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VOLUME 48 SEPTEMBER 1971 NUMBER 3
COMMENTARIES
NEONATAL
NECROTIZING
ENTEROCOLITIS-OLD
PIT-FALL
OR
NEW
PROBLEM?
No
pediatrician with responsibility forthe care of newborn infants,
prema-ture or full term, can fail to be interested in
the syndrome of neonatal necrotizing
en-terocolitis. The recent outpouring of reports
concerning the disease attests not only to
the growing recognition of the problem but
also the immediacy of the challenge which
it presents. The challenge is twofold,
de-manding clinical diagnosis of the disease at
an early stage as well as study directed
to-ward the elucidation of its etiology and
pathogenesis.
The most quoted articles from the
Euro-pean literature are Genersich’s’ original
case report in 1891, the series of 62 cases
described by Willi’ in 1944, and the series
reported by Rossier, et al. in 1959.
Few references to the disease were
avail-able in the American literature until the last
decade. Then, literally dozens of articles
concerned with neonatal necrotizing
en-terocolitis began to appear in the English
and American literature, the great majority
in the last 5 years.”4 In 1969 Stevenson
and associates19 counted 80 previously
re-ported cases in the American and English
literature and added 26 of their own.
In-cluded in this total was the series from the
Babies Hospital of New York,11 numbering
25. The disease is rare, but in each of the
two series mentioned, these patients
com-posed approximately 1% of admissions to
the premature nurseries involved. In the
in-stitution from which one of these series was
reported, necrotizing enterocolitis
ac-counted for 2.3% of all deaths in premature
infants,’#{176} and in the other institution it was
found as the cause of death in 3% of the
autopsies on premature infants.’3 It is likely that we are witnessing a true increase in the
incidence of neonatal necrotizing
enteroco-litis, but there are several factors which
make such a guess hazardous. The
in-creased awareness of the disease has
proba-bly resulted in increased recognition of the
syndrome at the bedside, in surgery, and at
necropsy. And, writers and investigators
with special interest in this disorder have
gleaned many cases from the literature
which have appeared under other
diag-noses and added them to the growing
num-ber of cases of necrotizing enterocolitis.
These renamed cases have been found in
the literature under many labels, such as
neonatal appendicitis with perforation,
neonatal peritonitis, pneumatosis
intesti-nalis, and perforations, “spontaneous” or
otherwise, of various segments of the small
and large intestine. The finding of
addi-tional cases of neonatal necrotizing
entero-colitis has in some instances involved the
retrieval of previously unrecognized cases
from hospital files. In the interest of clarity
and understanding, it is important to
ex-clude from the category of neonatal
necro-tizing enterocolitis those cases in which a
congenital structural cause for intestinal
ob-struction is Present”#{176}
Attention to predisposing factors is
346 NECROTIZING ENTEROCOLITIS
tremely important in a consideration of
ne-crotizing enterocolitis. The infants at risk
are not the healthy, “no problem” infants
with high Apgar scores who are proudly
whisked home from the maternity hospital
in
3 or 4 days following delivery. Rather,their numbers are drawn from those infants, usually premature, with perinatal problems such as apneic spells, cyanosis, jaundice, or
the respiratory distress syndrome.
A
typical
but hypothetical case history is as follows: A premature infant, birthweight1,500 gm, whose Apgar score had been 5 at
1 minute, is noted to be lethargic on the
second day. The baby looks sick. Sepsis is
suspected, and broad spectrum antibiotics
given. There is gastric retention. The baby
begins to vomit bile-stained fluid and then,
abdominal distension is noted. The stool
may be blood-streaked, but is usually not
diarrheal. Surgical consultation is obtained.
A plain film of the abdomen reveals
intesti-nal dilatation. The condition of the patient
worsens; a follow up x-ray in this
typical
in-stance reveals “pneumatosis intestinalis,” strongly suggesting the diagnosis of necro-tizing enterocolitis. At exploratory
laparot-omy the surgeon finds a dilated portion of
terminal ileum to be thickened,
hemor-rhagic, and friable. The involved gut is
re-sected. The baby recovers.
Fortunately, the happy ending to our
hy-pothetical case report is frequently
matched in real situations. In some of the
patients, however, the process goes on to
perforation with resultant peritonitis
lead-ing to shock and death from sepsis. While
some surgeons may choose to operate on
the basis of the x-ray evidence of
pneuma-tosis intestinalis, before perforation has
oc-curred, other surgeons may prefer to wait
for signs of perforation before operating. A
number of infants critically ill with
necro-tizing enterocolitis have survived following
surgery. A number of infants with milder
forms of the disease have survived without
benefit of surgery. It is apparent that in the
most severe cases, with radiologic signs of
increasing involvement and with clinical
evidence of peritonitis, surgical
interven-tion is indicated. In view of the extremely
high mortality reported
previously,
the
survival of 17 of 26 patients (65%) with
necrotizing
enterocolitis in the series ofSte-venson, et al.19 is a welcome and
encourag-ing statistic. When recovery occurs it is
usu-ally complete although strictures of bowel
have been reported in a few patients who
have recovered.19’23’24 These may or may
not occur at the site of operation.
Within the category of necrotizing
en-terocolitis there is a group of cases which
are set apart by the fact that in each
in-stance, the onset of necrotizing enterocolitis
was preceded by one or more exchange
transfusions.7,9,125,lO,20,2S The intestinal
lesions in this subgroup are similar to those
in the other cases, although there may be a
tendency to involvement of the colon
whereas in the remainder of instances the
ileum is most commonly affected. The
sur-vival rate among these infants is
compara-tively high.
The etiology and pathogenesis of
necro-tizing enterocolitis remain obscure. The
theories regarding causation which receive
most support can be included under the
two broad headings of infection and
isch-emia.
Blanc25 suggested that the swallowing of
infected amniotic fluid by infants born to
mothers with amnionitis might cause
enteri-tis in the newborn. Waldhausen, et al.,T
who recovered P. aeruginosa in four of six
patients with “necrotizing colitis of the
newborn” were convinced that this
orga-nism represented the etiologic agent.
Care-ful bacteriological studies in necrotizing
en-terocolitis have been carried out by many
competent observers, and gram-negative
bacteria, particularly E. coli, have been
re-covered in a number of instances from
blood and peritoneal fluid. Search for a
specific infectious agent has been fruitless,
and there is no evidence that necrotizing
enterocolitis is contagious. However, at this
stage of our inquiry the possibility of
bacte-rial or viral etiology cannot be dismissed.
Mizrahi and associates1#{176} have suggested
that the action of endotoxins of
gram-nega-tive organisms contained in the intestinal
called attention to the possibility that in
in-fants fed cow’s milk, the lack of lysozyme
might result in a predominance of
gram-negative bacteria in their intestines, making
them more susceptible to the action of
en-dotoxin. Denes, et al.14
point
out, however,that in their hospital in Budapest
prema-ture babies are fed human milk exclusively,
and that “necrotizing enterocolitis is not an
infrequent occurrence.” The possibility that
a Shwartzman type reaction is involved in
the pathogenesis of necrotizing enterocolitis
has also been raised by Rossier, et al. and
Hermann.9 Nine of 16 infants with
necrotiz-ing enterocolitis in the series of Wilson and
Woolley’#{176} displayed severe
thrombocy-topenia, a finding consistent with the
Shwartzman phenomenon.
The most interesting theory advanced to
explain the etiology of necrotizing
entero-colitis involves the concept of “selective
cir-culatory ischemia.” Lloyd’7 suggests that in
‘fetuses or newborn infants subjected to
stress, shock or hypoxia, reflex
redistri-bution of circulation may take place,
analo-gous to that occurring in the seal during
prolonged submergence.26 Thus, as in the
“diving reflex,” blood would be shunted
away from organs less vulnerable to anoxia, such as the kidneys and the intestinal tract,
to the heart and brain. Lloyd believes that
local hyperactivity of this mechanism in the
infant may be responsible for production of
areas of ischemic necrosis in the bowel.
Other evidence exists to support the
con-cept that there is an ischemic basis for
nec-rotizing enterocolitis. Corday, et al.’ have
shown that necrosis of the gastrointestinal
tract may occur in middle-aged or elderly
patients with the syndrome of “mesenteric vascular insufficiency.” In these patients, in
whom mesenteric thrombosis is not found,
the insufficiency is dependent upon such
clinical situations as shock or cardiac
de-compensation. The “ischemic enterocolitis”
described in adults by McGovern and
Goul-ston’8 is another example of a necrotizing
lesion of bowel considered to be dependent
upon ischemia for its genesis. If any clue to
the pathogenesis of necrotizing enterocolitis
lurks within the structural changes of the
intestinal
lesions,
it points to ischemia. Thishas been emphasized by a number of
ob-servers,3’12’17”9’22 but not all. However, the
gross and microscopic descriptions of the
intestinal lesions contained in the various
reports are practically interchangeable.
It is possible that more than one etiologic
factor may be involved in the pathogenesis
of necrotizing enterocolitis. Bacteria may of
course invade ischemic intestine. Too, the
determination of the localization of the
in-testinal involvement might be dependent
upon the interaction of another factor, that
of intestinal stasis.29
The role, if any, of iatrogenic factors in
the causation of necrotizing enterocolitis
has received much attention, but a ready
answer is not at hand. The instances
wherein the onset follows exchange
transfu-sion require examination. That a catheter
poorly placed during exchange transfusion
might be responsible for alterations in
he-modynamics leading to intestinal ischemia
has been suggested by a number of
investi-gators.12’13’18’22 The use of umbilical-vein
catheters for blood sampling and
intrave-nous therapy in newborn infants not
af-flicted with erythroblastosis has also been a
subject of concern.18 Umbilical artery or
vein catheters were used in at least 13 of
the infants in the series of necrotizing
en-terocolitis reported by Stevenson, et al.,19
but none was used in the series reported by
Mizrahi, et at.’#{176}The thought has also been
expressed that the increase in necrotizing
enterocolitis is in some way related to the
salvage of an increasing number of
prema-ture infants in recent years.23
One is reminded of the bridge described
in “The Vision of Mirza.”3#{176}
-‘The Bridge thou seest,’ said he, ‘is humane Life; consider it attentively.’-As I looked more
attentively, I saw several of the Passengers dropping
thro’ the Bridge, into the giant Tide that flowed
underneath it; and upon further Examination,
per-ceived there were innumerable Trap-doors that lay concealed in the Bridge, which the Passengers no sooner trod upon, but they fell through them into
the Tide and immediately disappeared. These
hid-den Pit-falls were set very thick at the Entrance of
348 NECROTIZING ENTEROCOLITIS
but multiplied and lay closer together toward the
End-.
Whether neonatal necrotizing
enteroco-litis represents a new or an old pitfall at the
entrance to the bridge,30 the advice given
Mirza, to “consider it attentively,” was
never more apt.
GEORGE H. FETrERMAN, M.D.
Children’s Hospital of Pittsburgh
Pittsburgh, Pennsylvania 15213
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