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Necrotizing enterocolitis
FETAL AND NEONATAL M E D I C I N E Richardr. Behrman, Editor
Necrotizing enterocolitis The clinical course o f 54 patients with necrotizing enterocolitis has been compared tO a matehed group of 98 control patients. On the day of life that NEC occurred, all 54 NEC patients and 63% of controls were receiving standard formula feedings, both at 80/cal/kg/day. Stool cultures at that time revealed a significantly increased frequency of Klebsiella in NEC as compared to control patients. Our data suggest that the combined presence o f certain intestinal bacteria and enteric feedings, perhaps requiring a background of mueosal ischemia, may be Of etiologic significance in the development o f NEC and its radiologie hallmark, pneumatosis intestinalis.
Ivan D. Frantz III, M.D., Boston, Mass., Philippe L'Heurenx, M.D., Roll R. Engel, M.D., and Carl E. Hunt, M.D.,* Minneapolis, Minn.
F I F T Y - F O U R CASES o f n e c r o t i z i n g e n t e r o c o l i t i s occurred in our neonatal intensive care unit in a recent 39-month period. The purposes of this paper are to report our experiences with the diagnosis, management, a n d o u t c o m e of N E C , a n d to c o m p a r e the clinical course of these patients to a group of control patients matched for birth weight and date of admission in order to gain additional insight into the etiology of NEC. Our e x p e r i e n c e s with N E C h a v e r e c e n t l y b e e n published in part elsewhere, t Publication of this manuscript, therefore, is based on the additional information and insights included regarding the etiologic relationships of enteric bacteria and enteric feedings to the development of NEC. NEC PATIENTS General. Between January, 1970, and March, 1973, 1,135 neonates were admitted to our NICU, 677 of w h o m were premature infants ( ( 38 weeks' gestation). Fifty-four cases of N E C occurred during this period, representing an incidence of 4.7% of all neonatal admissions. Forty-nine (91%) of the NEC patients were premature, representing an incidence of 7.3% of all premature infants admitted during this period (Table I). The other five patients included one older infant followFrom the Departments o f Pediatrics and Radiology, University o f Minnesota. *Reprintsaddress:Box 92Mayo, Universityof Minnesota, Minneapolis, Minn. 55455.
ing. corrective surgery for complete transposition of the great vessels and four full-term newborn infants: one with severe respiratory distress syndrome, one with severe birth asphyxia, and two with congenital heart disease (left-sided obstructive lesions). The average age at onset of N E C was 6.5 days (range 1-22 days); two cases occurred on the first day of life and nearly half occurred between the third and fifth days of life. Abbreviations used NEC: necrotizing enterocolitis NICU: neonatal intensive care unit RDS: respiratory distress syndrome DIC: disseminated intravascular coagulation PI: pneumatosis intestinalis
Clinical diagnosis. In patients without other abdominal pathology, a clinical diagnosis of N E C was suspected on the basis of abdominal distention and ileus. Guaiac positive or bloody stools were a c o m m o n , but not universal, finding. Other clinical findings, such as peritonitis and/or perforation, shock, Or disseminated intravascular coagulation, were present in patients with extensive involvement. Roentgenographic findings. The diagnosis of NEC was confirmed radiologically on the basis of pneumatosis intestinalis and adynamic ileus, la, 2 All b u t five patients had PI. Two of these five patients were successfully m a n a g e d m e d i c a l l y ; in the t h r e e o t h e r patients, the diagnosis was confirmed at surgery or autopsy. Vol. 86, No. 2, pp. 259-263
260
Frantz et aL
The Journal of Pediatrics February 1975
Table I. Percentage of NEC patients and of control pa= tients having a birth weight and gestational age within each of the listed ranges NEC 54patients (%)
Controls 98patients (%)
Birth weight (gm): ( 1,000 1,00 - 1,499 1,500- 1,999 2,00 - 2,499 i> 2,500
5.5 40.7 33.3 7.5 13.0
7.1 38.8 35.7 8.2 12.2
Gesmt~nalage(wk): ( 26 27 - 29 30 - 33 34 - 37 38 - 42
2 14 52 23 9
4 20 44 23 9
cally with continuous nasogastric decompression for a m i n i m u m o f t e n days, p a r e n t e r a l a n t i b i o t i c t h e r a p y (gentamicin and penicillin), and intravenous alimentation until enteric feedings were reinstituted after ten days. In several patients in whom enteric feedings were begun prior to ten days, clinical and radiologic signs reappeared, but responded to reinstitution of medical management. Except for one medically managed patient later requiring surgical intervention for intestinal obstruction secondary to stricture, no patients initially considered to be candidates for medical m a n a g e m e n t later required surgical treatment 9 Of the 54 patients with NEC, 16 (30%) were managed medically and 38 (70%) were treated surgically. Seven (44%) of the medically and 12 (31%) of the surgically managed patients survived for an overall survival of 19 patients (35%). Complete autopsies were obtained in all 35 nonsurvivors 9 CONTROL
Unrelated to the presence of an umbilical venous catheter, gas in the portal venous system occurred in eight patients. All eight patients required surgical intervention and two survived. Pneumoperitoneum secondary to intestinal perforation occurred in five patients; two of these patients survived and three died. There was no relationship of clinical severity or outc o m e to the e x t e n t o f e i t h e r PI or a d y n a m i c iieus. Several patients, for example, had extensive disease at surgery without severe radiologic findings, and several patients had extensive PI with benign clinical courses not requiring surgical intervention. Disseminated intravaseular coagulation. A l l b u t three of the 54 NEC patients were evaluated for DIC when N E C was suspected. A laboratory diagnosis of DIC was made on the basis of decreasing platelet concentration, increasing prothrombin and partial thromboplastin times, and a serum Factor V concentration of less than 40%. Five of the 26 NEC patients with DIC developed DIC more than 24 hours prior to the onset of N E C s y m p t o m s , p r e s u m a b l y s e c o n d a r y to s e v e r e perinatal hypoxia and acidosis. The other 21 patients developed DIC concomitant with the onset of NEC, and all 21 required surgical treatment for NEC. DIC in association with N E C did not occur in any of the patients successfully managed medically. Treatment. Based on our initial e x p e r i e n c e s with 9NEC, patients were treated surgically if one or more of the following were present at the time of diagnosis: (1) i n t e s t i n a l p e r f o r a t i o n , (2) m e t a b o l i c acidosis a n d / o r shock, or (3) DIC. All other patients were treated medi-
PATIENTS
A c o n t r o l g r o u p o f p a t i e n t s was s e l e c t e d r e t r o spectively on the basis of birth weight and date of admission in o r d e r to p r o v i d e p a t i e n t s of c o m p a r a b l e gestational age who received their neonatal care during the same time period. Two control patients were identified for each N E C patient by selecting the first neonate admitted to the N I C U before and after the N E C patient in whom birth weight (appropriate for gestational age) was within 50 gm (Table I). Since some overlap of control patients occurred, the final number of control patients obtained was 98. The average age when admitted to the N I C U was 15.9 hours for N E C and 17.3 hours for control patienis. Apgar scores, available in approximately two-thirds of the control and of the NEC patients, were not significantly different at either one or five minutes of age. In e a c h g r o u p , a p p r o x i m a t e l y 30% h a d a f i v e - m i n u t e Apgar score of ( 5 (Table II). Twenty percent of each group had a flush blood pressure ( 30 m m Hg before or at the time of admission to the NICU. During this same period, 20% of each group also had at least one rectal temperature recorded of ~< 36 ~ C. Reflecting the high incidence of RDS in our referral population, 73% of N E C patients and 75% of control patients had RDS. Even when classified according to severity of RDS on the basis of a need for assisted ventilation, the frequency of mild and severe RDS was similar in the two groups. In 52 (96%) of the NEC patients, umbilical arterial catheters, typically positioned in the low thoracic aorta, were inserted as part of their initial management. The
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Necrotizing enterocolitis
T a b l e II. Fre~luency o f a c u t e illness v a r i a b l e s in t h e N E C a n d c o n t r o l )atients*
261
T a b l e III. F r e q u e n c y of i n t e s t i n a l bacterial c o l o n i z a t i o n in N E C a n d c o n t r o l p a t i e n t s as d e t e r m i n e d b y stool Cult u r e s o b t a i n e d On t h e day o f life t h a t N E C o c c u r r e d *
Percent of patients Statistical NEC Conttvls signg/icance Acute illness variable (54patients) (98patients) (P) Perinatal stresses Birth asphy'xia Hypotension Hypothermia RDS Unassisted Assisted ventilation Total % Umbilical catheters Arterial Venous Enteric feedings Septicemia DIC
30 20 20 31 42 73 961" 695 100 37 48
32 20 20 29 46 75 73 43 63 14 16
NS NS NS NS NS NS 0.001 0.005 < 0.001 0.002 ( 0.001
*Birth asphyxia was defined as a five-minute Apgar score of ~< 5, hypotension as a flush blood pressure of < 30 mm Hg, and hypothermia as at least one recorded rectal temperature of ~<36~ For each NEC patient and his matched control(s), enteric feedings were evaluated on the day of life that NEC developed. The difference in frequency of use of umbilical catheters was not statistically significant when corrected for those removed more than 24 hours prior to onset of NEC. Although DIC and septicemia occurred significantly more often in NEC patients, they did not precede the development of abdominal symptoms. tOn day of life NEC developed, catheter was still in place in 80% of total group, a nonsignificant difference when compared to control patients. SOn day of life that NEC developed, only 43% of total group still had a catheter in place.
c a t h e t e r was r e m o v e d m o r e t h a n 24 h o u r s prior to o n s e t o f N E C s y m p t o m s in n i n e i n f a n t s ; only 80% o f N E C p a t i e n t s , t h e r e f o r e , h a d .an arterial c a t h e t e r in place o n t h e day of life t h a t N E C developed. I n t h e c o n t r o l group, a n u m b i l i c a l arterial c a t h e t e r was utilized in 73% o f t h e patients. A v e r a g e d u r a t i o n o f i n s e r t i o n of t h e arterial c a t h e t e r was 7.7 (___ 0.9) days in N E C as c o m p a r e d to 5.4 ( ___ 0.7) d a y s in c o n t r o l p a t i e n t s ( P ( . 0 5 ) . I n 69% o f N E C p a t i e n t s , a n u m b i l i c a l v e n o u s c a t h e t e r was i n s e r t e d arid typically p o s i t i o n e d in t h e i n f e r i o r v e n a c a v a Or r i g h t a t r i u m . T h e c a t h e t e r was r e m o v e d m o r e t h a n 24 h o u r s p r i o r to o n s e t of N E C s y m p t o m s in n i n e p a t i e n t s ; c o n s e q u e n t l y , o n t h e day o f life t h a t N E C o c c u r r e d , only 43% h a d a n u m b i l i c a l v e n o u s c a t h e t e r in place. U m b i l i c a l v e n o u s c a t h e t e r s w e r e utilized in 43% o f t h e c o n t r o l patients. All 54 N E C p a t i e n t s w e r e r e c e i v i n g oral f e e d i n g s u n til t h e o n s e t o f N E C s y m p t o m s . On t h e s a m e day o f life t h a t s y m p t o m s d e v e l o p e d in t h e m a t c h e d N E C patients, o n l y 63% ( P < 0.001) o f c o n t r o l p a t i e n t s w e r e also
Percent positive - ~ NEC [ Controls (51 patients) [(50 patients)
1 1 Statistical Isignificance 1 (P)
Organisms
Klebsiella E. coli Staphylococcus albus Alpha Streptococcus Candida albicans Enterococcus
Pseudomonas Group B
38
16
36 30 24 16 10 8 2
22 30 20 18 6 2 0
0.03
14
24
NS
47 7 47 14
42 6 35 10
NS NS NS NS
.:
NS NS NS NS NS NS NS
Streptococcus Sterile Antibiotics Penicillin Ampicillin Kanamycin Gentamicin
*In most patients, more than one organism was isolated. The only significant difference between the two groups was a higher frequency of Klebsiella colonization in NEC patients.
r e c e i v i n g oral feedings. F o r b o t h groups, a s t a n d a r d 20 c a l / o u n c e c o m m e r c i a l formula* was u s e d a n d t h e average v o l u m e p e r f e e d i n g was 15 m l / k g , g i v e n e v e r y two to t h r e e hours. F o r b o t h N E C a n d c o n t r o l p a t i e n t s t h e a v e r a g e total caloric i n t a k e was 80 cal/kg/day. Stool c u l t u r e s w e r e o b t a i n e d in 51 (94%) o f N E C patients at t h e o n s e t o f N E C s y m p t o m s . On t h e s a m e day o f life t h a t s y m p t o m s d e v e l o p e d in the m a t c h e d N E C p a t i e n t , stool c u l t u r e s w e r e o b t a i n e d in 50 (51%) o f t h e c o n t r o l p a t i e n t s ( T a b l e l i D . T h e o n l y statistically signif i c a n t difference ( P ( 0 . 0 3 ) was a h i g h e r f r e q u e n c y of Klebsiella c o l o n i z a t i o n in t h e N E C group. A l t h o u g h t h e majority of our NEC and control patients with intestinal Klebsiella c o l o n i z a t i o n h a d e i t h e r T y p e 33 or 26, t h e ass o c i a t i o n b e t w e e n N E C a n d i n t e s t i n a l Klebsiella colo n i z a t i o n was n o t r e s t r i c t e d to t h e s e two types. T h e r e w e r e n o statistically s i g n i f i c a n t differences b e t w e e n t h e N E C a n d c o n t r o l g r o u p s in r e s p e c t to a n t i b i o t i c treatm e n t at t h e t i m e i n t e s t i n a l c o l o n i z a t i o n was e v a l u a t e d ( T a b l e III). 9C o n c o m i t a n t with t h e o n s e t of N E C , 20 (45%) o f t h e 44 N E C p a t i e n t s w i t h p o s i t i v e stool c u l t u r e s d e v e l o p e d *Similac or SMA, with osmolar concentrations of 330 or 300 mOsm/l, respeCtively.
262
Frantz et al.
septicemia from one of the organisms present in the stool, typically Escherichia coli or Klebsiella. In the 38 control patients with positive stool cultures, six (16%) developed septicemia from one of the organisms present. Overall, 37% of the total NEC and 14% of the total control groups developed septicemia in the course of their acute illness. As described above, DIC occurred in 26 N E C patients, 21 in association with NEC and five (11% of all N E C patients) at an earlier time in association with severe hypoxia and acidosis. In the control group, DIC related to hypoxia and acidosis occurred with the same frequency (11%) as in the N E C patients. In total, 16% of c o n t r o l p a t i e n t s d e v e l o p e d D I C during their N I C U course. The only DIC survivors in either group were four N E C patients .who developed DIC concurrently with the onset of abdominal symptoms. DISCUSSION A variety of causes for N E C have been suggested, ranging from ischemic intestinal damage to infection, intolerance of enteric feedings, exchange transfusions, and reactions to umbilical catheters. 3-8The comparison between N E C and control patients was made in order to evaluate the potential relationship of NEC to any of these factors. Our experience does not indicate any relationship between exchange transfusion and NEC. 9, 10 Only three NEC patients had an exchange transfusion prior to onset of symptoms and the frequency of N E C was not higher in patients receiving exchange transfusion than in patients without exchange transfusion. The umbilical arterial catheter has been frequently mentioned as a possible etiologic factor. Although a high frequency of thrombi, most often asymptomatic, associated with umbilical arterial catehters has been reported, 11thrombi in the aortic or mesenteric artery were seen at autopsy in only three patients in this series a n d in only two previously reported cases? Furthermore, routine positioning of the arterial catheter just above the aortic bifurcation rather than in the low thoracic aorta has not led to a decreased incidence of NEC32 Other reports of N E C patients have cited a varying f r e q u e n c y of u m b i l i c a l arterial c a t h e t e r i z a t i o n . 5, 8 Almost all N E C patients in our series had an arterial catheter inserted as part of their initial management. If we do not include the patients in w h o m the catheter was removed more than 24 hours before onset of NEC Symptoms, however, the frequency becomes identical to that in control patients. The somewhat longer average d u r a t i o n o f u m b i l i c a l arterial c a t h e t e r i z a t i o n in
The Journal of Pediatrics February 1975
N E C patients may well be secondary to the deteriorating clinical status occurring at this time rather than a primary cause of NEC. Perinatal hypotension and/or hypoxemia, especially in the premature infant, have been suggested as a cause of intestinal mucosal ischemia, bacterial invasion of the b o w e l wall, and, s u b s e q u e n t l y , the d e v e l o p m e n t of NEC.8,13-15 Since frequency of the various gross indicators of perinatal hypoxia was identical in the NEG, and control patients, our data neither prove nor disprove the etiologic role of hypoxemic intestinal damage. In both infants and adult patients, an association between N E C and clinical and/or laboratory evidence of DIC has been recognized. 7,13,16 The DIC, which developed concurrently with the development of NEC in 21 patients Could not be directly related to septicemia, was observed to occur in those patients with more severe N.EC, and could not b e reversed unless treatment included surgical resection of necrotic bowel. Since the DIC associated with N E C occurred only in patients who, at surgery, had bowel necrosis requiring resection, it is probable that in such patients DIC occurred secondary to release of tissue thromboplastin from the necrotic bowel. Disseminated intravascular coagulation has not occurred in patients successfully managed medically and may, therefore, be helpful in defining those patients with intestinal necrosis who require surgical treatment. However, in one of the three patients with massive and unresectable NEC, no DIC was present. The development of PI has been shown to require carbohydrate in the intestinal tract plus the presence of bacteria in the duodenum. 17 We have previously reported data demonstrating that both substrate (formula feedings) and enteric bacteria are necessary for the production of hydrogen gas, and that hydrogen is a major constituent of the intramural gas found in NEC. 18 C o n s i d e r i n g t h e ability of Klebsiella to p r o d u c e hydrogen gas, 18it may be significant that the incidence of intestinal colonization with Klebsiella 19 w a s increased in the N E C patient as compared to the control patient. Although most reports have not contained detailed information on oral feedings, Bell and associates 2~ did mention that 42 of their 43 patients had been fed. Other i n v e s t i g a t o r s have s t r e s s e d the i m p o r t a n c e of c o w ' s milk feedings 2t or the early feeding of hypertonic solutions 22-24as being important in the etiology of NEC. All 54 patients in our series received oral feedings prior to the onset of symptoms. Although the percentage of patients being fed was much greater in the N E C group, the volume, caloric intake, and osmolarity were no dif-
Volume 86 Number 2
f e r e n t than in the c o n t r o l group. Our e x p e r i e n c e , therefore, does not support a relationship between hyperosmolar feedings and NEC. Pitt and associates 25 have demonstrated that breast milk protects rats against e x p e r i m e n t a l l y p r o d u c e d NEC, and that macrophages contained in the breast milk are able to kill Klebsiella. However, since none of the N E C or control patients in our series were fed breast milk, we cannot c o m m e n t on the clinical significance of this observation. During 1973, eight of ten patients managed medically and five of !5 managed surgically have survived, for an overall survival of 52%. Although the outlook for N E C seems to be improving, the etiology remains unclear. P e r h a p s requiring a background of mucosal ischemia, the combined presence of intestinal bacteria and enteric feedings appear to be of etiologic significance in the development of NEC. To further define the importance of enteric feedings and intestinal bacteria in the first two weeks of life, prospective studies need to be d o n e utilizing low-risk m e t h o d s for controlling intestinal bacterial colonization and alternate methods for providing appropriate nutrition. Acknowledgement is given to James Zarembinski, Siv Modler, B.S,, and Beverly Conerton, B.A. for their assistance in the collection of data and preparation of this report. REFERENCES
1. Roback SA, Foker J, Frantz 1, Hunt CE, Engel RR, and Leonard AS: Necrotizing enterocolitis: An emerging entity in the regional infant intensive care facility, Arch Surg 109:314, 1974. la. Bell RS, Graham CB, and Stevenson JK: Roentgenologic and clinical manifestations of neonatal necrotizing enterocolitis, Am J Roentgenol Rad Therapy Nucl Med 112:123, 1971. 2. Pochaczevsky R, and Kassner EG: Necrotizing enterocolitis Of infancy, Am J Roentgenol Rad Therapy Nucl Med 113:283, 1971. 3. Rosenfield CR: Necrotizing enterocolitis, NY Acad Med 47:161, 1971. 4. Tan KL, Tan AYO, and Wong TTT: Necrotizing enterocolitis in young infants, Clin Pediatr 11:44, 1972. 5. Cohn R, Sunshine P, and deVries P: Necrotizing en"terocolitis in the newborn infant, Am J Surg 124:165, 1972. 6. D~nes J, Gergely K, Wholmuth G, and Lgb J: Necrotizing enterocolitis of premature infants, Surgery 68:558, 1970. 7. Hopkins GB, Gould VE, Stevenson JK, and Oliver TK: Necrotizing enterocolitis in premature infants, Am J Dis Child 120:229, 1970.
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8. Stevenson JK, Oliver TK, Graham CB, Bell RS, and Gould VE: Aggressive treatment of neonatal necrotizing enterocolitis: 38 patients with 25 survivors, J Pediatr Surg 6:28, 1971. 9. Friedman AB, Abellera RM, Lidsky I, and Lubert M: Perforation of the colon after exchange transfusion in the newborn, N Engl J Med 282:796, 1970. 10. Touloukian RJ, Kadar A, and Spencer RP: The gastrointestinal complications of neonatal umbilical venous exchange transfusion: A clinical and experimental study, Pediatrics 51:36, 1973. 11. Neal WA, Reynolds JW, Jarvis CW and Williams HJ: Umbilical arterial catheterization: Demonstration of arterial thrombosis by aortography, Pediatrics 50:6, 1972. 12. Reynolds JWi Personal communication. 13. Wilson, SE, and Wooly MM: Primary necrotizing enterocolitis in infants, Arch Surg 99:563, 1969. 14. Touloukian RJ, Posch JN, and Spencer R: The pathogenesis of ischemic gastroenterocolitis of the neonate: Selective gut mucosal ischemic in asphyxiated neonatal piglets, J Pediatr Surg 7:194, 1972. 15. Broadie TA, Devedas M, Rysavy J, Delaney JP, and Leonard AS: The effect of hypoxia and posterior hypothalamic stimulation on colonic blood flow in the weanling puppy, J Pediatr Surg 8:747, 1973. 16. Whitehead R: Ischaemic enterocolitis: an expression of the intravascular coagulation syndrome, Gut 12:9!2, 1971. 17. Coello-Rami{ez P, Gutierrex-Topete G, and Lifshitz F: Pneumatosis intestinalis, Am J Dis Child 120:3, 1970. 18. Engel RR, Virnig NL, Hunt CE, and Levitt MD: Origin of mural gas in necrotizing enterocolitis, Pediatr Res 7:292/64, 1973. 19. Hill HR, Hunt CE, and Matsen JM: Nosocomial colonization with Klebsiella, Type 26, in a neonatal intensive-care Unit associated with an outbreak of sepsis, meningitis, and necrotizing enterocolitis, J PEDIATR85:415, 1974. 20. Bell RS, Graham CB, and Stevenson JK: Roentgenologic and clinical manifestations of neonatal necrotizing enterocolitis, Am J Roentgenol 112:123, 1971. 21. Mizrahi A, Barlow O, Berdon W, Blanc WA, and Silverman WA: Necrotizing enterocolitis in premature infants, J PEDIATR66:697, 1965. 22. Torma MJ, DeLemos RA, Rogers JR, and Diserens HW: Necrotizing enterocolitis in infants, Am J Surg 126:758, 1973. 23. Book LS, Herbst J J, and Jung AL: Necrotizing enterocolitis in infants fed an elemental formula, Pediatr Res 8:379/105, 1974. 24. Delemos RA, Rogers JH, and McLaughlin GW: Experimental production of necrotizing enterocolitis in newborn goats, Pediatr Res 8:380/106, 1974. 25. Pitt J, Barlow B, Heird WC, and Santulli TV: Macrophages and the protective action of breast milk in necrotizing entercolitis, Pediatr Res 8:384/110, 1974.
Necrotizing enterocolitis The clinical course o f 54 patients with necrotizing enterocolitis has been compared tO a matehed group of 98 control patients. On the day of life that NEC occurred, all 54 NEC patients and 63% of controls were receiving standard formula feedings, both at 80/cal/kg/day. Stool cultures at that time revealed a significantly increased frequency of Klebsiella in NEC as compared to control patients. Our data suggest that the combined presence o f certain intestinal bacteria and enteric feedings, perhaps requiring a background of mueosal ischemia, may be Of etiologic significance in the development o f NEC and its radiologie hallmark, pneumatosis intestinalis.
Ivan D. Frantz III, M.D., Boston, Mass., Philippe L'Heurenx, M.D., Roll R. Engel, M.D., and Carl E. Hunt, M.D.,* Minneapolis, Minn.
F I F T Y - F O U R CASES o f n e c r o t i z i n g e n t e r o c o l i t i s occurred in our neonatal intensive care unit in a recent 39-month period. The purposes of this paper are to report our experiences with the diagnosis, management, a n d o u t c o m e of N E C , a n d to c o m p a r e the clinical course of these patients to a group of control patients matched for birth weight and date of admission in order to gain additional insight into the etiology of NEC. Our e x p e r i e n c e s with N E C h a v e r e c e n t l y b e e n published in part elsewhere, t Publication of this manuscript, therefore, is based on the additional information and insights included regarding the etiologic relationships of enteric bacteria and enteric feedings to the development of NEC. NEC PATIENTS General. Between January, 1970, and March, 1973, 1,135 neonates were admitted to our NICU, 677 of w h o m were premature infants ( ( 38 weeks' gestation). Fifty-four cases of N E C occurred during this period, representing an incidence of 4.7% of all neonatal admissions. Forty-nine (91%) of the NEC patients were premature, representing an incidence of 7.3% of all premature infants admitted during this period (Table I). The other five patients included one older infant followFrom the Departments o f Pediatrics and Radiology, University o f Minnesota. *Reprintsaddress:Box 92Mayo, Universityof Minnesota, Minneapolis, Minn. 55455.
ing. corrective surgery for complete transposition of the great vessels and four full-term newborn infants: one with severe respiratory distress syndrome, one with severe birth asphyxia, and two with congenital heart disease (left-sided obstructive lesions). The average age at onset of N E C was 6.5 days (range 1-22 days); two cases occurred on the first day of life and nearly half occurred between the third and fifth days of life. Abbreviations used NEC: necrotizing enterocolitis NICU: neonatal intensive care unit RDS: respiratory distress syndrome DIC: disseminated intravascular coagulation PI: pneumatosis intestinalis
Clinical diagnosis. In patients without other abdominal pathology, a clinical diagnosis of N E C was suspected on the basis of abdominal distention and ileus. Guaiac positive or bloody stools were a c o m m o n , but not universal, finding. Other clinical findings, such as peritonitis and/or perforation, shock, Or disseminated intravascular coagulation, were present in patients with extensive involvement. Roentgenographic findings. The diagnosis of NEC was confirmed radiologically on the basis of pneumatosis intestinalis and adynamic ileus, la, 2 All b u t five patients had PI. Two of these five patients were successfully m a n a g e d m e d i c a l l y ; in the t h r e e o t h e r patients, the diagnosis was confirmed at surgery or autopsy. Vol. 86, No. 2, pp. 259-263
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The Journal of Pediatrics February 1975
Table I. Percentage of NEC patients and of control pa= tients having a birth weight and gestational age within each of the listed ranges NEC 54patients (%)
Controls 98patients (%)
Birth weight (gm): ( 1,000 1,00 - 1,499 1,500- 1,999 2,00 - 2,499 i> 2,500
5.5 40.7 33.3 7.5 13.0
7.1 38.8 35.7 8.2 12.2
Gesmt~nalage(wk): ( 26 27 - 29 30 - 33 34 - 37 38 - 42
2 14 52 23 9
4 20 44 23 9
cally with continuous nasogastric decompression for a m i n i m u m o f t e n days, p a r e n t e r a l a n t i b i o t i c t h e r a p y (gentamicin and penicillin), and intravenous alimentation until enteric feedings were reinstituted after ten days. In several patients in whom enteric feedings were begun prior to ten days, clinical and radiologic signs reappeared, but responded to reinstitution of medical management. Except for one medically managed patient later requiring surgical intervention for intestinal obstruction secondary to stricture, no patients initially considered to be candidates for medical m a n a g e m e n t later required surgical treatment 9 Of the 54 patients with NEC, 16 (30%) were managed medically and 38 (70%) were treated surgically. Seven (44%) of the medically and 12 (31%) of the surgically managed patients survived for an overall survival of 19 patients (35%). Complete autopsies were obtained in all 35 nonsurvivors 9 CONTROL
Unrelated to the presence of an umbilical venous catheter, gas in the portal venous system occurred in eight patients. All eight patients required surgical intervention and two survived. Pneumoperitoneum secondary to intestinal perforation occurred in five patients; two of these patients survived and three died. There was no relationship of clinical severity or outc o m e to the e x t e n t o f e i t h e r PI or a d y n a m i c iieus. Several patients, for example, had extensive disease at surgery without severe radiologic findings, and several patients had extensive PI with benign clinical courses not requiring surgical intervention. Disseminated intravaseular coagulation. A l l b u t three of the 54 NEC patients were evaluated for DIC when N E C was suspected. A laboratory diagnosis of DIC was made on the basis of decreasing platelet concentration, increasing prothrombin and partial thromboplastin times, and a serum Factor V concentration of less than 40%. Five of the 26 NEC patients with DIC developed DIC more than 24 hours prior to the onset of N E C s y m p t o m s , p r e s u m a b l y s e c o n d a r y to s e v e r e perinatal hypoxia and acidosis. The other 21 patients developed DIC concomitant with the onset of NEC, and all 21 required surgical treatment for NEC. DIC in association with N E C did not occur in any of the patients successfully managed medically. Treatment. Based on our initial e x p e r i e n c e s with 9NEC, patients were treated surgically if one or more of the following were present at the time of diagnosis: (1) i n t e s t i n a l p e r f o r a t i o n , (2) m e t a b o l i c acidosis a n d / o r shock, or (3) DIC. All other patients were treated medi-
PATIENTS
A c o n t r o l g r o u p o f p a t i e n t s was s e l e c t e d r e t r o spectively on the basis of birth weight and date of admission in o r d e r to p r o v i d e p a t i e n t s of c o m p a r a b l e gestational age who received their neonatal care during the same time period. Two control patients were identified for each N E C patient by selecting the first neonate admitted to the N I C U before and after the N E C patient in whom birth weight (appropriate for gestational age) was within 50 gm (Table I). Since some overlap of control patients occurred, the final number of control patients obtained was 98. The average age when admitted to the N I C U was 15.9 hours for N E C and 17.3 hours for control patienis. Apgar scores, available in approximately two-thirds of the control and of the NEC patients, were not significantly different at either one or five minutes of age. In e a c h g r o u p , a p p r o x i m a t e l y 30% h a d a f i v e - m i n u t e Apgar score of ( 5 (Table II). Twenty percent of each group had a flush blood pressure ( 30 m m Hg before or at the time of admission to the NICU. During this same period, 20% of each group also had at least one rectal temperature recorded of ~< 36 ~ C. Reflecting the high incidence of RDS in our referral population, 73% of N E C patients and 75% of control patients had RDS. Even when classified according to severity of RDS on the basis of a need for assisted ventilation, the frequency of mild and severe RDS was similar in the two groups. In 52 (96%) of the NEC patients, umbilical arterial catheters, typically positioned in the low thoracic aorta, were inserted as part of their initial management. The
Volume 86 Number 2
Necrotizing enterocolitis
T a b l e II. Fre~luency o f a c u t e illness v a r i a b l e s in t h e N E C a n d c o n t r o l )atients*
261
T a b l e III. F r e q u e n c y of i n t e s t i n a l bacterial c o l o n i z a t i o n in N E C a n d c o n t r o l p a t i e n t s as d e t e r m i n e d b y stool Cult u r e s o b t a i n e d On t h e day o f life t h a t N E C o c c u r r e d *
Percent of patients Statistical NEC Conttvls signg/icance Acute illness variable (54patients) (98patients) (P) Perinatal stresses Birth asphy'xia Hypotension Hypothermia RDS Unassisted Assisted ventilation Total % Umbilical catheters Arterial Venous Enteric feedings Septicemia DIC
30 20 20 31 42 73 961" 695 100 37 48
32 20 20 29 46 75 73 43 63 14 16
NS NS NS NS NS NS 0.001 0.005 < 0.001 0.002 ( 0.001
*Birth asphyxia was defined as a five-minute Apgar score of ~< 5, hypotension as a flush blood pressure of < 30 mm Hg, and hypothermia as at least one recorded rectal temperature of ~<36~ For each NEC patient and his matched control(s), enteric feedings were evaluated on the day of life that NEC developed. The difference in frequency of use of umbilical catheters was not statistically significant when corrected for those removed more than 24 hours prior to onset of NEC. Although DIC and septicemia occurred significantly more often in NEC patients, they did not precede the development of abdominal symptoms. tOn day of life NEC developed, catheter was still in place in 80% of total group, a nonsignificant difference when compared to control patients. SOn day of life that NEC developed, only 43% of total group still had a catheter in place.
c a t h e t e r was r e m o v e d m o r e t h a n 24 h o u r s prior to o n s e t o f N E C s y m p t o m s in n i n e i n f a n t s ; only 80% o f N E C p a t i e n t s , t h e r e f o r e , h a d .an arterial c a t h e t e r in place o n t h e day of life t h a t N E C developed. I n t h e c o n t r o l group, a n u m b i l i c a l arterial c a t h e t e r was utilized in 73% o f t h e patients. A v e r a g e d u r a t i o n o f i n s e r t i o n of t h e arterial c a t h e t e r was 7.7 (___ 0.9) days in N E C as c o m p a r e d to 5.4 ( ___ 0.7) d a y s in c o n t r o l p a t i e n t s ( P ( . 0 5 ) . I n 69% o f N E C p a t i e n t s , a n u m b i l i c a l v e n o u s c a t h e t e r was i n s e r t e d arid typically p o s i t i o n e d in t h e i n f e r i o r v e n a c a v a Or r i g h t a t r i u m . T h e c a t h e t e r was r e m o v e d m o r e t h a n 24 h o u r s p r i o r to o n s e t of N E C s y m p t o m s in n i n e p a t i e n t s ; c o n s e q u e n t l y , o n t h e day o f life t h a t N E C o c c u r r e d , only 43% h a d a n u m b i l i c a l v e n o u s c a t h e t e r in place. U m b i l i c a l v e n o u s c a t h e t e r s w e r e utilized in 43% o f t h e c o n t r o l patients. All 54 N E C p a t i e n t s w e r e r e c e i v i n g oral f e e d i n g s u n til t h e o n s e t o f N E C s y m p t o m s . On t h e s a m e day o f life t h a t s y m p t o m s d e v e l o p e d in t h e m a t c h e d N E C patients, o n l y 63% ( P < 0.001) o f c o n t r o l p a t i e n t s w e r e also
Percent positive - ~ NEC [ Controls (51 patients) [(50 patients)
1 1 Statistical Isignificance 1 (P)
Organisms
Klebsiella E. coli Staphylococcus albus Alpha Streptococcus Candida albicans Enterococcus
Pseudomonas Group B
38
16
36 30 24 16 10 8 2
22 30 20 18 6 2 0
0.03
14
24
NS
47 7 47 14
42 6 35 10
NS NS NS NS
.:
NS NS NS NS NS NS NS
Streptococcus Sterile Antibiotics Penicillin Ampicillin Kanamycin Gentamicin
*In most patients, more than one organism was isolated. The only significant difference between the two groups was a higher frequency of Klebsiella colonization in NEC patients.
r e c e i v i n g oral feedings. F o r b o t h groups, a s t a n d a r d 20 c a l / o u n c e c o m m e r c i a l formula* was u s e d a n d t h e average v o l u m e p e r f e e d i n g was 15 m l / k g , g i v e n e v e r y two to t h r e e hours. F o r b o t h N E C a n d c o n t r o l p a t i e n t s t h e a v e r a g e total caloric i n t a k e was 80 cal/kg/day. Stool c u l t u r e s w e r e o b t a i n e d in 51 (94%) o f N E C patients at t h e o n s e t o f N E C s y m p t o m s . On t h e s a m e day o f life t h a t s y m p t o m s d e v e l o p e d in the m a t c h e d N E C p a t i e n t , stool c u l t u r e s w e r e o b t a i n e d in 50 (51%) o f t h e c o n t r o l p a t i e n t s ( T a b l e l i D . T h e o n l y statistically signif i c a n t difference ( P ( 0 . 0 3 ) was a h i g h e r f r e q u e n c y of Klebsiella c o l o n i z a t i o n in t h e N E C group. A l t h o u g h t h e majority of our NEC and control patients with intestinal Klebsiella c o l o n i z a t i o n h a d e i t h e r T y p e 33 or 26, t h e ass o c i a t i o n b e t w e e n N E C a n d i n t e s t i n a l Klebsiella colo n i z a t i o n was n o t r e s t r i c t e d to t h e s e two types. T h e r e w e r e n o statistically s i g n i f i c a n t differences b e t w e e n t h e N E C a n d c o n t r o l g r o u p s in r e s p e c t to a n t i b i o t i c treatm e n t at t h e t i m e i n t e s t i n a l c o l o n i z a t i o n was e v a l u a t e d ( T a b l e III). 9C o n c o m i t a n t with t h e o n s e t of N E C , 20 (45%) o f t h e 44 N E C p a t i e n t s w i t h p o s i t i v e stool c u l t u r e s d e v e l o p e d *Similac or SMA, with osmolar concentrations of 330 or 300 mOsm/l, respeCtively.
262
Frantz et al.
septicemia from one of the organisms present in the stool, typically Escherichia coli or Klebsiella. In the 38 control patients with positive stool cultures, six (16%) developed septicemia from one of the organisms present. Overall, 37% of the total NEC and 14% of the total control groups developed septicemia in the course of their acute illness. As described above, DIC occurred in 26 N E C patients, 21 in association with NEC and five (11% of all N E C patients) at an earlier time in association with severe hypoxia and acidosis. In the control group, DIC related to hypoxia and acidosis occurred with the same frequency (11%) as in the N E C patients. In total, 16% of c o n t r o l p a t i e n t s d e v e l o p e d D I C during their N I C U course. The only DIC survivors in either group were four N E C patients .who developed DIC concurrently with the onset of abdominal symptoms. DISCUSSION A variety of causes for N E C have been suggested, ranging from ischemic intestinal damage to infection, intolerance of enteric feedings, exchange transfusions, and reactions to umbilical catheters. 3-8The comparison between N E C and control patients was made in order to evaluate the potential relationship of NEC to any of these factors. Our experience does not indicate any relationship between exchange transfusion and NEC. 9, 10 Only three NEC patients had an exchange transfusion prior to onset of symptoms and the frequency of N E C was not higher in patients receiving exchange transfusion than in patients without exchange transfusion. The umbilical arterial catheter has been frequently mentioned as a possible etiologic factor. Although a high frequency of thrombi, most often asymptomatic, associated with umbilical arterial catehters has been reported, 11thrombi in the aortic or mesenteric artery were seen at autopsy in only three patients in this series a n d in only two previously reported cases? Furthermore, routine positioning of the arterial catheter just above the aortic bifurcation rather than in the low thoracic aorta has not led to a decreased incidence of NEC32 Other reports of N E C patients have cited a varying f r e q u e n c y of u m b i l i c a l arterial c a t h e t e r i z a t i o n . 5, 8 Almost all N E C patients in our series had an arterial catheter inserted as part of their initial management. If we do not include the patients in w h o m the catheter was removed more than 24 hours before onset of NEC Symptoms, however, the frequency becomes identical to that in control patients. The somewhat longer average d u r a t i o n o f u m b i l i c a l arterial c a t h e t e r i z a t i o n in
The Journal of Pediatrics February 1975
N E C patients may well be secondary to the deteriorating clinical status occurring at this time rather than a primary cause of NEC. Perinatal hypotension and/or hypoxemia, especially in the premature infant, have been suggested as a cause of intestinal mucosal ischemia, bacterial invasion of the b o w e l wall, and, s u b s e q u e n t l y , the d e v e l o p m e n t of NEC.8,13-15 Since frequency of the various gross indicators of perinatal hypoxia was identical in the NEG, and control patients, our data neither prove nor disprove the etiologic role of hypoxemic intestinal damage. In both infants and adult patients, an association between N E C and clinical and/or laboratory evidence of DIC has been recognized. 7,13,16 The DIC, which developed concurrently with the development of NEC in 21 patients Could not be directly related to septicemia, was observed to occur in those patients with more severe N.EC, and could not b e reversed unless treatment included surgical resection of necrotic bowel. Since the DIC associated with N E C occurred only in patients who, at surgery, had bowel necrosis requiring resection, it is probable that in such patients DIC occurred secondary to release of tissue thromboplastin from the necrotic bowel. Disseminated intravascular coagulation has not occurred in patients successfully managed medically and may, therefore, be helpful in defining those patients with intestinal necrosis who require surgical treatment. However, in one of the three patients with massive and unresectable NEC, no DIC was present. The development of PI has been shown to require carbohydrate in the intestinal tract plus the presence of bacteria in the duodenum. 17 We have previously reported data demonstrating that both substrate (formula feedings) and enteric bacteria are necessary for the production of hydrogen gas, and that hydrogen is a major constituent of the intramural gas found in NEC. 18 C o n s i d e r i n g t h e ability of Klebsiella to p r o d u c e hydrogen gas, 18it may be significant that the incidence of intestinal colonization with Klebsiella 19 w a s increased in the N E C patient as compared to the control patient. Although most reports have not contained detailed information on oral feedings, Bell and associates 2~ did mention that 42 of their 43 patients had been fed. Other i n v e s t i g a t o r s have s t r e s s e d the i m p o r t a n c e of c o w ' s milk feedings 2t or the early feeding of hypertonic solutions 22-24as being important in the etiology of NEC. All 54 patients in our series received oral feedings prior to the onset of symptoms. Although the percentage of patients being fed was much greater in the N E C group, the volume, caloric intake, and osmolarity were no dif-
Volume 86 Number 2
f e r e n t than in the c o n t r o l group. Our e x p e r i e n c e , therefore, does not support a relationship between hyperosmolar feedings and NEC. Pitt and associates 25 have demonstrated that breast milk protects rats against e x p e r i m e n t a l l y p r o d u c e d NEC, and that macrophages contained in the breast milk are able to kill Klebsiella. However, since none of the N E C or control patients in our series were fed breast milk, we cannot c o m m e n t on the clinical significance of this observation. During 1973, eight of ten patients managed medically and five of !5 managed surgically have survived, for an overall survival of 52%. Although the outlook for N E C seems to be improving, the etiology remains unclear. P e r h a p s requiring a background of mucosal ischemia, the combined presence of intestinal bacteria and enteric feedings appear to be of etiologic significance in the development of NEC. To further define the importance of enteric feedings and intestinal bacteria in the first two weeks of life, prospective studies need to be d o n e utilizing low-risk m e t h o d s for controlling intestinal bacterial colonization and alternate methods for providing appropriate nutrition. Acknowledgement is given to James Zarembinski, Siv Modler, B.S,, and Beverly Conerton, B.A. for their assistance in the collection of data and preparation of this report. REFERENCES
1. Roback SA, Foker J, Frantz 1, Hunt CE, Engel RR, and Leonard AS: Necrotizing enterocolitis: An emerging entity in the regional infant intensive care facility, Arch Surg 109:314, 1974. la. Bell RS, Graham CB, and Stevenson JK: Roentgenologic and clinical manifestations of neonatal necrotizing enterocolitis, Am J Roentgenol Rad Therapy Nucl Med 112:123, 1971. 2. Pochaczevsky R, and Kassner EG: Necrotizing enterocolitis Of infancy, Am J Roentgenol Rad Therapy Nucl Med 113:283, 1971. 3. Rosenfield CR: Necrotizing enterocolitis, NY Acad Med 47:161, 1971. 4. Tan KL, Tan AYO, and Wong TTT: Necrotizing enterocolitis in young infants, Clin Pediatr 11:44, 1972. 5. Cohn R, Sunshine P, and deVries P: Necrotizing en"terocolitis in the newborn infant, Am J Surg 124:165, 1972. 6. D~nes J, Gergely K, Wholmuth G, and Lgb J: Necrotizing enterocolitis of premature infants, Surgery 68:558, 1970. 7. Hopkins GB, Gould VE, Stevenson JK, and Oliver TK: Necrotizing enterocolitis in premature infants, Am J Dis Child 120:229, 1970.
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263
8. Stevenson JK, Oliver TK, Graham CB, Bell RS, and Gould VE: Aggressive treatment of neonatal necrotizing enterocolitis: 38 patients with 25 survivors, J Pediatr Surg 6:28, 1971. 9. Friedman AB, Abellera RM, Lidsky I, and Lubert M: Perforation of the colon after exchange transfusion in the newborn, N Engl J Med 282:796, 1970. 10. Touloukian RJ, Kadar A, and Spencer RP: The gastrointestinal complications of neonatal umbilical venous exchange transfusion: A clinical and experimental study, Pediatrics 51:36, 1973. 11. Neal WA, Reynolds JW, Jarvis CW and Williams HJ: Umbilical arterial catheterization: Demonstration of arterial thrombosis by aortography, Pediatrics 50:6, 1972. 12. Reynolds JWi Personal communication. 13. Wilson, SE, and Wooly MM: Primary necrotizing enterocolitis in infants, Arch Surg 99:563, 1969. 14. Touloukian RJ, Posch JN, and Spencer R: The pathogenesis of ischemic gastroenterocolitis of the neonate: Selective gut mucosal ischemic in asphyxiated neonatal piglets, J Pediatr Surg 7:194, 1972. 15. Broadie TA, Devedas M, Rysavy J, Delaney JP, and Leonard AS: The effect of hypoxia and posterior hypothalamic stimulation on colonic blood flow in the weanling puppy, J Pediatr Surg 8:747, 1973. 16. Whitehead R: Ischaemic enterocolitis: an expression of the intravascular coagulation syndrome, Gut 12:9!2, 1971. 17. Coello-Rami{ez P, Gutierrex-Topete G, and Lifshitz F: Pneumatosis intestinalis, Am J Dis Child 120:3, 1970. 18. Engel RR, Virnig NL, Hunt CE, and Levitt MD: Origin of mural gas in necrotizing enterocolitis, Pediatr Res 7:292/64, 1973. 19. Hill HR, Hunt CE, and Matsen JM: Nosocomial colonization with Klebsiella, Type 26, in a neonatal intensive-care Unit associated with an outbreak of sepsis, meningitis, and necrotizing enterocolitis, J PEDIATR85:415, 1974. 20. Bell RS, Graham CB, and Stevenson JK: Roentgenologic and clinical manifestations of neonatal necrotizing enterocolitis, Am J Roentgenol 112:123, 1971. 21. Mizrahi A, Barlow O, Berdon W, Blanc WA, and Silverman WA: Necrotizing enterocolitis in premature infants, J PEDIATR66:697, 1965. 22. Torma MJ, DeLemos RA, Rogers JR, and Diserens HW: Necrotizing enterocolitis in infants, Am J Surg 126:758, 1973. 23. Book LS, Herbst J J, and Jung AL: Necrotizing enterocolitis in infants fed an elemental formula, Pediatr Res 8:379/105, 1974. 24. Delemos RA, Rogers JH, and McLaughlin GW: Experimental production of necrotizing enterocolitis in newborn goats, Pediatr Res 8:380/106, 1974. 25. Pitt J, Barlow B, Heird WC, and Santulli TV: Macrophages and the protective action of breast milk in necrotizing entercolitis, Pediatr Res 8:384/110, 1974.