal anoxia, but the etiology and significance of even massive puhnonary hemorrhage are obscure. The incidence of neonatal pulmonary hemorrhage declines with increasing gestational age, but its frequency as an autopsy finding is greatest in full-term deaths. ~ The finding of hyaline membrane disease was unexpected, and it was almost certainly the most important pulmonary abnormality. Its presence in gestationally mature infants has been disputed s and is at best infrequent. 9 In this infant the membranes were well formed and present throughout both lungs. Most of the membranes were localized to respiratory bronchioles (Fig. 3) with air trapping in the proximal airways and patchy atelectasis in the peripheral lung (Swiss cheese atelectasis). This pattern of membrane localization and atelectasis is identical to that seen in premature infants with the respiratory distress syndrome. In the sections of pancreas, islet tissue was scanty rather than hyperplastic. Careful examination of the placenta revealed occasional cytotrophoblastic cells. These were, perhaps, present in greater number than might be expected in a term placenta; they are variably prominent in placentas of diabetic patients. As has been stated, glycosuria had been absent during pregnancy, and diabetes was not suspected. A subsequent (16 weeks post partum) glucose tolerance test was somewhat abnormal: fasting blood sugar, 96 my. per 100 ml.; 30 minutes, 148 mg. per 100 ml.; 1 hour, 92 my. per 100 ml.; 2 hours, 104 mg. per 100 ml.; 3 hours, 61 mg. per 100 ml.; all urine samples negative for glucose. Does an abnormality in "maternal glucose metabolism help explain the respiratory distress syndrome in this case? Unfortunately, I think that no conclusive answer to this question can be given. The limited data on pregnancy with
The Journal of Pediatrics September 1970
gestational diabetes suggest that the complications for the infant are similar, but less frequent and less severe, than those of infants born to mothers with insulin-dependent diabetes,z~ Comparison with the latter, however, is not helpful, since the mortality rate of full-term infants of overtly diabetic mothers is largely due to intrauterine death. Furthermore, there is some doubt that the explanation for hyaline membrane disease in the infant of the diabetic mother is different from that in other infants. 11 In summary, we have a full-term infant who had both historical and morphologic evidence of acute antenatal anoxia. Hyaline membrane disease was the most important postmortem finding. The factors contributing to this condition are obscure in spite of the retrospective evidence of abnormal maternal glucose metabolism.
Pathological diagnoses H y a l i n e m e m b r a n e disease in a full-term infant A s p i r a t i o n of a m n i o n i c sac contents, focal p n e u m o n i a a n d focal p u l m o n a r y h e m o r rhage GENERAL
DISCUSSION
DR. ZUSPAN.e I would like to confine my remarks to points that relate to the pregnancy, labor, and delivery. The question that we need to try to answer is: What during the pregnancy, labor, or delivery might have contributed to the outcome of this pregnancy? A 25-year-old woman who is a gravida 6, para 5 is an individual with an active reproductive life, and statistically we could predict increasing difficulty in the outcome of subsequent pregnancies. When admitted in false labor at 37 weeks, she had a normal blood pressure, minimal edema, and 2+ albuminuria. The albuminuria, in retrospect, probably indicated the presence of a chronic urinary tract infection. Had the diagnosis been made at this point, the intrauterine distress might have been decreased, since a febrile reaction in a pregnant patient invariably results in fetal stress due to hyperthermia and possibly to other toxic bacterial or metabolic products. Fetal tachycardia is one of the last clinical indications of anoxia, and the fetal heart rate of 180 beats per minute indicated that the fetus had a low reserve for stress. The birth weight of over 4 kilograms should have alerted ~Predrlck P. Zuspan, M.D., Professor and Chairman, Department of Obstetrics and Gynecology.
Volume 77 Number 3
us to rule out gestational diabetes in the immediate postpartum period, but I question whether a maternal prediabetie state would account for the asphyxia manifested by meconinmstained amniotlc fluid. DR. WRmRT. ~ In spite of the pulmonary lesions that have been shown, it is clear that this infant clinically had a significant neurologic deficit. I wonder if this might not have been reflected in very minor, or even undetectable, alterations? DR. ST~IN. This infant's clinical course highlights the complicated pathogenesis of t h e respiratory distress syndrome of the newborn. There is no dispute that the infant had hyaline membrane disease, among other disorders. I believe, however, that the mechanism of death was within the central nervous system, affected by preterminal changes in oxygenation, or other biochemical disturbances, at the brainstem level. As Dr. Wright has suggested, precipitous changes of these types might not cause visible morphologic changes within the brain. One may postulate distinct, sequential events. The first was the asphyxia at the time of delivery, which predisposed to the development of the respiratory distress syndrome. If the immediate cause of the infant's death had been pulmonary parenchymal disease, the clinical course should have reflected progressive mechanical impairment of gas exchange. Increasing tachypnea, worsening chest retractions, and accelerating tachycardia are findings indicating that a relatively well-oxygenated respiratory center was "driving" a handicapped pulmonary system. This infant, however, did not demonstrate evidence of increasing respiratory impairment; rather, his muscular efforts decreased dramatically and abruptly, indicating failure of the controlling center. He was depressed initially, but had improved significantly; complete recovery from the initial insult to the central nervous system might have been possible. Preterminally, undefined events, possibly related to inadequate oxygenation of the brainstem, led to rapid decompensation in the respiratory center. I would be concerned if we were t o dismiss neurologic disease because we lack morphologic evidence. In retrospect, in cases like these, electroencephalography might be interesting. DR. ESTERLY. These comments emphasize ~F. ItoweR Wright, M.D-, Professor, Department of Pediatrics.
Clinical-pathological conference
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both the limitations of morphologic examination and how much we have yet to learn about the pathogenesis of the respiratory distress syndrome. Histologic examination of the central nervous system was limited to 6 routine sections. Since the brain in this case was not fixed by perfusion, it is possible that minor autolytic changes may, in fact, represent the residua of antenatal anoxia. However, no lesions were present that could be clearly distinguished from postmortem changes. Bleeding into the brain or meninges was n o t present, but these lesions are uncommon in full-term infants. If we accept the suggestion of antenatal damage to the central nervous system and the finding of hyaline membrane disease, we might consider that the two are etiologically related. Either or both may have been initiated by intrauterine asphyxia and stress. An antenatal origin of the respiratory distress syndrome has been a controversial subject, perhaps reflecting the techniques available for its detection. Membrane formation does not occur without an interval of air breathing, but Gruenwald's data on poor pulmonary stability in some stillborn infants support the hypothesis1~, 1~ of antenatal factors. Nevertheless, the relatively abrupt respiratory failure stressed by Dr. Stein remains unexplained. For this reason, it appears that two factors were important in the death of this infant. One was the brain damage, which for purposes of this conference, at least, can be documented only by history. The other was the uncommon combination of pulmonary lesions, including hyaline membrane disease, in a full-term infant. Until an hour or so before death, the patient's condition remained stable. This course suggests that the pulmonary lesions were not necessarily the lethal ones, although they were the only significant morphologic findings. REFERENCES 1. Kass, E. H.: Bacterluria and pyelonephrltis of pregnancy, Trans. A. Am. Physicians 72: 257, 1959. 2. Kass, E. H.: Pyel'onephritis and bacteriuria: A major problem in preventive medicine, Ann. Int. Med. 56: 46, 1962. 3. Miller, H. C., Behrle, F. C., and Smull, N. W.: Respiratory activity and function in newborn infants dying with pulmonary hyaline membranes, Pediatrics 22: 665, 1958. 4. Gruenwald, P.: Growth of the human fetus. I. Normal growth and its variation, Am. J. Obst. & Gynec. 94: 1112, 1966.
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5. Usher, R., McLean, F., and Scott, K. E.: Judgment of the fetal age. If. Clinical significance of gestational age and an objective method for its assessment, Pediat. Glin. North America 13:835, 1966. 6. Landing, B. H.: Pulmonary lesions of newborn infants, Pediatrics 19: 217, 1957. 7. gsterly, J. R., and Oppenheimer, E. H.: Massive pulmonary hemorrhage in the newborn. I. Pathology considerations, J. PI~DIAT. 69: 3, 1966. 8. Usher, R., McLean, F., and Maughan, C. B.: Respiratory distress in infants delivered by cesarean section, Am. J. Obst. & Gynec. 88: 806, 1964. 9. Esterly, J. R., Langegger, F., and Gruen-
The lournal of Pediatrics September 1970
I0. 11. 12. 13.
wald, P.: Hyaline membranes in full-size infants, Virchows Arch. Path. Anat. 341: 259, 1966. Warner, R. A., and Cornblath, M.: Infants of gestafional diabetic mothers, Amer. J. Dis. Child. 117: 678, 1969. Faxquhar, J. W.; Metabolic changes in the infant of the diabetic mother, Pedlar. Clin. North. America 12: 743, 1965. Gruenwald, P.: Prenatal origin of the respiratory distress (hyaline membrane) syndrome of premature infants, Lancet 1: 230, 1960. Gruenwald, P.: The course of the respiratory distress syndrome of newborn infants, Acta pediat. 53: 470, 1964.