Massive pulmonary hemorrhage in neonatal infection C.Y. Yeung,* mb, frcp(edin), frcp[c], Of 35 newborn infants who died from an infection 19 had postmortem evidence of massive pulmonary hemorrhage. All but 1 of the 19 had evidence of antemortem formation of intravascular fibrin clots in lung tissue. Seventeen infants had low platelet counts. Of the 11 infants in whom coagulation studies were done, 8 had evidence of disseminated intravascular coagulation (DIC) during life. Vasculitis in the lungs, associated with fibrin clots and hemorrhages, was detected in two infants. It is postulated that sepsis is an important cause of hemorrhage in the newborn, probably as a result of the development of DIC. Sur 35 nouveau-nes qui sont morts d'une infection 19 d'entre eux avaient des preuves postmortem d'une
hemorragie pulmonaire
massive. Tous les 19, sauf 1, avaient des signes de formation antemortem
de caillots de fibrine intravasculaire dans les tissus pulmonaires. Chez 17 avait note une deficience plaquettaire. Des 11 nouveau-nes ayant subi les epreuves de la coagulation 8 avaient des signes de coagulation intravasculaire disseminee (CID) durant la vie. Chez deux nourrissons on a decele une inflammation vasculaire des poumons, accompagnee de caillots de fibrine et d'hemorragie. On estime que nouveau-nes on
I'infection est une cause importante de I'hemorragie pulmonaire chez le nouveau-ne, dont le point de depart probable est la presence de la CID.
dch
Massive
pulmonary hemorrhage is a postmortem finding in new¬ born infants. It has been reported to occur in 0.7 to 3.8 per 1000 live births.12 The pathogenesis has not been clearly established and many conditions have been found to be associated. Its occurrence in a group of hypoxic immature infants has led Cole and col¬ leagues3 to hypothesize that acute left heart failure causes the hemorrhagic edema. However, this theory does not explain its occurrence in association with other conditions. The large number of infants admit¬ ted to our hospital with proven sepsis permitted this study correlating the definitive postmortem diagnosis of pulmonary hemorrhage with the clin¬ ical, microbiologic and hematologic features of the infected infants during life. In addition, the pathogenesis of the massive pulmonary hemorrhage was sought. common
Patients and methods
percentile in weight). Bleeding into organs other than the lungs was noted in 14. Results of hematologic studies done within 36 hours before death are shown in Table II. Eight infants showed fea¬ tures of disseminated intravascular co¬ agulation (DIC), with a low platelet count « 50 x 107/), abnormal PT and KPTT and low fibrinogen titre.7,8 Sixteen of the 19 infants also showed leukocyte changes compatible with those in infection.9 A further eight in¬ fants who did not show evidence of
pulmonary hemorrhage had a full hematologic work-up and only one had features of DIC. Antemortem fibrin clots were dem¬ onstrable in the lung sections of all but 1 (no. 3) of the 19 infants. Two illustrative case reports follow. Patient 11 This girl was born at term after 30 hours of labour, weighing 3400 g. She had an Apgar score of 2 at 1 minute and required resuscitation with positive pres¬ sure ventilation and oxygen for 1 hour before spontaneous respiration started. She remained limp and lethargic afterwards in 40% oxygen. Hemorrhage began in the mother immediately after labour and her temperature was 38.9°C. Mother and baby were referred to our hospital when the in¬ fant was 14 hours old. The infant was then hypothermic (rectal temperature, 34 °C) and hypoglycemic (blood glucose value, 20 mg/dl). She had
Thirty-five critically ill infants who subsequently died in the neonatal ward of Paediatric B Unit of Queen Eliza¬ beth Hospital, Hong Kong were studied. During life all had clinical features and subsequent bacteriologic confirmation of infection. Investiga¬ tions included complete blood count (in 11 infants), superficial and deep cul¬ tures, and examination of gastric aspir¬ ate. Lumbar puncture was avoided in bradycardia, peripheral vasoconstriction bilateral chest crepitations. Her abdo¬ patients with bleeding diathesis. Coagu¬ and men was distended with gas and bowel lation studies,4 including measurement sounds diminished. An endotracheal of prothrombin time (PT), kaolin par¬ lube waswere inserted and she was given posi¬ tial thromboplastin time (KPTT) and tive pressure ventilation. She was placed fibrinogen titre (FT), were done in 11 in a servocontrol isolette and given intra¬ infants with paired control specimens venous infusion of glucose and transfusion from healthy term infants. Postmortem of fresh blood. At 18 hours she started to pass fre¬ examination was performed in all in¬ fants. Sections of the lung were stained quently meconium with blood and mucus. for antemortem fibrin with Martius- By this time her body temperature and blood glucose value were normal and Scarlet blue (MSB).5 shock had been partially corrected. She given gentamicin and ampicillin but died at 22 hours. Initial hematologic studies showed the following values: hemoglobin, 12.3 g/dl; leukocyte count, 4.6 x 109// (neutrophils, 0.8 x 109//); platelet count, 26 x 109//; PT, 85 seconds (control, 42 seconds); KPTT, 120 seconds (control, 42 seconds); fibrinogen titre, < 1/27. These features were compatible with those of DIC and severe sepsis. Cultures of blood collected on admission and immediately after death yielded Klebsiella. Postmortem examination showed fea¬ tures of necrotizing enterocolitis with puwas
Unit, Queen Elizabeth Hospital, Hong Kong This work was presented in part at the annual meeting of the Canadian Paediatric Society at Quebec, June 23 to 27, 1973. ?Formerly pediatric specialist and head, Paediatric B Unit, Queen Elizabeth Hospital, Hong Kong; currently assistant professor, department of pediatrics, McMaster University Medical Centre, Hamilton Reprint requests to: Dr. C.Y. Yeung, Department of pediatrics, McMaster University Medical Centre, 1200 Main St. W, Hamilton, From Paediatric B
ON L8S 4J9
Results Massive pulmonary hemorrhage, de¬ fined as confluent hemorrhages in more than two lobes of the lung,6 was de¬ monstrated in 19 of the 35 infants at postmortem examination. The clinical features and other important postmor¬ tem findings in the 19 infants are shown in Table I. Only two infants (nos. 7 and 8) were born prematurely (before 37 weeks) and only one (no. 6) was "small for dates" (below the 3rd
CMA JOURNAL/IANUARY 24, 1976/VOL. 114 135
Table I.Clinical and postmortem features of 19 infants with infection and massive Patient Other bleeding Age at no.
Sex
death
Infection
Organism
sites
pulmonary hemorrhage
Remarks Mother had puerperal fever. Evidence of aspiration Umbilical vein filled with pus evidence of pneumonia. Evidence of vasculitis Histologic in lung Purulent peritonitis, necrotizing enterocolitis Mongolism; small for dates Immature, hyaline membrane disease. Evidence of vasculitis in lung Immature, hyaline membrane disease Peritonitis, necrotizing enterocolitis
Necrotizing enterocolitis, peritonitis Necrotizing enterocolitis, peritonitis Kernicterus, G6PD deficiency Umbilical vein filled with pus Unilateral pulmonary hemorrhage, associated pneumothorax Mongolism Meningitis
Minute abscesses in liver PS= puncture sites; SD= subdural space; IC= intracerebral ;SA= subarachnoid ;GI
Table II.Hematologic abnormalities of infants with infection and massive
pulmonary hemorrhage
?Prothrombin time: range in patients, 17 to 120 seconds; range in controls, 12 to 14 seconds. fKaolin partial thromboplastin time: range in pa¬ tients, 90 to > 120 seconds; range in controls, 30 to 46 seconds. fin patients, < 1/27;in controls, > 1/81. rulent peritonitis. Culture of material from the peritoneal cavity yielded Klebsiella. Massive hemorrhage was evident in both lungs, and the lung sections showed evid¬ ence of antemortem fibrin clots (Fig. 1). Patient 7 This boy
born by assisted breech weeks, weighing 1900 g. Severe hyaline membrane disease with recurrent apnea developed. He was ad¬ mitted to hospital at 4 hours of age and was immediately given positive pressure ventilation with 60% oxygen. His spleen was enlarged to 2 cm below the left costal margin. He was given antibio¬ tics after initial laboratory investigations had been completed. Four hours after his admission many petechiae in the lower limbs and fairly profuse bleeding from puncture sites (heel-prick and venipunc-
delivery
was
at 35
=
Mongolism gastrointestinal tract; IV= intraventricular.
ture) were noticed. Coagulation studies could not be performed because the blood obtained was hypercoagulable. His platelet 6 x 109//. count was very low His condition suddenly deteriorated when he was 12 hours old and copious fresh blood was suctioned from the endotracheal tube. Transfusion of fresh blood was given instead of the planned exchange transfusion. He died at the age of 26 hours. Cultures of blood collected on admis¬ sion and immediately after death yielded Escherichia coli. Postmortem examination showed evid¬ ence of hyaline membrane disease and massive pulmonary hemorrhage. Lung sections showed evidence of antemortem intravascular clots and vasculitis (Fig. 2). Other findings were subarachnoid and bilateral adrenal hemorrhages, purulent esophagitis, and small abscesses on the diaphragmatic and serosal surfaces of the liver.
pulmonary hemorrhage was the result hemorrhagic edema produced by acute left heart failure following as¬ phyxia at birth. In their series most of of
Discussion Massive pulmonary hemorrhage in the newborn occurs predominantly in infants of low birth weight and is as¬ sociated with many conditions that occur commonly in these infants, such as hyaline membrane disease,1'10 peri¬ natal hypoxia,3 intrauterine growth re¬
tardation,2,10 kernicterus,11 hypother¬ mia,12 aspiration13 and infection.11'14 The increasing use of oxygen in the management of small infants in years has led
toxicity
as
some
a
cause.15 However, the
production of the pul¬ hemorrhage in infants with
mechanism of monary
recent to consider oxygen
these conditions has not been estab¬ lished. Cole and colleagues3 recently ac¬ quired indirect evidence that massive
136 CMA JOURNAL/JANUARY 24, 1976/VOL. 114
FIG. 1.Evidence of antemortem intravascular formation of fibrin clots in lung: bright red intravascular matrix in centre of figure. Associated intra-alveolar hemorrhage (Martius-Scarlet blue [MSB]; x200).
the infants weighed less than 2500 g and more than half died before 2 days of age. Birth asphyxia may well be an important factor in fatal illnesses in these infants but this mechanism does not explain the occurrence of massive pulmonary hemorrhage in all the infants in the present study: 16 of the 19 infants were not immature, low in weight or small for dates, and birth asphyxia was a feature only in 8 (nos. 1, 2, 5, 7, 8, 11, 15 and 18). Peripheral circulatory collapse was frequent among the 19 infants. It is possible that the state of shock of these patients could have resulted in acute tissue hypoxia, which might in turn have precipitated acute left heart failure, leading to hemorrhagic pulmonary edema. However, this does not explain the antemortem clots in the lungs of these infants, for intravascular coagulation is not a feature of acute left heart failure in hypoxic infants.3 The occurrence of sepsis and massive pulmonary hemorrhage in three infants with mongolism (nos. 6, 16 and 19) probably reflects the general attitude in this community towards routine neonatal care for infants with mongolism; many with infections are probably left untreated. Pulmonary hemorrhage, therefore, should not be regarded as causally related to mongolism. In the four infants with evidence of necrotizing enterocolitis (nos. 5, 9, 10 and 11) antemortem formation of fibrin clots was deduced from findings in their lung sections. This strongly sug-
gests DIG as the cause of the necrotizing enterocolitis. Only 9 of the 19 infants with postmortem evidence of massive pulmonary hemorrhage showed evidence of bleeding from the lung during life (Table II). Because there are no pathognomonic laboratory or radiologic signs of the condition1 its diagnosis may be missed in surviving infants. The low platelet counts and abnormal results of coagulation studies (Table II) indicate that most of these infants had DIG during life.16 The demonstration of antemortem fibrin clots in the lung sections confirms this suspicion in all but one of these infants. The further finding of inflammation of the medium-sized vessels of the lung in two infants indicates that the vascular tree was involved by the infective process. All these features suggest a possible mechanism of production of pulmonary hemorrhage as a complication of infection in the newborn infant. The infection probably causes DIG either by directly injuring blood vessels, producing localized vasculitis, or by damaging the endothelium with the endotoxin of the infective organism.16'17 The DIG so produced may lead to a generalized hemorrhagic diathesis. Because the lung is an extremely vascular organ, the shearing and stretching of its tissue by respiratory movements will increase the chances of the damaged vessels rupturing. This may explain the frequent occurrence of pulmonary hemorrhage in these infected infants. Alternatively,
'Wi
El
/
a a 'p
infection might produce severe shock, resulting in acute hypoxia, which might precipitate acute left ventricular failure, leading to pulmonary edema, as some have suggested.3'18'19 This theory, however, is not supported by the finding of intravascular fibrin clots in this study. Even though massive pulmonary hemorrhage may not always be the result of infection, the finding that all but one infant in this series had evidence of antemortem intravascular formation of fibrin clots suggests that evidence of DIC should be sought during life in all newborn infants with suspected pulmonary hemorrhage. The results of this study also emphasize the importance of monitoring the hematologic changes and the coagulation status of infants with severe sepsis. I am grateful to all my resident staff of the Paediatric B Unit for their valuable assistance in this study. I also thank the staff of the institute of pathology of Queen Elizabeth Hospital for their help, particularly Dr. Susan Leong for arranging the lung sections, and Mr. T.S. Cheung for help with the coagulation studies. References 1. AVERY ME: The lung and its disorders in the newborn infant, second ed, Philadelphia, Saunders, 1968, p 253 2. BUTLER NR, BONHAM DO: Perinatal mortality, London, Churchill Livingstone, 1963, p 263 3. COLE VA, NORMAND ICS, REYNOLDS HOR, et al: Pathogenesis of hemorrhagic pulmonary edema and massive pulmonary hemorrhage in the newborn. Pediatrics 51: 175, 1973 4. HARDIsTY RM, INGRAM GIC: Bleeding disorders: Investigations and Management, Oxford, Blackwell Sci PubI, 1965 5. LENDRUM AC, FRASER DS, SLmDERs W, et al: Studies on the character and staining of fibrin. I Clin Pathol 15: 401, 1962 6. EsmitLy JR, OPPENHEIMER EH: Massive pulmonary hemorrhage in the newborn. I. Pathologic considerations. I Pedtatr 69: 3, 1966 7. ABILDGAARD CF: Recognition and treatment of intravascular coagulation. J Pediatr 74: 163, 1969 8. LAscAsu AD, WALLACE PD: Disseminated intravascular coagulation in newborns. Clin Pediatr (Phila) 10: 11, 1971 9. XANTHOU M: Leucocyte blood picture in ili newborn babies. Arch Dis Child 47: 741, 1972 10. Rowa 5, AVERY ME: Massive pulmonary hemorrhage in the newborn. II. Clinical considerations. I Pediatr 69: 12, 1966 11. AHYENAINEN EK, CALL JD: Pulmonary hemorrhage in infants. A descriptive study. Am I Pathol 28: 1, 1952 12. MANN TP, ELLuYr RIK: Neonatal cold injury due to accidental exposure to cold. Lancet 1: 229, 1957 13. CEBALLOs R: Aspiration of maternal blood in the etiology of massive pulmonary hemorrhage in the newborn infant. J Pedtatr 72: 390, 1968 14. LANDING BH: Pulmonary lesions of newborn infants. A statistical study. Pediatrics 18: 217, 1957 15. BoornaY CB, DESA DJ: Massive pulmonary hemorrhage in the newborn. A changing pat-
tern. Arch Dis Child 48: 21, 1973 16. CORRIGAN JJ, WAsicxR RI, MAY N: Changes in the blood coagulation system associated with septicemia. N Engl J Med 279: 851, 1968
17. ALEBOYEH M, REMIF,N A, MARGET W: Incidence of disseminated intravascular coagulation in the course of septicemia in newborn infants. Z Kinderheilkd 109: 326, 1971 18. DOWNING
SE,
TALNER
NS,
GARDNER
TH:
Ventricular function in the newborn lamb.
FIG. 2-Evidence of inflammation (vasculitis) of medium-sized and small vessels in lung adjacent to artery (MSB: x950). 138 CMA JOURNAL/JANUARY 24, 1976/VOL. 114
Am I Physiol 208: 931, 1965 19. ADAMSON TM, BOYD RCH, HILL JR, et al: Effect of asphyxia due to umbilical cord occlusion in the fetal lamb on leakage of liquid from the circulation and on permeability of lung capillaries to albumin. I Physiol 207: 493, 1970
hemorragie pulmonaire
massive. Tous les 19, sauf 1, avaient des signes de formation antemortem
de caillots de fibrine intravasculaire dans les tissus pulmonaires. Chez 17 avait note une deficience plaquettaire. Des 11 nouveau-nes ayant subi les epreuves de la coagulation 8 avaient des signes de coagulation intravasculaire disseminee (CID) durant la vie. Chez deux nourrissons on a decele une inflammation vasculaire des poumons, accompagnee de caillots de fibrine et d'hemorragie. On estime que nouveau-nes on
I'infection est une cause importante de I'hemorragie pulmonaire chez le nouveau-ne, dont le point de depart probable est la presence de la CID.
dch
Massive
pulmonary hemorrhage is a postmortem finding in new¬ born infants. It has been reported to occur in 0.7 to 3.8 per 1000 live births.12 The pathogenesis has not been clearly established and many conditions have been found to be associated. Its occurrence in a group of hypoxic immature infants has led Cole and col¬ leagues3 to hypothesize that acute left heart failure causes the hemorrhagic edema. However, this theory does not explain its occurrence in association with other conditions. The large number of infants admit¬ ted to our hospital with proven sepsis permitted this study correlating the definitive postmortem diagnosis of pulmonary hemorrhage with the clin¬ ical, microbiologic and hematologic features of the infected infants during life. In addition, the pathogenesis of the massive pulmonary hemorrhage was sought. common
Patients and methods
percentile in weight). Bleeding into organs other than the lungs was noted in 14. Results of hematologic studies done within 36 hours before death are shown in Table II. Eight infants showed fea¬ tures of disseminated intravascular co¬ agulation (DIC), with a low platelet count « 50 x 107/), abnormal PT and KPTT and low fibrinogen titre.7,8 Sixteen of the 19 infants also showed leukocyte changes compatible with those in infection.9 A further eight in¬ fants who did not show evidence of
pulmonary hemorrhage had a full hematologic work-up and only one had features of DIC. Antemortem fibrin clots were dem¬ onstrable in the lung sections of all but 1 (no. 3) of the 19 infants. Two illustrative case reports follow. Patient 11 This girl was born at term after 30 hours of labour, weighing 3400 g. She had an Apgar score of 2 at 1 minute and required resuscitation with positive pres¬ sure ventilation and oxygen for 1 hour before spontaneous respiration started. She remained limp and lethargic afterwards in 40% oxygen. Hemorrhage began in the mother immediately after labour and her temperature was 38.9°C. Mother and baby were referred to our hospital when the in¬ fant was 14 hours old. The infant was then hypothermic (rectal temperature, 34 °C) and hypoglycemic (blood glucose value, 20 mg/dl). She had
Thirty-five critically ill infants who subsequently died in the neonatal ward of Paediatric B Unit of Queen Eliza¬ beth Hospital, Hong Kong were studied. During life all had clinical features and subsequent bacteriologic confirmation of infection. Investiga¬ tions included complete blood count (in 11 infants), superficial and deep cul¬ tures, and examination of gastric aspir¬ ate. Lumbar puncture was avoided in bradycardia, peripheral vasoconstriction bilateral chest crepitations. Her abdo¬ patients with bleeding diathesis. Coagu¬ and men was distended with gas and bowel lation studies,4 including measurement sounds diminished. An endotracheal of prothrombin time (PT), kaolin par¬ lube waswere inserted and she was given posi¬ tial thromboplastin time (KPTT) and tive pressure ventilation. She was placed fibrinogen titre (FT), were done in 11 in a servocontrol isolette and given intra¬ infants with paired control specimens venous infusion of glucose and transfusion from healthy term infants. Postmortem of fresh blood. At 18 hours she started to pass fre¬ examination was performed in all in¬ fants. Sections of the lung were stained quently meconium with blood and mucus. for antemortem fibrin with Martius- By this time her body temperature and blood glucose value were normal and Scarlet blue (MSB).5 shock had been partially corrected. She given gentamicin and ampicillin but died at 22 hours. Initial hematologic studies showed the following values: hemoglobin, 12.3 g/dl; leukocyte count, 4.6 x 109// (neutrophils, 0.8 x 109//); platelet count, 26 x 109//; PT, 85 seconds (control, 42 seconds); KPTT, 120 seconds (control, 42 seconds); fibrinogen titre, < 1/27. These features were compatible with those of DIC and severe sepsis. Cultures of blood collected on admission and immediately after death yielded Klebsiella. Postmortem examination showed fea¬ tures of necrotizing enterocolitis with puwas
Unit, Queen Elizabeth Hospital, Hong Kong This work was presented in part at the annual meeting of the Canadian Paediatric Society at Quebec, June 23 to 27, 1973. ?Formerly pediatric specialist and head, Paediatric B Unit, Queen Elizabeth Hospital, Hong Kong; currently assistant professor, department of pediatrics, McMaster University Medical Centre, Hamilton Reprint requests to: Dr. C.Y. Yeung, Department of pediatrics, McMaster University Medical Centre, 1200 Main St. W, Hamilton, From Paediatric B
ON L8S 4J9
Results Massive pulmonary hemorrhage, de¬ fined as confluent hemorrhages in more than two lobes of the lung,6 was de¬ monstrated in 19 of the 35 infants at postmortem examination. The clinical features and other important postmor¬ tem findings in the 19 infants are shown in Table I. Only two infants (nos. 7 and 8) were born prematurely (before 37 weeks) and only one (no. 6) was "small for dates" (below the 3rd
CMA JOURNAL/IANUARY 24, 1976/VOL. 114 135
Table I.Clinical and postmortem features of 19 infants with infection and massive Patient Other bleeding Age at no.
Sex
death
Infection
Organism
sites
pulmonary hemorrhage
Remarks Mother had puerperal fever. Evidence of aspiration Umbilical vein filled with pus evidence of pneumonia. Evidence of vasculitis Histologic in lung Purulent peritonitis, necrotizing enterocolitis Mongolism; small for dates Immature, hyaline membrane disease. Evidence of vasculitis in lung Immature, hyaline membrane disease Peritonitis, necrotizing enterocolitis
Necrotizing enterocolitis, peritonitis Necrotizing enterocolitis, peritonitis Kernicterus, G6PD deficiency Umbilical vein filled with pus Unilateral pulmonary hemorrhage, associated pneumothorax Mongolism Meningitis
Minute abscesses in liver PS= puncture sites; SD= subdural space; IC= intracerebral ;SA= subarachnoid ;GI
Table II.Hematologic abnormalities of infants with infection and massive
pulmonary hemorrhage
?Prothrombin time: range in patients, 17 to 120 seconds; range in controls, 12 to 14 seconds. fKaolin partial thromboplastin time: range in pa¬ tients, 90 to > 120 seconds; range in controls, 30 to 46 seconds. fin patients, < 1/27;in controls, > 1/81. rulent peritonitis. Culture of material from the peritoneal cavity yielded Klebsiella. Massive hemorrhage was evident in both lungs, and the lung sections showed evid¬ ence of antemortem fibrin clots (Fig. 1). Patient 7 This boy
born by assisted breech weeks, weighing 1900 g. Severe hyaline membrane disease with recurrent apnea developed. He was ad¬ mitted to hospital at 4 hours of age and was immediately given positive pressure ventilation with 60% oxygen. His spleen was enlarged to 2 cm below the left costal margin. He was given antibio¬ tics after initial laboratory investigations had been completed. Four hours after his admission many petechiae in the lower limbs and fairly profuse bleeding from puncture sites (heel-prick and venipunc-
delivery
was
at 35
=
Mongolism gastrointestinal tract; IV= intraventricular.
ture) were noticed. Coagulation studies could not be performed because the blood obtained was hypercoagulable. His platelet 6 x 109//. count was very low His condition suddenly deteriorated when he was 12 hours old and copious fresh blood was suctioned from the endotracheal tube. Transfusion of fresh blood was given instead of the planned exchange transfusion. He died at the age of 26 hours. Cultures of blood collected on admis¬ sion and immediately after death yielded Escherichia coli. Postmortem examination showed evid¬ ence of hyaline membrane disease and massive pulmonary hemorrhage. Lung sections showed evidence of antemortem intravascular clots and vasculitis (Fig. 2). Other findings were subarachnoid and bilateral adrenal hemorrhages, purulent esophagitis, and small abscesses on the diaphragmatic and serosal surfaces of the liver.
pulmonary hemorrhage was the result hemorrhagic edema produced by acute left heart failure following as¬ phyxia at birth. In their series most of of
Discussion Massive pulmonary hemorrhage in the newborn occurs predominantly in infants of low birth weight and is as¬ sociated with many conditions that occur commonly in these infants, such as hyaline membrane disease,1'10 peri¬ natal hypoxia,3 intrauterine growth re¬
tardation,2,10 kernicterus,11 hypother¬ mia,12 aspiration13 and infection.11'14 The increasing use of oxygen in the management of small infants in years has led
toxicity
as
some
a
cause.15 However, the
production of the pul¬ hemorrhage in infants with
mechanism of monary
recent to consider oxygen
these conditions has not been estab¬ lished. Cole and colleagues3 recently ac¬ quired indirect evidence that massive
136 CMA JOURNAL/JANUARY 24, 1976/VOL. 114
FIG. 1.Evidence of antemortem intravascular formation of fibrin clots in lung: bright red intravascular matrix in centre of figure. Associated intra-alveolar hemorrhage (Martius-Scarlet blue [MSB]; x200).
the infants weighed less than 2500 g and more than half died before 2 days of age. Birth asphyxia may well be an important factor in fatal illnesses in these infants but this mechanism does not explain the occurrence of massive pulmonary hemorrhage in all the infants in the present study: 16 of the 19 infants were not immature, low in weight or small for dates, and birth asphyxia was a feature only in 8 (nos. 1, 2, 5, 7, 8, 11, 15 and 18). Peripheral circulatory collapse was frequent among the 19 infants. It is possible that the state of shock of these patients could have resulted in acute tissue hypoxia, which might in turn have precipitated acute left heart failure, leading to hemorrhagic pulmonary edema. However, this does not explain the antemortem clots in the lungs of these infants, for intravascular coagulation is not a feature of acute left heart failure in hypoxic infants.3 The occurrence of sepsis and massive pulmonary hemorrhage in three infants with mongolism (nos. 6, 16 and 19) probably reflects the general attitude in this community towards routine neonatal care for infants with mongolism; many with infections are probably left untreated. Pulmonary hemorrhage, therefore, should not be regarded as causally related to mongolism. In the four infants with evidence of necrotizing enterocolitis (nos. 5, 9, 10 and 11) antemortem formation of fibrin clots was deduced from findings in their lung sections. This strongly sug-
gests DIG as the cause of the necrotizing enterocolitis. Only 9 of the 19 infants with postmortem evidence of massive pulmonary hemorrhage showed evidence of bleeding from the lung during life (Table II). Because there are no pathognomonic laboratory or radiologic signs of the condition1 its diagnosis may be missed in surviving infants. The low platelet counts and abnormal results of coagulation studies (Table II) indicate that most of these infants had DIG during life.16 The demonstration of antemortem fibrin clots in the lung sections confirms this suspicion in all but one of these infants. The further finding of inflammation of the medium-sized vessels of the lung in two infants indicates that the vascular tree was involved by the infective process. All these features suggest a possible mechanism of production of pulmonary hemorrhage as a complication of infection in the newborn infant. The infection probably causes DIG either by directly injuring blood vessels, producing localized vasculitis, or by damaging the endothelium with the endotoxin of the infective organism.16'17 The DIG so produced may lead to a generalized hemorrhagic diathesis. Because the lung is an extremely vascular organ, the shearing and stretching of its tissue by respiratory movements will increase the chances of the damaged vessels rupturing. This may explain the frequent occurrence of pulmonary hemorrhage in these infected infants. Alternatively,
'Wi
El
/
a a 'p
infection might produce severe shock, resulting in acute hypoxia, which might precipitate acute left ventricular failure, leading to pulmonary edema, as some have suggested.3'18'19 This theory, however, is not supported by the finding of intravascular fibrin clots in this study. Even though massive pulmonary hemorrhage may not always be the result of infection, the finding that all but one infant in this series had evidence of antemortem intravascular formation of fibrin clots suggests that evidence of DIC should be sought during life in all newborn infants with suspected pulmonary hemorrhage. The results of this study also emphasize the importance of monitoring the hematologic changes and the coagulation status of infants with severe sepsis. I am grateful to all my resident staff of the Paediatric B Unit for their valuable assistance in this study. I also thank the staff of the institute of pathology of Queen Elizabeth Hospital for their help, particularly Dr. Susan Leong for arranging the lung sections, and Mr. T.S. Cheung for help with the coagulation studies. References 1. AVERY ME: The lung and its disorders in the newborn infant, second ed, Philadelphia, Saunders, 1968, p 253 2. BUTLER NR, BONHAM DO: Perinatal mortality, London, Churchill Livingstone, 1963, p 263 3. COLE VA, NORMAND ICS, REYNOLDS HOR, et al: Pathogenesis of hemorrhagic pulmonary edema and massive pulmonary hemorrhage in the newborn. Pediatrics 51: 175, 1973 4. HARDIsTY RM, INGRAM GIC: Bleeding disorders: Investigations and Management, Oxford, Blackwell Sci PubI, 1965 5. LENDRUM AC, FRASER DS, SLmDERs W, et al: Studies on the character and staining of fibrin. I Clin Pathol 15: 401, 1962 6. EsmitLy JR, OPPENHEIMER EH: Massive pulmonary hemorrhage in the newborn. I. Pathologic considerations. I Pedtatr 69: 3, 1966 7. ABILDGAARD CF: Recognition and treatment of intravascular coagulation. J Pediatr 74: 163, 1969 8. LAscAsu AD, WALLACE PD: Disseminated intravascular coagulation in newborns. Clin Pediatr (Phila) 10: 11, 1971 9. XANTHOU M: Leucocyte blood picture in ili newborn babies. Arch Dis Child 47: 741, 1972 10. Rowa 5, AVERY ME: Massive pulmonary hemorrhage in the newborn. II. Clinical considerations. I Pediatr 69: 12, 1966 11. AHYENAINEN EK, CALL JD: Pulmonary hemorrhage in infants. A descriptive study. Am I Pathol 28: 1, 1952 12. MANN TP, ELLuYr RIK: Neonatal cold injury due to accidental exposure to cold. Lancet 1: 229, 1957 13. CEBALLOs R: Aspiration of maternal blood in the etiology of massive pulmonary hemorrhage in the newborn infant. J Pedtatr 72: 390, 1968 14. LANDING BH: Pulmonary lesions of newborn infants. A statistical study. Pediatrics 18: 217, 1957 15. BoornaY CB, DESA DJ: Massive pulmonary hemorrhage in the newborn. A changing pat-
tern. Arch Dis Child 48: 21, 1973 16. CORRIGAN JJ, WAsicxR RI, MAY N: Changes in the blood coagulation system associated with septicemia. N Engl J Med 279: 851, 1968
17. ALEBOYEH M, REMIF,N A, MARGET W: Incidence of disseminated intravascular coagulation in the course of septicemia in newborn infants. Z Kinderheilkd 109: 326, 1971 18. DOWNING
SE,
TALNER
NS,
GARDNER
TH:
Ventricular function in the newborn lamb.
FIG. 2-Evidence of inflammation (vasculitis) of medium-sized and small vessels in lung adjacent to artery (MSB: x950). 138 CMA JOURNAL/JANUARY 24, 1976/VOL. 114
Am I Physiol 208: 931, 1965 19. ADAMSON TM, BOYD RCH, HILL JR, et al: Effect of asphyxia due to umbilical cord occlusion in the fetal lamb on leakage of liquid from the circulation and on permeability of lung capillaries to albumin. I Physiol 207: 493, 1970
