CLINICAL-PATHOLOGICAL C O N F E R E N C E * JayBernstein, Editor
Massive pulmonary hemorrhage in a neonate William J. Keenan, M.D., and Geoffrey Altshuler, M.B., B.S.,** CincinnatL Ohio
T H E P AT I E N T was a 4,140 gm term white boy transferred to the Children's Hospital at 2 hours of age because of cyanosis, hepatomegaly, and a cardiac murmur. T h e m o t h e r was 27 years o f age, allegedly n o n diabetic, gravida 2, para 1; she described no problems with the current or previous pregnancy. The only medications taken during pregnancy were vitamins and iron. Buccal administration of Pitocin was used to induce labor; three doses were given. The total duration of labor and delivery was 8 hours. The m e m b r a n e s ruptured 4 hours prior to delivery. Although no fetal distress was noted, continuous fetal heart rate monitoring was not performed. The delivery was achieved with the application of low forceps. During labor and delivery the m o t h e r ' s t r e a t m e n t i n c l u d e d m e p e r i d i n e , prom e t h a z i n e , scopolamine, and spinal a n e s t h e s i a . T h e placenta was said to be very large, approximately 3 pounds; the Apgar scores were 7 and 9 at 1 and 5 minutes, respectively. The overall clinical status, however, was stated by the obstetrician to have seemed worse than the Apgar scores indicated. Immediately after the cord was clamped, the infant turned blue and remained cyanotic in 40% oxygen. In the nursery there were persistent generalized cyanosis and a heart murmur; the liver edge was palpable below the level of the umbilicus. Blood aspirated from the stomach was Apt test positive. Vitamin K was not given prior to transfer of the infant. The infant's condition rapidly deteriorated, and he required positive pressure ventilation with 100% oxygen during transit to this hospital. From the Departments o f Pediatrics and Pathology, the Cincinnati General Hospital and the CitJ'cinnati Children's Hospital, and the University o f Cincinnati Medical Center. *Sponsored by the Pediatric Pathology Club. **Supported in part by the Fels Division of Pediatric Research. Reprint address: Children's Hospital Medical Center, Department of Pathology, Cincinnati, Ohio 45229. Vol. 86, No. 3, pp. 466-471
Examination at 2 hours of age revealed an acutely ill, severely cyanotic newborn infant with gasping attempts at respiration. He was flaccid and minimally responsive, with no suck or Moro reflex. His head was normal; the anterior fontanel was fiat. The heart rate was regular at 160/rain.; there was no murmur. Bilateral chest rales were present. All pulses were markedly decreased initially. The liver edge was 5 to 6 cm below the right costal margin. There was mottling of the lowel extremities. There were no petechiae or ecchymoses. No congenital anomalies were noted. Bight red unclotted blood was aspirated from both the stomach and trachea. Initial laboratory data: Hemoglobin concentration 19.1 gm/dl; white blood cell count 23,500/mm3 with 27% polymorphonuclear leukocytes, 4% eosinophils, 60% lymphocytes, 9% mononuclear leukocytes, and adequate platelets. There were no burr cells or fragmentation of erythrocytes on the blood smear. Both mother and patient were blood type Rh positive. The Coombs' test was negative. Electrolyte and blood urea nitrogen values were normal, as was the urinalysis. The blood sugar concentration was 177 mg/dl (without parenteral fluids running), and the serum bilirubin concentration was 0 mg/dl. Initial blood gas values: pH 6.72, Pco 2 85 m m Hg and Po 2 34 m m Hg. Base excess was minus mEq/1. Within 30 minutes of arrival the patient had cathet e r i z a t i o n of t h e u m b i l i c a l vessels and u n d e r w e n t nasotracheal intubation for assisted ventilation. Furosemide, 5 rag, sodium bicarbonate, 5 mEq and digoxin, 80/xg, were given rapidly by intravenous infusion. A cardiology consultant felt that with a normal electrocardiogram and normal echocardiogram the diagnosis was m o s t likely p u l m o n a r y h e m o r r h a g e with m y o c a r d i a l failure secondary to acidosis and hypoxia. The infant was given 1 ml of Aquamephyton intramuscularly several hours after his arrival. Penicillin and gentamicin were administered after bacterial cultures h a d b e e n t a k e n . D e s p i t e n o r m a l i z a t i o n of values
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o f t h e P c o 2 a n d P o 2 by artificial ventilation, t h e p H did n o t rise a b o v e 6.8 with t h e a d m i n i s t r a t i o n o f s o d i u m bic a r b o n a t e a n d s u b s e q u e n t l y tris buffer. Systolic b l o o d p r e s s u r e m e a s u r e d by u m b i l i c a l artery line was 25 m m / Hg. T h e i n f a n t was g i v e n h u m a n s e r u m a l b u m i n int r a v e n o u s l y . T h e o n l y u r i n e o u t p u t was 2-3 ml. following m a n u a l c o m p r e s s i o n o f t h e bladder, in spite o f several d o s e s o f f u r o s e m i d e . The patient remained
flaccid a n d his l o w e r e x -
t r e m i t i e s w e r e p e r s i s t e n t l y m o t t l e d . N o p e t e c h i a e appeared. Bright red blood was repeatedly s u c t i o n e d f r o m his e n d o t r a c h e a l t u b e . A t 5 h o u r s o f age b l u r r cells w e r e noted on blood smear with a normal number
of
platelets a n d n o f r a g m e n t a t i o n o f e r y t h r o c y t e s . D e s p i t e all efforts at r e s u s c i t a t i o n , t h e i n f a n t was p r o n o u n c e d d e a d at 8 h o u r s o f age. DISCUSSION DR. WILLIAMJ. KEENAN.We are faced with the problems of an infant whose existence in utero is said to have been entirely uncomplicated and who is nonetheless dead 16 short hours from the time that labor first began. In such a case I cannot accept that labor and delivery were really uncomplicated. The initial diagnostic procedures were roentgenograms of the abdomen and chest; I would like to ask Dr. Silverman for his interpretations. DR. FREDERICK M. SILVERMAN. The first roentgenograms, taken in the nursery at the referring hospital, showed a relatively large thorax and a central mediastinal shadow of nondistinctive configuration with a somewhat prominent right atrial component. There was some congestion in, the lungs, with diffuse densities throughout the central portion that did not conform to the usual reticulogranular pattern of hyaline membrane disease, but resembled rather the pattern of "0ascular congestion and possible aspiration, perhaps even infedtion and/or hemorrhage within the lungs. The bones were not remarkable. There was no pneumothorax or pneumomediastinum. A relatively gas-free abdomen is evident in roentgenograms of the abdomen taken at the same time, except for a small amount of gas within the stomach. By 2 to 4 hours of age we usually see gas filling some of the small bowel loops, and this finding suggests that intestinal tract function was severely depressed. The possibility of fluid or hemorrhage in the abdomen certainly did exist. At 4 hours of age, when films were taken here, the lungs had become more opaque; they did not show the diffuse, fine, stippled appearance of black spots on a white background that is characteristic of hyaline membrane disease, but rather diffuse densities throughout the lungs with air bronchograms suggestive of either inflammatory reaction or hemorrhage, or both. An endotracheal tube was present, inserted a little too far; it was in the right main-stem bronchus, but apparently not obstructing the aeration of the left lung. Abdominal radiograms showed an umbilical venous catheter in place with its tip at the level of the diaphragm. An arterial cath-
467
eter had its tip just barely at the junction of the hypogastric and common lilac arteries, a little lower than we usualty like to see it. At this time, at 4 hours of age, there was some gas in the small bowel, but it tended to be clustered in the central portion of the abdomen as seen when air-filled loops float on fluid in the peritoneal cavity and become pressed together. The rapid evolution of the lung disease is most suggestive of pulmonary hemorrhage or overwhelming sepsis, a condition often associated with pulmonary hemorrhage. The only other radiograph that was taken was a total "babygram" after the baby had die& this showed practically no aeration of the lungs, which had the same density as the liver. It was obvious also that the baby was very large, and that there was only a very minute ossification center at the distal end of the femur. In other words, the baby demonstrates retarded maturation but large size, features commonly observed in infants of diabetic mothers. DR. WILLIAM J. KEENAN. Mindful of the diagnostic and therapeutic problems that faced the clinician in this case, I will discuss the following two points: (1) the problems that presented in the delivery room and (2) the patient's diagnosis while he was cared for at this hospital. In dealing with the desperately ill, newly born infant in the delivery room, there are many problems, not all of which can be clarified by postmortem examination. Many of the enigmatic emergencies that take place in the delivery room occur when the infant has suffered blood loss that may or may not be apparent. Placenta previa, vasa previa, abruptio placentae, twin-to-twin transfusion, and cesarean section can each result in catastrophic fetal blood loss. The normal hemoglobin concentration in this infant does not exclude severe perinatal blood loss, but none of these conditions appears to fit the problem under discussion. Uncommonly, infants with overwhelming sepsis are seen in the delivery room. The history of a 3-pound placenta would make one suspicious of congenital syphilis or toxoplasmosis, but in the case of this sick patient I think that the placental weight probably was grossly overestimated, just as were the Apgar scores. Although the rapid downward course of this patient is consistent with some forms of perinatal sepsis, little else in the protocol supports this diagnosis. I would suggest that this infant probably suffered intrauterine asphyxia. The state of fetal oxygenation is critically dependent upon both adequate maternal and fetal perfusion of the placental exchange interface. An inverse relationship between uterine contraction and uterine blood flow has been well demonstrated, t During the course of normal labor a healthy fetus appears to tolerate this intermittent interruption of oxygen supply very well, but the already compromised fetus may become hypoxic. This intolerance is illustrated by the frequent occurrence of fetal distress during the labor of toxemic women. 2 It has been well demonstrated that the oxygenation of a fetus with normal reserve will be compromised whenever abnormal uterine dynamics reduce uterine blood flow even more than does normal labor. 3 The abnormal uterine dynamics can include an increase in resting tonus, abnormally frequent con-
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Fig. 1. Placenta. The villi feature congestion and a severe increase in the number of blood vessels; hence the term "chorangiosis." Original magnification x250. Hematoxylin and eosin. tractions, abnormally prolonged contractions, or any combination thereof. This labor was augmented with buccal Pitocin, i.e., tablets of synthetic Pitocin designed to be held in the buccal pouch and absorbed by the mucous membranes of the mouth. Used since the early 1960s, this form of Pitocin administration has been receiving considerable obstetric criticism in the 1970s.4 Studies of buccal administration Of Pitocin, while usually focusing upon efficiency rather than safety, have shown an incidence of undesirable uterine hyperactivity from less than 1% to 10%.5, 6 The incidence of fetal distress is as high as 21%.7 The most dangerous feature of buccal administration of Pitocin, however, is its widespread use for the stimulation of unmonitored labors. Significant and ominous degrees of fetal distress may occur. There is increasing agreement that every labor augmented by Pitocin requires the constant attendance of appropriately trained personnel, assisted by continuous monitoring of the inst0ntaneous fetal heart rate and of uterine contractions. I postulate that the patient we are now discussing suffered a prolonged period of severe hypoxia during a hypertonic labor. The infant's birth weight is above the ninetieth percentile for 40 weeks' gestation; given Dr. Silverman's observations that this patient was somewhat immature, there is the additional strong possibility of maternal diabetes, which would significantly increase the chances of fetal hypoxic compromise during labor. The description of a shocklike state in a newborn infant accompanied by large amounts of bloody tracheal fluid quite clearly indicates that this infant had massive pulmonary hemorrhage. The best therapeutic efforts appear to be of no avail in this condition. Massive pulmonary hemorrhage is a common problem, occurring in about 6-10% of autopsied newborn infants.8 Relevant to this patient, two articles deserve our attention. McAdams 8 analyzed 332 autopsies of infants less than 2
weeks of age. He .demonstrated a significant association between severe central nervous system injury and the occurrence of pulmonary hemorrhage. The ischemic central nervous system injury preceded the mortal event of pulmonary hemorrhage. Cole and associates9 have more recently reported their study of 12 infants with pulmonary hemorrhage. All infants had had a severe hypoxic insult. All had profound vasoconstriction and a severe metabolic acidosis at the time of the pulmonary hemorrhage. From ingenious analysis of the bloody tracheal fluid, they concluded that it was hemorrhagic edema rather than whole blood. They reasoned that left ventricular failure related to asphyxia increased the pulmonary capillary filtration pressure, resulting in hemorrhagic pulmonary edema. In summary, I think that this patient suffered from prolonged asphyxia during the Pitocin-augmented labor. The possibility of maternal diabetes would increase the infant's risk of intrapartum hypoxia. The prolonged fetal asphyxia resulted in severe shock, manifested after delivery by a low systolic blood pressure, elevated blood sugar, intense vasoconstriction, and a profound metabolic acidosis unresponsive to the administration of alkali. I think that the prolonged asphyxial state resulted in severe injury to the central nervous system which, as Sarnoff and Berglund 1~have demonstrated in dogs, led to an elevated left ventricular end diastolic pressure. Following the lead of Cole and her co-workers,9 1 think that the elevated left ventricular pressure increased the pulmonary capillary pressure, and that the increased capillary filtration pressure resulted in hemorrhagic pulmonary edema. If I am correct concerning the timing of the asphyxia, Dr. Altshuler will be able to show us early changes in the adrenal cortex, and perhaps in the- central nervous SYstem, that are consistent with shock. Given the currently available fetal monitoring techniques, I think that the initiating event of prolonged fetal asphyxia was preventable. A successful system for management of massive
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neonatal pulmonary hemorrhage has not yet been described, but volume expansion and possibly alpha adenergic blockade in this patient with vasomotor collapse would appear to have been more rational than the attempted diuresis.
Dr. Keenan's diagnoses S e v e r e perinatal a s p h y x i a Massive pulmonary hemorrhage P r o b a b l e i n f a n t o f a diabetic m o t h e r DR. ALTSHULER.Dr. Keenan has captured the essence of this case, namely, the elucidation of what can go wrong following uncontrolled administration of oxytocin. Dr. Barden, I wonder if, before I present'the pathologic findings, you would like to speak to this point. DR. TOM P. BARDEN.Review of obstetric literature pertaining to oxytocin reveals that uterine response is quite variable, and especially unpredictable when oxytocin is administered by the transbuccal route. Although most authors discuss the frequency of uterine hypertonus, the term is rarely defined and, with few exceptions, the studies have not used techniques for monitoring labor to quantitate uterine response to the drug. In one study, 12 which employed monitoring of amniotic fluid pressure, there was a wide range of sensitivity to buccal oxytocin. The authors concluded that buccal administration of oxytocin is a convenient method of inducing labor, but that it should be used only w h e n the patient is carefully supervised. In a report from Evanston Hospital, 13 of clinical experience with buccal administration of oxytocin in over 900 patients, 30% of primigravidas had labor lasting 3 hours or less versus only 5% incidence of brief labors in the control patients. The average length of spontaneous labor in untreated primigravidas is 10 to 12 hours. From such reports, as well as our own experience, I conclude that uterine overresponse to buccal administration of oxytocin is not uncommon. The fetal response and neonatal outcome of such accelerated labors is not well documented. It is clear that the emphasis must shift from providing a rapid and convenient labor for the mother, to providing the safest method of delivery for both the mother and the fetus, The evidence strongly suggests that use of buccal oxytocin is contrary to this goal. PATHOLOGICAL FINDINGS D~. GEOFFREYALTSHULER.This was a 4,140 gm infant whose crown-heel length was 59 cm. The placenta, when stripped of its membranes, blood clots, and umbilical cord, weighed 630 gin, which is considerably less heavy than the "approximately 3 pounds." recorded in the labor and delivery room. Gross and light microscopy examination did not reveal any evidence of meconium staining or infection. There was no decidual arteriopathy, an abnormality which may be seen in placentas of diabetic and pre-eclamptic mothers. The placenta did, however, include areas of villous capillary hyperplasia (Fig. 1). This "chorangiosis" has been associated with maternal diabetes. 14 There were no pathologic features of diabetes on examination of the infant. In particular, neither the pancreatic islets nor the adrenal glands were hyperplastic.
Fig. 2. Adrenal gland. Hemorrhagic necrosis is seen at the inferior aspect of the illustration in contrast to extravasation of red blood ceils throughout the adjacent sinusoids. Original magnification xl00. Hematoxylin and eosin. The adrenal glands contained occasional sinusoidal thrombi and early hemorrhagic necrosis (Fig. 2). In a retrospective study of 162 cases, Russell 15 has shown hemorrhagic necrosis and thrombi in the adrenal glands of 15% of adult patients who died with shock of various causes. From the results of this study he asserts that adrenal hemorrhage results from shock and is not a consequence of any specific disease process. Studies of adrenal hemorrhage in newborn infants are few, but I draw the same implication from the findings. Evidence of acute left ventricular failure in our patient included early centrilobular necrosis in the liver and anoxicischemic necrosis of occasional neurones in the arterial border zone of the cerebral cortex and in the hippocampus. Lindenberg 16 has described the role of temporary, sudden, and severe left ventricular failure in the genesis of these lesions. Recently, Brierley and associates17 have claimed that anoxic-ischemic neuronal change is the neuropathologic common denominator in all types of hypoxia be this associated with circulatory arrest, profound hypotension without hypoxemia, hypotension with hypoxemia, primary hypoxemia with secondary myocardial failure, pure hypoglygemia, carbon monoxide poisoning, cyanide poisoning, or status epilepticus. Brierley and associates t7 emphasize that ischemic cell change can be seen when
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Fig. 3. Lung. Blood and tissue debris is present within the bronchus in addition to severe hemorrhagic edema throughout the parenchyma. Original magnification • Hematoxylin and eosin. the interval between the hypoxic episode and death is only 5 to 6 hours. The most dramatic finding in the present autopsy was the gross observation of massive bilateral lung hemorrhage and hemorrhagic edema (Fig. 3). The combined weight of the lungs was 120 gin, which is almost one and three-quarters of that expected for an infant of this weight and length. Dr. Keenan has cited the work of Cole and associates, 9 who claimed that acute !eft ventricular failure of asphyxial origin is the most important contributory factor to pulmonary hemorrhage. Dr. Keenan has questioned whether there were also autopsy features of right ventricu!ar failure. Although the liver was not heavy (218 gm), it descended 7 cm beneath the costal margin. Twenty-five milliliters of clear fluid were Present in each thoracic cavity, and the ratio of the circumference of the pulmonic valve to that of the aortic valve was 1.22 (2.2 cm/1.8 cm). From Landing and Hughes' data of valve circumferences in newborn infants, we would expect this ratio to be 1.16.18 The combination of all of these findings, therefore, may be indicative ot" right-sided cardiac failure. DR. JEANNE BALLARD. Approximately 6 weeks after the death of her infant, the mother of this baby was shown to have a diabetic glucose tolerance test curve. DR. At.TSHULER.This emphasizes the value of placental examination. Other than for macrosomia, there were no autopsy features in this baby which might have suggested maternal diabetes. 'Dr. Silverman has stated that retarded skeletal maturation is commonly seen in infants of diabetic mothers. The point that we would emphasize is that placental villous capillary hyperplasia (chorangiosis) is additional evidence of that diagnosis. DR. KEE~AN.The large size for gestational age taken together
with the abnormal glucose tolerance test in the mother certainly convinces me that we are dealing with an infant of a diabetic mother. DR. BRUCE LIDSTON. Had this infant survived longer, what would have been his steroid status in relation to the adrenal lesions ? DR. ALTSHULER.As I indicated earlier, there is a lack of studies of adrenal hemorrhage in neonates. Black and Williams 19 have recently provided a review of the natural history of adrenal hemorrhage in the newborn infant. They state that in cases of unilateral adrenal hemorrhage, shock is due to blood loss, but that in cases of bilateral involvement, acute adrenal failure may occur. Some of their patients with bilateral adrenal hemorrhage survived without the use of corticosteroids. From biopsies taken at laparotomy, the authors have suggested that residual adrenal tissue accounted for the lack of acute adrenal failure.
Pathological diagnoses M a s s i v e l u n g h e m o r r h a g e , bilateral C e n t r i l o b u l a r n e c r o s i s o f t h e liver Focal h e m o r r h a g i c n e c r o s i s o f a d r e n a l g l a n d s Anoxic-ischemic neuronal necrosis R i g h t v e n t r i c u l a r dilatation, h e a r t REFERENCES 1.
Borrell U: Effect of uterine contractions of h u m a n uteroplacental blood circulation, A m J Obstet Gynecol 89:881, 1964. 2. Weingold AB, et al: Fetal heart rate response in the preeclamptic hypertensive patient during spontaneous and oxytocin stimulated labor, J Reprod Med 5:35, 1970.
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3. Greiss FC, and Anderson SG: Uterine blood flow during labor, Clin Obstet GynecoI 11:96, 1968. 4. Zuspan FP, et al: Induction of labor, J Reprod Med 6:2, 34, 1971. 5. Dillon TF, Douglas RG, and du Vigneaud V: Further observations on transbuccal administration of pitocin for induction and stimulation of labor, Obstet Gynecol 20:434, 1962. 6. Sjostedt S: Induction of labor, Acta Obstet Gynecol Scand 49(Suppl. 7): 1, 1969. 7. Chung HK: Use of buccal oxytocin in induction of labor in Chinese patients, Br Med J 1:710, 1966. 8. McAdams AJ: Pulmonary hemorrhage in the newborn, Am J Dis Child 113:255, 1967. 9. Cole VA, et al: Pathogenesis of hemorrhagic pulmonary edema and massive pulmonary hemorrhage in the newborn, Pediatrics 51:175, 1973. 10. SarnoffSJ, and Berglund E: Neurohemodynamics of pulmonary edema, Am J Physiol 170:588, 1952. 11. Coen RJ, and McAdams AJ: Visceral manifestation of shock in congenital heart disease, Am J Dis Child 119:383, 1970. 12. Newman JW, and Hon E: Induction of labor with transbuccal oxytocin, Obstet Gynecol 21:3, 1963.
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13. Claypool DR, Reeves BD, and McElin TW: Use of buccal pitocin for the elective induction of labor, Am J Obstet Gynecol 113:261, 1972. 14. Benirschke K, and.Driscoll SG: The pathology of the human Placenta, New York, 1967, Springer-Verlag, pp 390 and 458. 15. Russell P: The adrenal glands in shock, Pathology 4:5, 1972. 16. Lindenberg R: Patterns of CNS vulnerability in acute hypoxaemia, including anaesthesia accidents, in Schade JP, and McMenemey WH, editors: Selective vulnerability of' the brain in hypoxaemia, symposium, Oxford, 1963, Blackwell Scientific Publications, pp 189-209. 17. Brierley JB, et al: The threshold and neuropathology of cerebral "Anoxic-lschemic" cell change. Arch Neurol. 29:367, 1973. 18. Landing , BH, and Hughes, ML: Statistical analysis of pulmonary to aortic valve ring ratios in children, Lab Invest 11:372, 1962. 19. Black J, and Williams DI: Natural history of adrenal haemorrhage in-, the newborn, Arch Dis Child 48:183, 1973.
Massive pulmonary hemorrhage in a neonate William J. Keenan, M.D., and Geoffrey Altshuler, M.B., B.S.,** CincinnatL Ohio
T H E P AT I E N T was a 4,140 gm term white boy transferred to the Children's Hospital at 2 hours of age because of cyanosis, hepatomegaly, and a cardiac murmur. T h e m o t h e r was 27 years o f age, allegedly n o n diabetic, gravida 2, para 1; she described no problems with the current or previous pregnancy. The only medications taken during pregnancy were vitamins and iron. Buccal administration of Pitocin was used to induce labor; three doses were given. The total duration of labor and delivery was 8 hours. The m e m b r a n e s ruptured 4 hours prior to delivery. Although no fetal distress was noted, continuous fetal heart rate monitoring was not performed. The delivery was achieved with the application of low forceps. During labor and delivery the m o t h e r ' s t r e a t m e n t i n c l u d e d m e p e r i d i n e , prom e t h a z i n e , scopolamine, and spinal a n e s t h e s i a . T h e placenta was said to be very large, approximately 3 pounds; the Apgar scores were 7 and 9 at 1 and 5 minutes, respectively. The overall clinical status, however, was stated by the obstetrician to have seemed worse than the Apgar scores indicated. Immediately after the cord was clamped, the infant turned blue and remained cyanotic in 40% oxygen. In the nursery there were persistent generalized cyanosis and a heart murmur; the liver edge was palpable below the level of the umbilicus. Blood aspirated from the stomach was Apt test positive. Vitamin K was not given prior to transfer of the infant. The infant's condition rapidly deteriorated, and he required positive pressure ventilation with 100% oxygen during transit to this hospital. From the Departments o f Pediatrics and Pathology, the Cincinnati General Hospital and the CitJ'cinnati Children's Hospital, and the University o f Cincinnati Medical Center. *Sponsored by the Pediatric Pathology Club. **Supported in part by the Fels Division of Pediatric Research. Reprint address: Children's Hospital Medical Center, Department of Pathology, Cincinnati, Ohio 45229. Vol. 86, No. 3, pp. 466-471
Examination at 2 hours of age revealed an acutely ill, severely cyanotic newborn infant with gasping attempts at respiration. He was flaccid and minimally responsive, with no suck or Moro reflex. His head was normal; the anterior fontanel was fiat. The heart rate was regular at 160/rain.; there was no murmur. Bilateral chest rales were present. All pulses were markedly decreased initially. The liver edge was 5 to 6 cm below the right costal margin. There was mottling of the lowel extremities. There were no petechiae or ecchymoses. No congenital anomalies were noted. Bight red unclotted blood was aspirated from both the stomach and trachea. Initial laboratory data: Hemoglobin concentration 19.1 gm/dl; white blood cell count 23,500/mm3 with 27% polymorphonuclear leukocytes, 4% eosinophils, 60% lymphocytes, 9% mononuclear leukocytes, and adequate platelets. There were no burr cells or fragmentation of erythrocytes on the blood smear. Both mother and patient were blood type Rh positive. The Coombs' test was negative. Electrolyte and blood urea nitrogen values were normal, as was the urinalysis. The blood sugar concentration was 177 mg/dl (without parenteral fluids running), and the serum bilirubin concentration was 0 mg/dl. Initial blood gas values: pH 6.72, Pco 2 85 m m Hg and Po 2 34 m m Hg. Base excess was minus mEq/1. Within 30 minutes of arrival the patient had cathet e r i z a t i o n of t h e u m b i l i c a l vessels and u n d e r w e n t nasotracheal intubation for assisted ventilation. Furosemide, 5 rag, sodium bicarbonate, 5 mEq and digoxin, 80/xg, were given rapidly by intravenous infusion. A cardiology consultant felt that with a normal electrocardiogram and normal echocardiogram the diagnosis was m o s t likely p u l m o n a r y h e m o r r h a g e with m y o c a r d i a l failure secondary to acidosis and hypoxia. The infant was given 1 ml of Aquamephyton intramuscularly several hours after his arrival. Penicillin and gentamicin were administered after bacterial cultures h a d b e e n t a k e n . D e s p i t e n o r m a l i z a t i o n of values
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o f t h e P c o 2 a n d P o 2 by artificial ventilation, t h e p H did n o t rise a b o v e 6.8 with t h e a d m i n i s t r a t i o n o f s o d i u m bic a r b o n a t e a n d s u b s e q u e n t l y tris buffer. Systolic b l o o d p r e s s u r e m e a s u r e d by u m b i l i c a l artery line was 25 m m / Hg. T h e i n f a n t was g i v e n h u m a n s e r u m a l b u m i n int r a v e n o u s l y . T h e o n l y u r i n e o u t p u t was 2-3 ml. following m a n u a l c o m p r e s s i o n o f t h e bladder, in spite o f several d o s e s o f f u r o s e m i d e . The patient remained
flaccid a n d his l o w e r e x -
t r e m i t i e s w e r e p e r s i s t e n t l y m o t t l e d . N o p e t e c h i a e appeared. Bright red blood was repeatedly s u c t i o n e d f r o m his e n d o t r a c h e a l t u b e . A t 5 h o u r s o f age b l u r r cells w e r e noted on blood smear with a normal number
of
platelets a n d n o f r a g m e n t a t i o n o f e r y t h r o c y t e s . D e s p i t e all efforts at r e s u s c i t a t i o n , t h e i n f a n t was p r o n o u n c e d d e a d at 8 h o u r s o f age. DISCUSSION DR. WILLIAMJ. KEENAN.We are faced with the problems of an infant whose existence in utero is said to have been entirely uncomplicated and who is nonetheless dead 16 short hours from the time that labor first began. In such a case I cannot accept that labor and delivery were really uncomplicated. The initial diagnostic procedures were roentgenograms of the abdomen and chest; I would like to ask Dr. Silverman for his interpretations. DR. FREDERICK M. SILVERMAN. The first roentgenograms, taken in the nursery at the referring hospital, showed a relatively large thorax and a central mediastinal shadow of nondistinctive configuration with a somewhat prominent right atrial component. There was some congestion in, the lungs, with diffuse densities throughout the central portion that did not conform to the usual reticulogranular pattern of hyaline membrane disease, but resembled rather the pattern of "0ascular congestion and possible aspiration, perhaps even infedtion and/or hemorrhage within the lungs. The bones were not remarkable. There was no pneumothorax or pneumomediastinum. A relatively gas-free abdomen is evident in roentgenograms of the abdomen taken at the same time, except for a small amount of gas within the stomach. By 2 to 4 hours of age we usually see gas filling some of the small bowel loops, and this finding suggests that intestinal tract function was severely depressed. The possibility of fluid or hemorrhage in the abdomen certainly did exist. At 4 hours of age, when films were taken here, the lungs had become more opaque; they did not show the diffuse, fine, stippled appearance of black spots on a white background that is characteristic of hyaline membrane disease, but rather diffuse densities throughout the lungs with air bronchograms suggestive of either inflammatory reaction or hemorrhage, or both. An endotracheal tube was present, inserted a little too far; it was in the right main-stem bronchus, but apparently not obstructing the aeration of the left lung. Abdominal radiograms showed an umbilical venous catheter in place with its tip at the level of the diaphragm. An arterial cath-
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eter had its tip just barely at the junction of the hypogastric and common lilac arteries, a little lower than we usualty like to see it. At this time, at 4 hours of age, there was some gas in the small bowel, but it tended to be clustered in the central portion of the abdomen as seen when air-filled loops float on fluid in the peritoneal cavity and become pressed together. The rapid evolution of the lung disease is most suggestive of pulmonary hemorrhage or overwhelming sepsis, a condition often associated with pulmonary hemorrhage. The only other radiograph that was taken was a total "babygram" after the baby had die& this showed practically no aeration of the lungs, which had the same density as the liver. It was obvious also that the baby was very large, and that there was only a very minute ossification center at the distal end of the femur. In other words, the baby demonstrates retarded maturation but large size, features commonly observed in infants of diabetic mothers. DR. WILLIAM J. KEENAN. Mindful of the diagnostic and therapeutic problems that faced the clinician in this case, I will discuss the following two points: (1) the problems that presented in the delivery room and (2) the patient's diagnosis while he was cared for at this hospital. In dealing with the desperately ill, newly born infant in the delivery room, there are many problems, not all of which can be clarified by postmortem examination. Many of the enigmatic emergencies that take place in the delivery room occur when the infant has suffered blood loss that may or may not be apparent. Placenta previa, vasa previa, abruptio placentae, twin-to-twin transfusion, and cesarean section can each result in catastrophic fetal blood loss. The normal hemoglobin concentration in this infant does not exclude severe perinatal blood loss, but none of these conditions appears to fit the problem under discussion. Uncommonly, infants with overwhelming sepsis are seen in the delivery room. The history of a 3-pound placenta would make one suspicious of congenital syphilis or toxoplasmosis, but in the case of this sick patient I think that the placental weight probably was grossly overestimated, just as were the Apgar scores. Although the rapid downward course of this patient is consistent with some forms of perinatal sepsis, little else in the protocol supports this diagnosis. I would suggest that this infant probably suffered intrauterine asphyxia. The state of fetal oxygenation is critically dependent upon both adequate maternal and fetal perfusion of the placental exchange interface. An inverse relationship between uterine contraction and uterine blood flow has been well demonstrated, t During the course of normal labor a healthy fetus appears to tolerate this intermittent interruption of oxygen supply very well, but the already compromised fetus may become hypoxic. This intolerance is illustrated by the frequent occurrence of fetal distress during the labor of toxemic women. 2 It has been well demonstrated that the oxygenation of a fetus with normal reserve will be compromised whenever abnormal uterine dynamics reduce uterine blood flow even more than does normal labor. 3 The abnormal uterine dynamics can include an increase in resting tonus, abnormally frequent con-
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Fig. 1. Placenta. The villi feature congestion and a severe increase in the number of blood vessels; hence the term "chorangiosis." Original magnification x250. Hematoxylin and eosin. tractions, abnormally prolonged contractions, or any combination thereof. This labor was augmented with buccal Pitocin, i.e., tablets of synthetic Pitocin designed to be held in the buccal pouch and absorbed by the mucous membranes of the mouth. Used since the early 1960s, this form of Pitocin administration has been receiving considerable obstetric criticism in the 1970s.4 Studies of buccal administration Of Pitocin, while usually focusing upon efficiency rather than safety, have shown an incidence of undesirable uterine hyperactivity from less than 1% to 10%.5, 6 The incidence of fetal distress is as high as 21%.7 The most dangerous feature of buccal administration of Pitocin, however, is its widespread use for the stimulation of unmonitored labors. Significant and ominous degrees of fetal distress may occur. There is increasing agreement that every labor augmented by Pitocin requires the constant attendance of appropriately trained personnel, assisted by continuous monitoring of the inst0ntaneous fetal heart rate and of uterine contractions. I postulate that the patient we are now discussing suffered a prolonged period of severe hypoxia during a hypertonic labor. The infant's birth weight is above the ninetieth percentile for 40 weeks' gestation; given Dr. Silverman's observations that this patient was somewhat immature, there is the additional strong possibility of maternal diabetes, which would significantly increase the chances of fetal hypoxic compromise during labor. The description of a shocklike state in a newborn infant accompanied by large amounts of bloody tracheal fluid quite clearly indicates that this infant had massive pulmonary hemorrhage. The best therapeutic efforts appear to be of no avail in this condition. Massive pulmonary hemorrhage is a common problem, occurring in about 6-10% of autopsied newborn infants.8 Relevant to this patient, two articles deserve our attention. McAdams 8 analyzed 332 autopsies of infants less than 2
weeks of age. He .demonstrated a significant association between severe central nervous system injury and the occurrence of pulmonary hemorrhage. The ischemic central nervous system injury preceded the mortal event of pulmonary hemorrhage. Cole and associates9 have more recently reported their study of 12 infants with pulmonary hemorrhage. All infants had had a severe hypoxic insult. All had profound vasoconstriction and a severe metabolic acidosis at the time of the pulmonary hemorrhage. From ingenious analysis of the bloody tracheal fluid, they concluded that it was hemorrhagic edema rather than whole blood. They reasoned that left ventricular failure related to asphyxia increased the pulmonary capillary filtration pressure, resulting in hemorrhagic pulmonary edema. In summary, I think that this patient suffered from prolonged asphyxia during the Pitocin-augmented labor. The possibility of maternal diabetes would increase the infant's risk of intrapartum hypoxia. The prolonged fetal asphyxia resulted in severe shock, manifested after delivery by a low systolic blood pressure, elevated blood sugar, intense vasoconstriction, and a profound metabolic acidosis unresponsive to the administration of alkali. I think that the prolonged asphyxial state resulted in severe injury to the central nervous system which, as Sarnoff and Berglund 1~have demonstrated in dogs, led to an elevated left ventricular end diastolic pressure. Following the lead of Cole and her co-workers,9 1 think that the elevated left ventricular pressure increased the pulmonary capillary pressure, and that the increased capillary filtration pressure resulted in hemorrhagic pulmonary edema. If I am correct concerning the timing of the asphyxia, Dr. Altshuler will be able to show us early changes in the adrenal cortex, and perhaps in the- central nervous SYstem, that are consistent with shock. Given the currently available fetal monitoring techniques, I think that the initiating event of prolonged fetal asphyxia was preventable. A successful system for management of massive
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neonatal pulmonary hemorrhage has not yet been described, but volume expansion and possibly alpha adenergic blockade in this patient with vasomotor collapse would appear to have been more rational than the attempted diuresis.
Dr. Keenan's diagnoses S e v e r e perinatal a s p h y x i a Massive pulmonary hemorrhage P r o b a b l e i n f a n t o f a diabetic m o t h e r DR. ALTSHULER.Dr. Keenan has captured the essence of this case, namely, the elucidation of what can go wrong following uncontrolled administration of oxytocin. Dr. Barden, I wonder if, before I present'the pathologic findings, you would like to speak to this point. DR. TOM P. BARDEN.Review of obstetric literature pertaining to oxytocin reveals that uterine response is quite variable, and especially unpredictable when oxytocin is administered by the transbuccal route. Although most authors discuss the frequency of uterine hypertonus, the term is rarely defined and, with few exceptions, the studies have not used techniques for monitoring labor to quantitate uterine response to the drug. In one study, 12 which employed monitoring of amniotic fluid pressure, there was a wide range of sensitivity to buccal oxytocin. The authors concluded that buccal administration of oxytocin is a convenient method of inducing labor, but that it should be used only w h e n the patient is carefully supervised. In a report from Evanston Hospital, 13 of clinical experience with buccal administration of oxytocin in over 900 patients, 30% of primigravidas had labor lasting 3 hours or less versus only 5% incidence of brief labors in the control patients. The average length of spontaneous labor in untreated primigravidas is 10 to 12 hours. From such reports, as well as our own experience, I conclude that uterine overresponse to buccal administration of oxytocin is not uncommon. The fetal response and neonatal outcome of such accelerated labors is not well documented. It is clear that the emphasis must shift from providing a rapid and convenient labor for the mother, to providing the safest method of delivery for both the mother and the fetus, The evidence strongly suggests that use of buccal oxytocin is contrary to this goal. PATHOLOGICAL FINDINGS D~. GEOFFREYALTSHULER.This was a 4,140 gm infant whose crown-heel length was 59 cm. The placenta, when stripped of its membranes, blood clots, and umbilical cord, weighed 630 gin, which is considerably less heavy than the "approximately 3 pounds." recorded in the labor and delivery room. Gross and light microscopy examination did not reveal any evidence of meconium staining or infection. There was no decidual arteriopathy, an abnormality which may be seen in placentas of diabetic and pre-eclamptic mothers. The placenta did, however, include areas of villous capillary hyperplasia (Fig. 1). This "chorangiosis" has been associated with maternal diabetes. 14 There were no pathologic features of diabetes on examination of the infant. In particular, neither the pancreatic islets nor the adrenal glands were hyperplastic.
Fig. 2. Adrenal gland. Hemorrhagic necrosis is seen at the inferior aspect of the illustration in contrast to extravasation of red blood ceils throughout the adjacent sinusoids. Original magnification xl00. Hematoxylin and eosin. The adrenal glands contained occasional sinusoidal thrombi and early hemorrhagic necrosis (Fig. 2). In a retrospective study of 162 cases, Russell 15 has shown hemorrhagic necrosis and thrombi in the adrenal glands of 15% of adult patients who died with shock of various causes. From the results of this study he asserts that adrenal hemorrhage results from shock and is not a consequence of any specific disease process. Studies of adrenal hemorrhage in newborn infants are few, but I draw the same implication from the findings. Evidence of acute left ventricular failure in our patient included early centrilobular necrosis in the liver and anoxicischemic necrosis of occasional neurones in the arterial border zone of the cerebral cortex and in the hippocampus. Lindenberg 16 has described the role of temporary, sudden, and severe left ventricular failure in the genesis of these lesions. Recently, Brierley and associates17 have claimed that anoxic-ischemic neuronal change is the neuropathologic common denominator in all types of hypoxia be this associated with circulatory arrest, profound hypotension without hypoxemia, hypotension with hypoxemia, primary hypoxemia with secondary myocardial failure, pure hypoglygemia, carbon monoxide poisoning, cyanide poisoning, or status epilepticus. Brierley and associates t7 emphasize that ischemic cell change can be seen when
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Fig. 3. Lung. Blood and tissue debris is present within the bronchus in addition to severe hemorrhagic edema throughout the parenchyma. Original magnification • Hematoxylin and eosin. the interval between the hypoxic episode and death is only 5 to 6 hours. The most dramatic finding in the present autopsy was the gross observation of massive bilateral lung hemorrhage and hemorrhagic edema (Fig. 3). The combined weight of the lungs was 120 gin, which is almost one and three-quarters of that expected for an infant of this weight and length. Dr. Keenan has cited the work of Cole and associates, 9 who claimed that acute !eft ventricular failure of asphyxial origin is the most important contributory factor to pulmonary hemorrhage. Dr. Keenan has questioned whether there were also autopsy features of right ventricu!ar failure. Although the liver was not heavy (218 gm), it descended 7 cm beneath the costal margin. Twenty-five milliliters of clear fluid were Present in each thoracic cavity, and the ratio of the circumference of the pulmonic valve to that of the aortic valve was 1.22 (2.2 cm/1.8 cm). From Landing and Hughes' data of valve circumferences in newborn infants, we would expect this ratio to be 1.16.18 The combination of all of these findings, therefore, may be indicative ot" right-sided cardiac failure. DR. JEANNE BALLARD. Approximately 6 weeks after the death of her infant, the mother of this baby was shown to have a diabetic glucose tolerance test curve. DR. At.TSHULER.This emphasizes the value of placental examination. Other than for macrosomia, there were no autopsy features in this baby which might have suggested maternal diabetes. 'Dr. Silverman has stated that retarded skeletal maturation is commonly seen in infants of diabetic mothers. The point that we would emphasize is that placental villous capillary hyperplasia (chorangiosis) is additional evidence of that diagnosis. DR. KEE~AN.The large size for gestational age taken together
with the abnormal glucose tolerance test in the mother certainly convinces me that we are dealing with an infant of a diabetic mother. DR. BRUCE LIDSTON. Had this infant survived longer, what would have been his steroid status in relation to the adrenal lesions ? DR. ALTSHULER.As I indicated earlier, there is a lack of studies of adrenal hemorrhage in neonates. Black and Williams 19 have recently provided a review of the natural history of adrenal hemorrhage in the newborn infant. They state that in cases of unilateral adrenal hemorrhage, shock is due to blood loss, but that in cases of bilateral involvement, acute adrenal failure may occur. Some of their patients with bilateral adrenal hemorrhage survived without the use of corticosteroids. From biopsies taken at laparotomy, the authors have suggested that residual adrenal tissue accounted for the lack of acute adrenal failure.
Pathological diagnoses M a s s i v e l u n g h e m o r r h a g e , bilateral C e n t r i l o b u l a r n e c r o s i s o f t h e liver Focal h e m o r r h a g i c n e c r o s i s o f a d r e n a l g l a n d s Anoxic-ischemic neuronal necrosis R i g h t v e n t r i c u l a r dilatation, h e a r t REFERENCES 1.
Borrell U: Effect of uterine contractions of h u m a n uteroplacental blood circulation, A m J Obstet Gynecol 89:881, 1964. 2. Weingold AB, et al: Fetal heart rate response in the preeclamptic hypertensive patient during spontaneous and oxytocin stimulated labor, J Reprod Med 5:35, 1970.
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3. Greiss FC, and Anderson SG: Uterine blood flow during labor, Clin Obstet GynecoI 11:96, 1968. 4. Zuspan FP, et al: Induction of labor, J Reprod Med 6:2, 34, 1971. 5. Dillon TF, Douglas RG, and du Vigneaud V: Further observations on transbuccal administration of pitocin for induction and stimulation of labor, Obstet Gynecol 20:434, 1962. 6. Sjostedt S: Induction of labor, Acta Obstet Gynecol Scand 49(Suppl. 7): 1, 1969. 7. Chung HK: Use of buccal oxytocin in induction of labor in Chinese patients, Br Med J 1:710, 1966. 8. McAdams AJ: Pulmonary hemorrhage in the newborn, Am J Dis Child 113:255, 1967. 9. Cole VA, et al: Pathogenesis of hemorrhagic pulmonary edema and massive pulmonary hemorrhage in the newborn, Pediatrics 51:175, 1973. 10. SarnoffSJ, and Berglund E: Neurohemodynamics of pulmonary edema, Am J Physiol 170:588, 1952. 11. Coen RJ, and McAdams AJ: Visceral manifestation of shock in congenital heart disease, Am J Dis Child 119:383, 1970. 12. Newman JW, and Hon E: Induction of labor with transbuccal oxytocin, Obstet Gynecol 21:3, 1963.
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13. Claypool DR, Reeves BD, and McElin TW: Use of buccal pitocin for the elective induction of labor, Am J Obstet Gynecol 113:261, 1972. 14. Benirschke K, and.Driscoll SG: The pathology of the human Placenta, New York, 1967, Springer-Verlag, pp 390 and 458. 15. Russell P: The adrenal glands in shock, Pathology 4:5, 1972. 16. Lindenberg R: Patterns of CNS vulnerability in acute hypoxaemia, including anaesthesia accidents, in Schade JP, and McMenemey WH, editors: Selective vulnerability of' the brain in hypoxaemia, symposium, Oxford, 1963, Blackwell Scientific Publications, pp 189-209. 17. Brierley JB, et al: The threshold and neuropathology of cerebral "Anoxic-lschemic" cell change. Arch Neurol. 29:367, 1973. 18. Landing , BH, and Hughes, ML: Statistical analysis of pulmonary to aortic valve ring ratios in children, Lab Invest 11:372, 1962. 19. Black J, and Williams DI: Natural history of adrenal haemorrhage in-, the newborn, Arch Dis Child 48:183, 1973.
