Acute
Necrotizing
Enterocolitis
in Infancy:
A Review
of
64 Cases
Thomas V. S#{225}ntulli,M.D., John N. Schullinger, M.D., William C. Heird, M.D.,
Robert D. Gongaware, M.D., Joachim Wigger, M.D., Barbara Barlow, M.D.,
William A. Blanc, M.D., and Walter E. Berdon, M.D.
From the Departments of Surgery, Pediatrics, Pathology, and Radiology, college of Physicians and Surgeons, Columbia (Juiversity, and tile Surgical Sercice of Babies Hospital, The Childrens Medical and Surgical Center, Columbia-Presbyterian Medical Center, New York
ABSTRACT. Sixty-four cases of necrotizing enterocolitis
are reviewed. The diagnosis was based on tissue examination in 57 and on the clinical syndrome, including pneumatosis,
in 7. Three factors are important in the development of the disease: injury to the intestinal mucosa, bacteria, and feedings. The indications for surgical intervention are
pneumoperitoneum, signs of peritonitis, and intestinal
obstruction. The importance of stress in the etiology of the
disease is confirmed by the high incidence of perinatal
complications, particularly hypoxia. The mortality was
high, but results are improving with the institution of ear-ly aggressive treatment. Pediatrics, 55:376, 1975,
NECR0TIz-IN(; F:NTI:luX:0LITIS, PREMATURITY, PNEUMATOSI5, STRESS,
hYPOXIA.
Necrotizing enterocolitis is a highly lethal
dis-ease in the newborn infant which is characterized
by ischemic necrosis of the gastrointestinal tract
frequently leading to perforation. It is seen
pni-manly in low-birthweight infants who have
undergone stress, such as hypoxia. Initially, the
clinical picture may be that of a nonmechanical or
functional intestinal obstruction. The
charactenis-tic syndrome consists of gastric retention,
bile-stained vomiting, abdominal distention, and
usually diarrhea with blood in the stools.
Roentgen-ographic examination of the abdomen reveals an
abnormal gas pattern with intramural air
(pneu-matosis) or pneumopenitoneum. The course is
often fulminating with progressive lethargy,
pen-odic apnea, jaundice, shock-like state resembling
sepsis, and death.
HISTORY
Necrotizing enterocolitis has been a poorly
defined entity for many years. Although the
dis-ease may have been represented in the collected
series of 25 cases of peritonitis by Simpson in
1838, 1 it was Genersich2 who probably first
re-ported on the entity in 1891. He described a
45-hour-old premature infant with vomiting,
ab-dominal distention, and cyanosis who died within
24 hours. Postmortem examination revealed an
area of inflammation and perforation of the ileum
without mechanical obstruction. The same
dis-ease process also seems to have appeared in
Thelander’s3 series of 83 collected cases of
un-explained gastrointestinal perforations in 1939.
Agerty, Zisermann, and Shollenberger may have
reported the first surgical survival in 1943,
al-though the pathology was inconclusive.
Subse-quently, the same entity appears to have been
reported in a large number of articles on a variety
of conditions including functional ileus,5
pen-tonitis in the newborn,69 spontaneous or
idio-pathic perforations,1012 13.14
malig-nant entenitis,15 ischemic enterocolitis in the
new-born,’6 necrotizing colitis of the newborn,’7 and
(Received April 29; revision accepted for publication
August 9, 1974.)
TABLE I
SITES OF INVOLVEMENT IN 57 CAsEs#{176}
#{176}Allwith surgical or autopsy specimens.
neonatal gut infarction.’8 Other more descriptive
reports appeared in the European literature
dur-ing the same period.1927
The first comprehensive reports on necrotizing
enterocolitis appeared from the Babies Hospital,
New York, in 1964 and in 1965,2829 and the first
significant surgical experience was recorded from
the same institution in 1967.#{176}Since then other
reports have been published on large series of
pa-tients3136 which probably represent a true
in-crease in incidence as well as an increased
aware-ness of the disease.37
CASE MATERIAL
The current study comprises our clinical
ex-penience with 64 patients seen at the Babies
Hospital from 1955 through June 1974. Two
groups are included on the basis of the diagnostic
criteria: (1) Pathologic examination of
opera-tive or autopsy specimens (57 patients). (2) The
clinical syndrome, including roentgenographic
evidence of pneumatosis (7 patients).
In reference to the second ‘group, it is
impor-tant to note that patients who have shown all or
part of the clinical syndrome of necrotizing
en-terocolitis but who have not demonstrated
pneu-matosis on roentgen examination have been
ex-cluded from the study. In recent years, this has
constituted a significant number of infants in
whom the diagnosis is suspected early and in
whom treatment is promptly instituted before
they develop the full syndrome, as we have defined
it. This is a difficult and extremely important
group whose symptom complex vanes but which
we believe may represent early or developing
necrotizing enterocolitis. Currently, we are
unable to clearly assess this group without a more
objective parameter such as we have in the
roent-genographic finding of pneumatosis in the fully
developed disease.
RESULTS
Pathological Findings
Lesions were found in all parts of the alimentary
tract except the duodenum. The ileum and colon
were by far the most common sites of involvement
(Table I).
Grossly, the diseased intestine was dilated and
hemorrhagic, gray, or necrotic, depending upon
the extent of involvement (Fig. 1). The grossly
involved areas and seemingly normal adjacent
portions of intestine showed considerable
hi-ability.
Microscopically, the earliest recognizable
le-sion was coagulation necrosis of the mucosa with
a ghost-like appearance of the mucosal cells
Site No.
Esophagus 5
Stomach 9
Duodenum 0
Jejunum 16
Ileum 49
Appendix 5
Colon 42
Rectum 2
(Fig. 2). This could be differentiated from
post-mortem autolysis only by the fact that the
sur-gically removed intestine had been immediately
fixed in formalin. There was very little
inflam-mation or cellular response in the early lesions.
Microthrombi were occasionally present.
The more severe lesions revealed a progression
from coagulation necrosis to superficial mucosal
ulceration and submucosal hemorrhage (Fig. 3).
In areas, denuded mucosa was covered by a slimy
grayish coat of agglutinated inflammatory cells,
fibrin, and necrotic epithelium, forming a
pseu-domembrane. Impending perforation in the form
of “ballooned-out” zones was relatively frequent
with only intact serosa preventing actual
break-through. Perforation occurred in 29 patients. In
21, there were single perforations: jejunum, one;
ileum, eight; appendix, three; cecum, one; and
colon, eight. In eight patients the perforations
were multiple: jejunum and ileum, one; ileum,
one; ileum and colon, four; and colon, two. In
addition to perforation and pseudomembrane
formation, there was gross and microscopic
evi-dence of intramural gas (pneumatosis) in the
form of gaseous strips and bubbles, which
in-volved both the submucosa and subserosa. There
was little cellular organization at the margins
of these spaces.
Ganglion cells were normally distributed
throughout the intestine, including the areas
adjacent to the sites of necrosis and perforation.
Thrombosis of mesentenic arteries and veins
was not present in the surgical specimens although
platelet fibrin thrombi were sometimes noted
intramurally, especially in the arterioles and small
arteries of the submucosa. Thrombosis of small
mesentenic vessels, however, was not uncommon
in postmortem specimens where it was felt to be
compatible with the intravascular coagulation
and hemorrhagic state frequently seen terminally.
Fn;. I. Cross specimen of distal ileum and right colon. The agglutinated distended segments of ileum were adherent to a perforation of the right colon. The open right colon shows
hemorrhagic ulcerations, greyish areas of pseudolnembrane formation, and elevated lesions representing pneumatosis in the submucosa.
most strikingly, intracerebral hemorrhages were
frequent autopsy findings.
Severe infection was often found at other sites,
including pneumonia, omphalitis, meningitis,
and brain abscess. Positive postmortem blood
cultures were obtained in 73% of the patients
(35 of 48 recorded).
Clinical Picture
Patient Population. There were 35 girls and 29
boys. Forty-seven of the infants were born
pre-maturely (73%). The incidence of low birthweight
was 78%; only 14 of the 64 patients weighed more
than 2,500 gm (Table II). Major associated
anomalies existed in three patients of low
birth-weight (one with esophageal atresia and
prob-able 17 to 18 tnisomy, one with hypoplastic left
heart syndrome, and one with patent ductus
arteniosis causing congestive failure), and in
four hill-term infants (two with hypoplastic left
heart syndrome, one with a massive
arteniove-flOuS malformation of the brain with early heart
failure, and one with Down’s syndrome).
Perinatal Complications. The incidence of
pen-natal complications was high; in only five patients
were the delivery and immediate postpartum
period recorded as normal (Table III). These
complications included respiratory distress
syn-drome in one half of the patients, apneic spells,
cyanosis, low Apgar score, and resuscitation in
the delivery room. Premature rupture of the
mem-branes was recorded in 18 patients; in two of these
there was amnionitis. Umbilical vein
catheteriza-tion had been done in 17 patients. The frequency
of breech deliveries was 19%. This may be
com-pared to a large group of normal full-term and
low-birthweight infants in whom the incidence
was 2% and 14%, respectively.38 Ten patients had
exchange transfusions. Nine of the infants were
delivered by caesarean section (14%) which is
higher than the usual 6% to 7% incidence.39
Maternal Diseases. In the last trimester of
preg-nancy a number of diseases were noted in the
mother (Table IV). Attention is called to the
interesting finding of two mothers with ulcerative
colitis under treatment in the peninatal period.
Age at Onset. Onset was usually in the first five
days of life (48 patients). Twelve patients
de-veloped symptoms between 6 and 14 days and
four between 15 and 23 days of age.
Relation to Feeding. All but one of the 64 infants
were fed prior to development of the disease. The
one exception was a 1,370-gm infant who was the
first born of quadruplets. The infant was severely
asphyxiated at birth requiring tracheal intubation
BIRTHWEIGHT
Grams No.
501 to 1,000 11
1,001 to 1,500 25
1,501 to 2,000 9
2,001 to 2,500 5
2,501 to 4,000 14
Total 64
5 5 3 2 2
I I
TABLE II TABLE IV
MATERNAL DISEASES
Diseases No.
Puerperal sepsis Toxemia of pregnancy
Urinary tract infection (last trimester) Ulcerative colitis
Heart disease
Suture of incompetent cervix Rubella in pregnancy
Sickle trait
TABLE III
INCIDENCE OF PERINATAL COMPLICATIONS IN 64 PATIENTS
Complication No.
Respiratory distress syndrome 32
Apneic spells 28
Cyanosis 24
Apgar score <7 (recorded in 50 only) 23
Resuscitation in delivery room 17
Premature rupture of membranes 18
Umbilical vessel catheterization 17
Breech delivery 12
Exchange transfusions 10
Cesarian section 9
Amnionitis 2
of respiration. Despite continued ventilatory
assistance throughout the three days of life, the
infant remained flaccid and unresponsive with
severe hypoxemia and acidemia. In addition to
the finding of necrotizing enterocolitis (which
was not suspected clinically), postmortem
ex-amination revealed massive intracranial
hemor-rhage. Although this infant was not fed, it is
in-teresting that blood was aspirated from the
stomach during the final 24 hours of life.
Symptoms. The disease was characterized by
a pattern of poor feeding, apneic episodes, and
lethargy, often in a jaundiced patient with
asso-ciated abdominal distention and prolonged gastric
emptying. Emesis was usually present and
fre-quently bile-stained. Initially, the stools were
normal or constipated, but tended to become
diarrheal and sometimes blood-streaked.
Occa-sionally, even in the small infants, signs of
peri-tonitis were elicited, i.e., abdominal resistance,
induration, and/or edema of the abdominal wall.
If no treatment was instituted, increasing lethargy
and pallor developed which was usually followed
by shock and death.
Cultures. Routine antemortem cultures of the
stool and cerebrospinal fluid were consistently
FIG. 2. Photomicrograph of distal ileuln showing the ear-liest recognizable lesion in acute necrotizing enterocolitis: coagulation necrosis of the mucosa with ghost-like appear-ance of the mucosal cells, marked edema of the sul)Inucosa,
and minimal inflammatory cellular response.
negative for pathogens. Blood cultures were
positive in 17 babies, with E. coli identified in 7
cases, Aerogenes 1, Clostridium 1, Staphylococcus
FIG. 3. Photomicrograph of involved intestine in more advanced lesion showing mucosal necrosis and ulcerations, submucosal hemorrhage, and intramural air (pneumatosis).
Roentgenographic Findings
In order of decreasing frequency the
radio-graphic features included: (1) intestinal distention,
(2) intramural gas (pneumatosis), (3) free air in the
peritoneum (pneumoperitoneum), and (4) gas
in the portal vein.
Intestinal Distention. Intestinal distention in
the form of multiple, dilated loops of small bowel
was most common; as an isolated finding it most
often suggested intestinal obstruction. Air fluid
levels were frequently observed in the erect
posi-tion. Separation of intestinal loops was often
noted suggesting mural edema or peritoneal fluid.
intramural Air (Pneumatosis). This was often
subtle and difficult to demonstrate on
roentgeno-grams. It appeared as small linear or bubbly
intramural collections of air, usually in the right
lower quadrant (Fig. 4). It was easy to misinterpret
as stool mixed with air. Usually the terminal
ileum and right colon were involved, but, on
occasion, the entire colon and even the gastric
wall showed similar findings (Fig. 5).
Free Penitoneal Air (Pneumoperitoneum).
Pneu-mopenitoneum varied from a small volume seen
only in the erect film to massive amounts of free
air. Where there was a large pneumopenitoneum,
supine films showed a radiolucent area over the
liver, the so-called football sign with the
“stitch-ing of the football” represented by the falciform
ligament outlined by air on either side of it. These
signs of free air were seen at first examination in
some cases or developed following a pattern of
intestinal distention and intramural air in other
instances (Fig. 6).
Portal Vein Gas. This serious sign has been noted
in infants with necrotizing enterocolitis and in
adults with intestinal gangrene.4#{176} Such portal
vein gas was first noted in infants by Wolfe and
Evans,4’ who reported on six patients in 1955.
Portal flow towards the liver causes the gas to be
seen as fine arbonizing channels within the liver
distributed well out to the periphery (Fig. 5).
Death, which occurred in most infants with this
finding, was secondary to overwhelming
septice-mia due to gram-negative organisms.
The question of mechanical, including
agan-glionic, obstruction was often raised in the
differ-ential diagnosis. Barium enema which was done
in nine patients showed delayed evacuation of the
“pseudo-transition” zone strikingly mimicking aganglionic
megacolon in one patient.
Treatment and Results
The following is a review of the treatment and
results in the 64 patients. It should be noted that
in the early years of this study treatment varied,
particularly in those instances where the
diag-nosis was not suspected clinically and was made
at autopsy only.
Thirty-seven patients were treated medically;
six survived. Their management included
nasogas-tnic decompression, intravenous fluid therapy,
close attention to their acid-base and electrolyte
balance, broad-spectrum antibiotics parenterally,
frequent physical examination, and
roentgeno-graphic studies every four hours to detect the
presence of pneumoperitoneum.
Twenty-seven patients were operated upon;
eight survived. The indications for operation were
pneumopenitoneum, peritonitis, and intestinal
obstruction.
Pneuinoperitoneum was considered a clearcut
indication for laparotomy. This occurred in 13
of the 27 patients operated upon in this series.
There were four survivors in this group.
Seven patients were operated upon because
of the development of peritonitis as manifested
by localized abdominal wall induration, redness
or edema, or by the palpation of an abdominal
mass. All had received a course of medical
ther-apy for three to eight days prior to surgery. There
were three survivors.
Three of the patients were operated upon
be-FI;. 4. Roentgenogram showing pneumatosis as l)tlbbly
(
U7)CT arrou’) and linear (lower (Irrow) intraniuralcollec-tions of air.
cause of signs of intestinal obstruction; none had
pneumatosis on plain X-ray films. The diagnosis of necrotizing enterocolitis was made at operation.
There was one survivor.
TABLE V
TREATMENT AND SURVIVAL OF 64 PATIENTS
Alice
Treatment No. No. %
No operation 37 6 16
Operation 27 8 30
Exploration only 2 0
Appendectomy 1 0
Closure of perforation 1 0
Enterostomy (at 2 1
perforation_site)_________________________________
Resection
End-to-end anastomosis 5 2
Side-to-end anastomosis 5 2
with proximal enterostomy (chimney)
Double enterostomy 1 1 3
Total 64 14 22
TABLE VI
RESULTS RELATED TO BIRTHWEIGHT
Siirt-ived
No
Birthweight (gm) No. Operation Operation
501 to 1,000 11 0 of 2 0 of 9
1,001 to 1,500 25 3 of 10 5 of 15
1,501 to 2,000 9 2 of 3 0 of 6
2,001 to 2,500 5 2 of 4 0 of 1
2,501 to 4,000 14 1 of 8 1 of 6
Total 64 8 of27 6of37
% survived 22 30 16
Since pneumatosis is frequently a sign of
im-pending perforation, in the earlier years of this
study operation was undertaken for pneumatosis
alone in hopes of improving our results. The policy
was abandoned because in four patients so
man-aged the outcome was fatal. In one of these
pa-tients the bowel appeared entirely normal from
inspection of its serosal aspect in the operating
room. Death occurred three days later and
necrop-sy revealed widespread necrotizing enterocolitis
involving the ileum and colon. The extensive
mucosal involvement was not detectable at
sur-gery. The other patients also had more widespread
disease at autopsy than had been demonstrated at
surgery.
It should be emphasized that pneumatosis is
a grave finding in infants, not to be confused with
benign gas cysts (pneumatosis cystoides
intesti-nalis) seen as an incidental finding in adults.42 Very
rarely, intramural air can be seen in newborns
who are markedly distended from an obstructing
lesion such as Hirschsprung’s disease, imperforate
anus, or meconium ileus. Presumably, a mucosal
tear from distention alone allows the penetration
of normal luminal gas into the intestinal wall.
Ad-ditional possible mechanisms for the development
of pneumatosis have been described.3’ From
our study we conclude that pneumatosis
intesti-nalis in an infant is associated with necrotizing
enterocolitis.
Radiologic evidence of peritoneal fluid in a
patient suspected of having necrotizing
enter-ocolitis has been cited as an indication for
opera-tion.45 Although we did not have experience with
this indication, we are in agreement.
The overall survival rate was 14 of 64 patients
or 22%. Survival was 16% without and 30% with
operation. The surgical procedures performed
are listed in Table V. Resection of involved bowel
with or without anastomosis was the most common
procedure (21 cases). There was no statistical
difference in survival rate for any particular
opera-tion. The preferred procedure in Babies Hospital
is resection of all involved portions of bowel with
a proximal enterostomy (chimney) type of
side-to-end anastomosis as first described by one of
us,46 or resection with double enterostomy when
the former is not feasible.
The results related to birthweight are
sum-manized in Table VI. It should be noted that there
were no survivors in patients under 1,000gm, with
or without operation.
Three survivors went on to form benign
intesti-nal strictures five to seven weeks following the
acute episode (Fig. 7). Two of these were colonic
and one was ileal. All three required operation for
obstruction. Others have reported similar
stric-tunes of the intestine as a complication of the
heal-ing phase of the disease.7
Malabsonption and short bowel syndrome have
occasionally been seen in the postoperative
peri-od. Some of these patients required long-term
to-tal intravenous alimentation.
The discouraging results of treatment, whether
medical on surgical, made it necessary to
fre-quently modify our treatment during the course of
this study. The current plan of management,
which we have followed since October 1972,
con-sists of the immediate cessation of oral or gavage
feedings, the institution of nasogastric tube
suc-tion, and the administration of appropriate
intra-venous fluids. Parenteral antibiotics are given,
kan-FIG. 6. Roentgenogram at left shows intramural air and small-bowel dilatation in a premature infant with acute necrotizing enterocolitis who progressed to perforation and free air over the liver, as seen in the erect film at right.
. FIG. 7. Stenosis of the transverse colon due to fibrosis which required resection in a patient
amycin (15 mg/kg/24 hr) or gentamycin (3 to 5
mg/kg/24 hi). Topical antibiotics are
adminis-tered by gavage at one or two times the
parenter-al dose of kanamycin or gentamycin per day in six
divided doses.5#{176}Low molecular weight Dextran
40 is given intravenously in 10% solution, 10
ml/kg every six hours for 48 hours.5’ Also, we have
resorted to the early use of total intravenous
ali-mentation in a few selected babies in whom it was
felt that oral feeding was contraindicated for an
extended period.
Supine and left side down decubitus X-ray films
are taken every four to six hours to detect
clini-cally unrecognized pneumoperitoneum or
perito-neal fluid, and the infant is examined frequently
for signs of localized peritonitis. The appearance
of any of these changes are considered an
indica-tion for operation.
Only one patient of the last ten so treated was
operated upon and she survived. Five of the nine
who were treated without operation died while
four survived.
DISCUSSION
A variety of factors have been implicated in the
etiology of necrotizing enterocolitis including
segmental volvulus,’4 bacteremia,’5 viremia,25
de-creased lysozyme in the intestinal contents of
non-breast-fed infants,29 the ingestion of infected
amniotic fluid,52 and localized Shwartzman
reac-tion related to the formation of endotoxins by
gram-negative bacteria acting on an
intesti-nal wall previously sensitized to these
sub-stances.24’5355 Pneumatosis and intestinal
gan-grene have also been described in infectious
em-physema of the gastrointestinal tract56 and in
asso-ciation with infantile diarrhea occurring beyond
the neonatal peniod.5759
There would appear to be three essential
corn-ponents to the development of the disease: injury
to the intestinal mucosa, the presence of bacteria,
and the availability of a metabolic substrate, i.e.,
feedings.6064
Direct injury to the mucosa may be related to
hyperosmolar feedings.6567 A few of our full-term
infants who developed the disease at a later age
received hyperosmolar feedings (e.g.,
Nutrami-gen) prior to the onset of the disease68; however,
such feedings were not used routinely.
Indirect injury to the mucosa may result from
selective circulatory ischernia. This is the most
acceptable theory of pathogenesis. It is supported
by our clinical and pathological data. The theory
is based on the knowledge that stress evokes a
re-flex which results in the redistribution of blood
away from those organs which can better tolerate
ischemia (rnesenteric, renal, and peripheral
vas-cular bed) to those which would suffer irreversible
damage (heart and brain) if deprived of adequate
perfusion. The stress may be in the form of
hypox-ia, cold, low-flow states as in certain congenital
heart diseases, and vasospasm or altered
hemody-namics from umbilical vessel catheters ot’
ex-change transfusions.697 All of these conditions
were commonly seen in our series of patients.
This
reflex, which has been called “the masterswitch of life,”75 occurs as a physiologic and
protective mechanism in diving mammals and
birds.7678 Lloyd emphasized its importance in the
etiology of gastrointestinal perforations of the
newborn infant.79 Touloukian and his associates
demonstrated the effects of diminished mucosal
perfusion on the intestinal tract in asphyxiated and resuscitated piglets.8#{176}In our previous report3#{176}
it was postulated that the diminished enteric
pen-fusion leads to decreased mucus production. The
loss of the protective mucus exposes the mucosal
cells to enzymatic digestion and allows bacterial
invasion.8183 The proliferation of gas-forming
or-ganisms which occurs produces the pneumatosis
and the sequence of pathological events which
characterizes the disease.
This review has demonstrated the high
mci-dence of infection in these infants as have others.
Also, most of the positive blood cultures were of
gram-negative bacteria. These two facts
impli-cate enteric bacteria in the pathogenesis of the
disease.
The study also confirms the importance of
feed-ings in the pathogenesis. All but one of our
pa-tients were fed before developing symptoms. The
feedings included, for the most part, dextrose
so-lution or simulated breast milk.
The results of a series of experiments in an
ani-mal model which was developed in our
laborato-ry63 have added to the current theory of
pathogen-esis. These observations have demonstrated the
importance of stress (resulting in mucosal
dam-age), bacteria, and feedings in the production of
necrotizing enterocolitis and have helped explain
the fact that premature and low-bmrthweight
in-fants are more susceptible to the disease. It was
found that formula feeding in conjunction with
hypoxia produced enterocolitis in newborn rats
and that breast milk was completely protective.
Furthermore, it was shown that the important
protective component of breast milk was the
macnophage.84 Entenic overgrowth of potentially
pathogenic bacteria which occurred in the
formu-la-fed rats demonstrated the importance of the
intestinal flora in the pathogenesis of the disease.
breast milk is due to its host resistance factors
and/or its control of the intestinal flora. This is
best explained by the knowledge that the
new-born rat is relatively immune-deficient at birth
and receives part of its immunoglobulin G from
breast milk. This antibody and immunoglobulin A
are found in the mucus layer of the intestine and
protect the body from invasive microorganisms.
Premature infants, like newborn rats, are also
relatively immune-deficient with the degree of
deficiency dependent upon gestational age.
The incidence of necrotizing enterocolitis has
been reported to be from 1% to as high as 7.5% in
newborn and premature nurseries and intensive
care units.31’61’66 It has also been reported as the
cause of death in 3% of autopsies on premature
in-fants.37 The true incidence is probably unknown.
In the 64 patients reviewed here, it should be
em-phasized, the diagnosis was based on tissue
exam-ination in 57, and the clinical syndrome,
includ-ing pneumatosis, in 7 patients from whom tissue
was not available for pathological examination.
During this period we have seen a larger number
of infants in whom the diagnosis was suspected
early and who were treated promptly without
ever developing clear evidence of pneumatosis.
We believe that there are probably various
grada-tions of necrotizing enterocolitis, but in the
ab-sence of pneumatosis or tissue for examination the
diagnosis cannot be made with certainty at the
present time. If these patients indeed have “early
disease” then the institution of prompt and
vigor-ous medical therapy is more likely to succeed in
contrast to the group of patients in whom the
di-agnosis is unequivocal or in whom surgical
inter-vention is necessary.
From our study, the prognosis is serious. The
disease, once established, has a very high
mortali-ty. Only 14 of 64 patients survived (22%). There
are some reports with much higher survival rates,
ranging from 56% to 80% ascribed to more
aggres-sive therapy and earlier operation.32’36’50’65’85 Our
mortality has been high in spite of having added
to our indications for surgical intervention since
our earlier report in 1967 when we considered
pneumoperitoneum as the only indication.
How-ever, it is encouraging that there have been five
survivors of our last ten patients who have been
treated since the institution of our current
proto-col (October 1972), as previously stated.
SPECULATION
Although the prognosis of necrotizing
enteno-colitis is serious once the disease is established, it
appears from this study that the survival rate
would be significantly improved by the institution
of early and aggressive therapy. This demands an
acute awareness of the significance of the
symp-torn complex, particularly in the premature
in-fant. In our institution we are applying the phrase
“candidate for necrotizing enterocolitis” for the
stressed premature infant who shows any
abnor-mality of gastrointestinal function, however
mini-mal. It may be predicted that the incidence of the
fully established disease will decrease as
treat-ment, particularly the cessation offeedings, is
insti-tuted at the first suspicion of the disease.
SUMMARY
Sixty-four cases of necnotizing enterocolitis are
reviewed. The diagnosis was based on tissue
ex-amination in 57 and on the clinical syndrome,
in-cluding pneumatosis, in 7.
Although the incidence of the fully developed
disease appears to be relatively low, the study
in-dicates that there are probably different
grada-tions of the disease and that a much larger number
of infants are seen and treated before developing
the complete syndrome as we have defined it.
The study indicates that three factors are
im-portant in the development of the disease: injury
to the intestinal mucosa, the presence of intestinal
bacteria, and feedings (as a substrate for the
bac-tenia).
The importance of stress in the pathogenesis of
the disease is confirmed by the high incidence of
peninatal complications, particularly hypoxia. In
addition, it was found that all but one infant had
been fed before the onset of symptoms, indicating
that feedings play a role in the development of
the disease.
Indirect injury to the mucosa on the basis of
se-lective mesenteric ischemia in response to stress
was thought to be more important than direct
in-jury to the mucosa from hyperosmolar feedings in
this study.
The indications for surgical intervention are
pneumopenitoneum, signs of peritonitis (localized
abdominal wall induration, redness or edema, or
palpation of an abdominal mass), and intestinal
obstruction.
The mortality was high in this series (78%).
However, the study indicates that the prognosis
has improved in the last two years. Further
im-provement may be expected by an acute
aware-ness of the significance of the symptom complex,
especially in the premature infant, and the
prompt institution of medical treatment.
REFERENCES
1. Simpson, J. Y.: Peritonitis in the fetus in uterus.
2. Genersich, A.: Bauchfellentzundung beim neugebore-nen in folge von perforation des ileums. Arch. Pa-thol. Anat., 126:485, 1891.
3. Thelander, II. E.: Perforation of the gastro-intestinal tract of the newborn infant. Am. J. Dis. Child., 58:371, 1939.
4. Agerty, H. A., Ziserman, A. J., and Shollenberger, C. L.: A case of perforation of the ileum in a newborn in-fant with operation and recovery. J.Pediatr., 22:233, 1943.
5. Dunn, P.: Intestinal obstruction in the newborn with special reference to transient functional ileus associ-ated with respiratory distress syndrome. Arch. Dis. Child., 38:459, 1963.
6. Birtch, A. C., Coran, A. C., and Gross, R. E.: Neonatal peritonitis. Surgery, 61:305, 1967.
7. Fonkalsrud, E. W., Ellis, D. C., and Clatworthy, H. W., Jr.: Neonatal peritonitis. J. Pediatr. Surg., 3:227,
1966.
8. Rickham, P. P.: Peritonitis in the neonatal period. Arch. Dis. Child., 30:23, 1955.
9. Scott, J. E. S.: Intestinal obstruction in the newborn as-sociated with peritonitis. Arch. Dis. Child., 38:120, 1963.
10. Hyde, G. A., Jr., and Santulli, T. V.: Idiopathic perfora-tion of the small intestine in the neonatal period. Pe-diatrics, 28:261, 1960.
11. Kianouri, M.: Spontaneous rupture of the ileum in a newborn infant: Operation and recovery: Report of a case and review of the literature. J. Int. Coll. Surg., 36:707, 1961.
12. Thomas, C. S., Jr., and Broekman, S. K.: Idiopathic per-foration of the colon in infancy: Report of two cases and literature review. Ann. Surg., 164:853, 1966. 13. Firor, H. V., and Myers, H. A. P.: Perforating
appendi-citis in premature infants. Surgery, 56:581, 1964.
14. Walker, R. H.: Appendicitis in newborn infants. J. Pe-diatr., 51:429, 1958.
15. Willi, H. von: Ueber eine bosartige enteritis bei s#{228}ug-lingen der ersten tnmenons. Ann. Paediatr., 162:87, 1944.
16. Nixon, II. H.: Ischemic enterocolitis in the newborn. Proc. R. Soc. Med., 63(suppl):137, 1970.
17. Waldhausen, J. A., Herendeen, T., and King, H.: Necro-tizing colitis of the newborn: Common cause of per-foration of the colon. Surgery, 54:365, 1963. 18. Desa, D. J., Mucklow, E. S., and Cough, M. H.:
Neona-tal gut infarction. J. Pediatr. Surg., 5:454, 1970. 19. Claret-Corominas, L.: Perforation intestinal en un
lac-tante (Mongolico) de 46 dias por colitis ulcerativa
grave. Rev. Esp. Pediatr., 12:217, 1956.
20. Clement, R., Caron, J., Richir, Cl., Levy-Lemann, S., and Duque, M.: Form suraique avec perforations
multiples de colite ulcereuse et hemorragique chez
(In nourisson de 6 semaines. Bull. Soc. Med. Hop. Paris, 9-10:259, 1958.
21. Pauly, H.: Pneumoperitoneuln bei ulzerose
fruhgebore-nen enteritis. Kinderartzl. Prax., 2:69, 1957. 22. Pouyanne, M. M., Triassac, M., Lassere, J., Chabot, and
Ilonton: Enterite necrosante du grele chez tin non-veau-ne. J. Med. Bordeaux, 133:610, 1956.
23. Refinetti, P., De Carvalho Pinto, V. A., and Moraes, R. De V.: Perfuracao intestinal en recemnascidos prematuros. Pediatr. Pratica, 24:219, 1953. 24. Rossier, A., Sarrut, S., and Deiplanque, J.:
L’enteroco-lite ulceronecrotique due premature. La Semaine l)e Ilopitaux, Ann. Pediatr., 34:1428, 1959. 25. Schmid, 0., and Quaiser, K.: tJber eine besondere
schwere verlaufende form von enteritis beim san-gling. Oest&r. Z. Kinderheilkd., 8:114, 1953. 26. Zampi, C., and Corradini, E.: L’enterocolite
ulcero-necrotica del neonato immaturo. Arch. de Vecchi Anat. Patol., 36:155, 1961.
27. Denes, J., Gergely, K., Leb, J., and Mohacsi, A.: Ne-crotizing enterocolitis in premature infants. Acta Paediatr. Acad. Sci. Hung., 9:237, 1968.
28. Berdon, W. E., Grossman, H., Baker, D. H., Mizrahi, A., Barlow, 0., and Blanc, W. A. : Necrotizing entero-colitis in the premature infant. Radiology, 83:879, 1964.
29. Mizrahi, A., Barlow, 0., Berdon, W., Blanc, W. A., and Silverman, W. A.: Necrotizing enterocolitis in premature infants. J. Pediatr., 66:697, 1965.
30. Touloukian, R. J., Berdon, W. E., Amoury, R. A., and Santulli, T. V.: Surgical experience with necrotiz-ing enterocolitis in the infant. J. Pediatr. Surg., 2:389, 1967.
31. Stevenson, J. K., Graham, C. B., Oliver, T. K., Jr., and Goldenberg, V. E. : Neonatal necrotizing entero-colitis: A report of twenty-one cases with fourteen survivors. Am. J. Surg., 118:260, 1969.
32. Stevenson, J. K., Oliver, T. K., Graham, C. B., Bell, R. S., and Gould, V. E.: Aggressive treatment of neonatal necrotizing enterocolitis. J. Pediatr. Surg., 6:28, 1971.
33. Wilson, S. E., and Woolley, M. M.: Primary necrotizing enterocolitis in infants. Arch. Surg., 99:563, 1969.
34. Denes, J., Gergely, K., Wohlmuth, C., and Leb, J.:
Necrotizing enterocolitis of premature infants. Surgery, 68:558, 1970.
35. Waget, J., and Scott, J.E. S.: Necrotizing enterocolitis in the newborn. Z. Kinderchir., 7:242, 1969.
36. Dudgeon, D. L., Coran, A. C., Lauppe, F. A., Hodg-man, J.E., and Rosenkrantz, J.G.: Surgical manage-ment of acute necrotizing enterocolitis in infancy. J. Pediatr. Surg., 8:607, 1973.
37. Fetterman, C. H. : Neonatal necrotizing enterocolitis-old pit-fall or new problem? Pediatrics, 48:345, 1971.
38. Reid, D. E.: A Textbook of Obstetrics. Philadelphia: W. B. Saunders Co., 1962, p. 521.
39. Hellman, L. M., and Pritchard, J. A.: Williams’ Oh-stetrics, ed. 14. New York: Appleton-Century Crofts, Inc., 1971, p. 1168.
40. Sheiner, N. M., Palayew, M. J., and Sedlezky, I.: Gas in the portal vein: A report of two cases. Can. Med. Assoc. J., 95:611, 1966.
41. Wolfe, J. N., and Evans, W. A.: Gas in the portal veins of the liver in infants. A roentgenographic demon-stration with post-mortem anatomical correlation. Am. J. Roentgenol. Radium Ther. Nucl. Med., 74:486, 1955.
42. Elliott, G. B., and Elliott, K. A.: The roentgenologic pa-thology of so-called pneumatosis cystoides intesti-nalis. Am. J. Roentgenol. Radium Ther. Nucl. Med., 89:720, 1963.
43. Stiennon, A. 0. : Pneumatosis intestinalis in the new-born. Am. J. Dis. Child., 81:651, 1951.
44. Schorr, S.: Small intestinal intra-mural air. Radiology, 81:285, 1963.
45. Leonidas, J. C., Krasna, I. H., Fox, H. A., and Broder, M. S.: Peritoneal fluid in necrotizing enterocolitis: A radiologic sign of clinical deterioration. J. Pediatr., 82:672, 1973.
Surg., 154:939, 1961.
47. Krasna, I. H., Becker, J. M., Schneider, K. M., and Beck, A. R. : Colonic stenosis following necrotizing en-terocolitis of the newborn. J. Pediatr. Surg., 5:200, 1970.
48. Joshi, V. V., Winston, Y. E., and Kay, S.: Neonatal necrotizing enterocolitis. Am. J. Dis. Child., 126:113, 1973.
49. Lloyd, D. A., and Cywes, S.: Intestinal stenosis and en-terocyst formation as late complications of neona-tal necrotizing enterocolitis. J. Pediatr. Surg., 8:479, 1973.
50. Bell, M. J., Kosloske, A. M., Benton, C., and Martin, L. W. : Neonatal necrotizing enterocolitis: Pre-vention of perforation. J. Pediatr. Surg., 8:601, 1973.
51. Krasna, I. H., Fox, H. A., Schneider, K. M., and Becker, J. M.: Low molecular weight Dextran in the treat-ment of enterocolitis and midgut volvulus in in-fants. J. Pediatr. Surg., 8:615, 1973.
52. Blanc, W. A: Amniotic infection syndrome:
Pathogen-esis, morphology, and significance in circumnatal mortality. Clin. Obstet. Gynecol., 2:705, 1959. 53. Hermann, R. E. : Perforation of the colon from
necrotiz-ing colitis in the newborn: Report of a survival and a new etiologic concept. Surgery, 58:436, 1965.
54. Berry, C. L., and Fraser, C. C.: The experimental pro-duction of colitis in the rabbit with particular ref-erence to Hirschsprung’s disease. J.Pediatr. Surg., 3:36, 1968.
55. Stone, H. H., Allen, W. B., Smith, R. B. III, and Haynes, C. D.: Infantile pneumatosis intestinalis. J. Surg.
Res., 8:301, 1968.
56. Sawyer, R. B., Sawyer, K. C., and List, J. E.: Infectious emphysema of the gastrointestinal tract in the adult. Am. J. Surg., 120:579, 1970.
57. Rath, H., Rath, 0., Margolin, J. M., and Schenken, J.: Intestinal gangrene with infantile diarrhea: Sur-vival following resection and ileorectostomy. Stir-gery, 69:1271, 1966.
58. Coello-Ramirez, P., Gutierres-Topete, C., and Lifshitz, F.: Pneumatosis intestinalis. Am. J. Dis. Child., 120:3, 1970.
59. Shor-Pinsker, E., and Hernandez, 0. A.: Intestinal in-farction-a complication of gastroenteritis and en-dotoxic shock in children. Arch. Surg., 102:187, 1971.
60. Engel, R. R., Virnig, N. L., Hunt, C. E., and Levitt, M. D.: Origin of mural gas in necrotizing entero-colitis, abstracted. Pediatr. Res., 7:292, 1973. 61. Frantz, I. D., III, L’Heureux, P., Engel, R. R., Leonard,
A. S., and Hunt, C. E.: Clinical correlates of necrotizing enterocolitis (NEC), abstracted. Pe-diatr. Res., 8:381, 1974.
62. Krouskop, R. W., Brown, E. G., and Sweet, A. Y.: The
relationship of feeding to necrotizing
enterocoli-tis, abstracted. Pediatr. Res., 8:383, 1974. 63. Barlow, B., Santulli, T. V., Heird, W. C., Pitt, J., Blanc,
W. A., and Schullinger, J. N.: An experimental
study of acute necrotizing enterocolitis-The
im-portance of breast milk. J. Pediatr. Surg., to be published.
64. Polin, R. A., Pollack, P. F., Barlow, B., Santulli, T. V., and Heird, W. C.: A fresh look at necrotizing en-terocolitis, abstracted. Pediatr. Res., 8:384, 1974. 65. Torma, M. J., DeLemos, R. A., Rogers, J. R., and Dise-rens, H. W. : Necrotizing enterocolitis in infants:
Analysis of forty-five consecutive cases. Am. J. Surg., 126:758, 1973.
66. Book, L. S., Herbst, J. J., and Jung, A. L.: Necrotizing
enterocolitis in infants fed an elemental formula, abstracted. Pediatr. Res., 8:379, 1974.
67. DeLemos, R. A., Roger, J. H., Jr., and McLaughlin, C. W. : Experimental production of necrotizing enterocolitis in newborn goats, abstracted. Pe-diatr. Res., 8:380, 1974.
68. Polin, R. A., Pollack, P. F., Santulli, T. V., and Heird, W. C.: Necrotizing enterocolitis in the older term infant. To be published.
69. Corkery, J. J., Dubowitz, V., Lister, J., and Moosa, A.: Colonic perforation after exchange transfusion. Br. Med. J., 4:345, 1968.
70. Caralps-Riera, J. M., and Cohn, B. D.: Bowel
perfora-tion after exchange transfusion in the neonate: Review of the literature and report of a case. Sur-gery, 68:895, 1970.
71. Sommerschild, H. C.: Intestinal perforation in the new-born infant as a complication in umbilical vein infusion or exchange transfusion. Surgery, 70:609, 1971.
72. Hardy, J. D., Savage, T. R., and Shirodaria, C.: Intesti-nal perforation following exchange transfusion. Am. J. Dis. Child., 124:136, 1972.
73. Touloukian, R. J., Kadar, A., and Spencer, H. P.: The gastrointestinal complications of neonatal umbili-cal venous exchange transfusion: A clinical and
experimental study. Pediatrics, 51:36, 1973.
74. Livaditis, A., Wallgren, C., and Faxelius, C.: Necrotiz-ing enterocolitis after catheterization of the um-bilical vessels. Acta Paediatr. Scand., 63:277, 1974.
75. Scholander, P. F.: The master switch of life. Sci. Amer. 209:92, 1963.
76. Johansen, K.: Regional distribution of circulating blood
during submersion asphyxia in the duck. Acta Physiol. Scand., 62:1, 1964.
77. Corday, E., Irving, D. W., Gold, H., Bernstein, H., and Skelton, R. B. T. : Mesenteric vascular insufficien-cy. Am. J. Med., 33:365, 1962.
78. Eisner, R., Kenney, D. W., and Burgess, K.: Diving bra-dycardia in the trained dolphin. Nature, 212:407,
1966.
79. Lloyd, J. R.: The etiology of gastrointestinal perfora-tions in the newborn. J. Pediatr. Surg., 4:77, 1969. 80. Touloukian, R. J., Posch, J. N., and Spencer, R.: The
pa-thogenesis of ischemic gastroenterocolitis of the neonate. J. Pediatr. Surg., 7:194, 1972.
81. Bounous, G., McArdie, A. H., hodges, D. M., et al.: Biosynthesis of intestinal mucin in shock. Am. Surg., 164:13, 1966.
82. Chin, C. J., McArdle, A. H., Brown, R., et a!.: Intestinal
mucosal lesion in low-flow states: I. A
morpholog-ical, hemodynamic, and metabolic reappraisal. Arch. Surg., 101:478, 1970.
83. Chiti, C. J., Scott, H. J., and Gurd, F. N.: Intestinal mucosal lesion in low-flow states: II. The
protec-tive effect of intraluminal glucose as energy
sub-strate. Arch. Surg., 101:484, 1970.
84. Pitt, J., Barlow, B., Heird, W. C., and Santulli, T. V.: Macrophages and the protective action of breast milk in necrotizing enterocolitis, abstracted. Pe-diatr. Res., 8:384, 1974.
