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An update on necrotizing enterocolitis
Current Paediatrics (1997) 7, 207-212 © 1997 Harcourt Brace & Co Ltd
Mini-symposium: Gastroenterology
An update on necrotizing enterocolitis
J. A. Morecroft, R. C. Coombs
Neonatal necrotizing enterocolitis (NEC) is an inflammatory condition of the bowel that is characterized by abdominal distension, intolerance of enteral feeds, the passage of blood per rectum and pneumatosis intestinalis and predominantly affects premature babies. The reported incidence ranges from 0.4 to 14 per 1000 live births and affects up to 5% of admissions to neonatal intensive care units. A recent UK survey revealed around 300 cases per year while OPCS data show NEC caused or contributed to death in between 70 and 100 cases annually. There is also considerable short-term morbidity from stricture formation and from liver failure as a result of prolonged total parenteral nutrition. Despite familiarity with the condition, little has changed in the management of these patients since Bell et al rationalized the treatment of NEC according to clinical staging.1 In this review we highlight some of the more important advances or observations, review management, staging and the indications for surgery, and speculate a little on where future advances may come from.
severe asphyxia or exchange transfusion. In more mature infants (30-40 weeks) NEC is often associated with significant growth retardation? INTRAUTERINE GROWTH RETARDATION AND ABSENT END DIASTOLIC FLOW
Abnormal flow patterns in the umbilical artery or fetal descending aorta detected by D6ppler ultrasound have been associated with intrauterine growth retardation and perinatal asphyxia, and several studies have reported an incidence of NEC up to 50% in these high-risk babies. 3,4 The antenatal ultrasound finding of bright or echogenic bowel also seems to be associated with growth retardation, sticky meconium, delayed tolerance of oral feed and the development of NEC. Kempley et al reported significantly lower bloodflow velocity in the superior mesenteric artery in very low birth-weight growth-retarded infants compared to weight and gestation matched controls, and this was most marked in those babies with absent end diastolic flow documented on antenatal scans? There are very little data on the histological characteristics of the preterm human gut because of rapid autolysis. However, in an ovine model of intrauterine growth retardation the small intestine shows a significant decrease in villus height and both crypt and villus density, characteristics of a more immature gut. This might explain the association between growth retardation and NEC. 6
W H O IS AT RISK?
While prematurity has always been recognized as an important factor, it has not proved a good predictor for those at risk. NEC is mainly seen in infants under 30 weeks' gestation increasing in incidence as age decreases to 10% at 25 weeks. It is uncommon in term infants, when it is associated with events such as
AGE AT O N S E T James A. Morecroft MA, MChir, FRCS(Paed), Paediatric Surgery
In many reported series, there is an inverse relationship between the age at onset of symptoms and birth weight, with larger more mature infants presenting early, possibly reflecting a predictable response to a
Unit, Sheffield Children's Hospital. Robert C. Coombs BSe, MRCP, Neonatal Intensive Care Unit, Jessop Hospital for Women, Leavygreave Road, Sheffield $3 7RE, UK. Correspondence and requests for offprints to RCC.
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Fig. 1. Age at onsetof necrotizingenterocolitisrelatedto birth weightin a seriesof 55 patients.
recognized insult (Fig. 1). The development of NEC also depends on what the infant is fed, with several studies demonstrating a protective effect of breast milk. Lucas and Cole found a threefold increase in incidence of NEC in those babies fed formula over those fed with breast milk2
AETIOLOGY OF NECROTIZING ENTEROCOLITIS Attempts to explain the pathogenesis of this devastating neonatal condition have focused on three separate areas: mucosal injury secondary to mesenteric ischaemia occurring during perinatal stress, the role of bacteria and viruses, and the importance of enteral feeding, particularly with infant formulas. Attempts to integrate these three concepts into a unified hypothesis on a quantitative basis have proved unsatisfactory as 95% of neonates exposed to the same perinatal stress, colonized with the same organisms and fed the same formula do not develop NEC, suggesting that other factors, such as host susceptibility, play an important role) While the gastrointestinal tract has been the primary focus of attention with regard to the clinical manifestation, aetiology and treatment of NEC, little note has been taken of failure in other organ systems. The development of renal failure, coagulopathy and disseminated intravascular coagulation, hepatic dysfunction and the need for respiratory or circulatory support are seen as a result of secondary sepsis rather than part of a primary multisystem disorder. Multisystem organ failure is a well characterized syndrome of sequential organ failure, often related to gram-negative sepsis or trauma, in which inflammatory mediators, such as cytokines, oxygen derived free radicals, platelet activating factor, leukotrienes, thromboxane and complement play an important role. Cytokines, such as tumour necrosis factor c~(TNF) and interleukin 6 (IL-6), play an important role in the
pathogenesis of multisystem organ failure following septic shock and have recently been implicated in NEC. The development of anti-cytokine therapy and monoclonal antibodies offers promise for the treatment of multisystem organ failure associated with septic shock and may also be appropriate for the treatment of necrotizing enterocolitis, /f these cytokines can be shown to be active in the clinical disease. A review of 46 infants treated for NEC revealed evidence of respiratory failure in 42 (91%), renal failure in 39 (85%), cardiovascular failure in 38 (83%), haematological failure in 37 (80%), microvascular failure in 15 (33%) and hepatic failure in 7 (15%).9While such high rates of failure are not unexpected, in view of the life threatening nature of the disease, failure of other systems occurred in over 50% of infants before NEC became clinically apparent, raising the possibility that it is not simply a disorder of the gastrointestinal tract. In a prospective study of 24 infants with NEC, TNF was detected in the plasma of 79% of the patients, but at levels which were considerably lower than those previously reported in neonatal septic shock?° The initial plasma TNF concentration was neither helpful as an indicator of disease severity nor as a predictor of outcome? z IL-6 was detected in the plasma of 75% of the patients and was significantly higher in those infants with advanced disease that required surgery. A persistently raised IL-6 was a sensitive indicator of such advanced disease, but the wide range of initial plasma levels resulted in IL-6 being a poor predictor of outcome.
MUCOSAL INJURY As histological evidence of mucosal injury is one of the predominant features of NEC, it is not surprising that direct or indirect injury to the mucosa has been suggested as the cause of NEC. Direct injury from hyperosmolar feeds and indirect injury by cellular hypoxia from asphyxia, hypovolaemia, hypothermia, umbilical artery catheters, exchange transfusions and indomethacin have all been proposed as the initiating event. While there are some data on time to first stool in the neonatal population, there is little information on time to changing stool. This is often delayed in the preterm or growth-retarded infant resulting in the retention of undigested food, such as lactose, that can facilitate bacterial overgrowth and possible subsequent mucosal injury.
ASPHYXIA With the development of special care baby units in the 1960s, necrotizing enterocolitis became widely recognized. Many of these early series highlighted prematurity and perinatal stress, particularly birth asphyxia, as factors which might be important in the
An update on necrotizing enterocolitis development of NEC. Lloyd's review of 87 infants with gastrointestinal perforations suggested over 80% had experienced perinatal asphyxia? 2 Following Scholander's description of the diving reflex, they suggested that after a perinatal episode of hypoxia or cooling, ischaemia of the bowel wall leads to loss of mucosal integrity with invasion by gas-forming organisms. INDOMETHACIN Indomethacin is a prostaglandin synthetase inhibitor used in the treatment of symptomatic patent-ductus arteriosus. Nagaraj et al reported an increased incidence of NEC following indomethacin treatment compared to primary ligation or fluid restriction and diuretics. 13 Infants with patent-ductus arteriosus, characteristically, have absent or retrograde diastolic flow in the superior mesenteric artery suggesting a compromised flow. A rapid and profound fall in superior mesenteric artery peak systolic velocity further compromising the mucosa occurs after bolus administration of indomethacin and can be prevented by slow intravenous infusion. 14 CLINICAL PRESENTATION NEC presents, initially, with non-specific symptoms such as lethargy, refusal of feeds, temperature instability and episodes of bradycardia and apnoea. The symptoms of intestinal obstruction, namely bile stained vomiting or nasogastric aspirate and abdominal distension, develop later followed by evidence of gastrointestinal bleeding with the passage of blood stained stools. Examination may reveal an unresponsive child with abdominal distension and visible loops of bowel. An umbilical flare progressing to erythema of the abdominal wall indicates parietal inflammation. Rarely, a mass may be palpable as the result of localized intra-abdominal inflammation. Intra-abdominal crepitus from extensive pneumatosis is a late feature of advanced disease.
HAEMATOLOGICAL ASPECTS OF NEC Neutropenia is frequently seen and thrombocytopaenia may be the first indication of unhealthy bowel in an otherwise well neonate. There may be evidence of disseminated intravascular coagulation with prolonged thrombin and partial thromboplastin times, decreased plasma fibrinogen, elevated fibrin-split products and markedly reduced antithrombin-III.
THOMSEN-FRIEDENREICH CRYPTANTIGEN The Thomsen-Friedenreich cryptantigen, (T anti-gen) is a naturally occurring antigen on the surface of red
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cells that is normally concealed by a N-acetylneuraminic-acid residue. Neuraminidase, produced by Clostridia, Bacteroides and Streptococcus pneumoniae, can remove the N-acetylneuraminic acid to expose the cryptantigen and render the red cells susceptible to haemolysis by anti-T-antigen antibodies, that are present in human plasma from the age of 6 months onwards and develop in the same way as anti-A and anti-B isohaemagglutinins. The presence of T-activation can be detected, by a rapid agglutination test using peanut lectin, in up to 11% of babies with NEC compared to 0.1% for all other neonatal admissions. '5 Exchange transfusion has been advocated prior to surgery in infants with established haemolysis using saline-adenine-glucose-mannitol (SAGM blood)? 6 Many units do not see this haemolysis, possibly because of their use of SAGM blood for routine neonatal top-up transfusions.
RADIOLOGICAL FEATURES The hallmark of NEC is the presence of intramural gas (Fig. 2b), which is distinct from a more benign form, pneumatosis cystoides intestinalis, found in adults with chronic obstructive airways disease in which air tracks from the mediastinum via the aortic adventitia to the mesenteric vessels and out into the subserosa. Pneumatosis may be linear (subserosal) or cystic (submucosal), is notably transient and may be difficult to distinguish from air mixed with meconium. In 20%-30% of cases pneumatosis may not be seen. Absorption of the intramural gas into the portal venous system may lead to its detection within the extrahepatic or intrahepatic portal vein in up to 25% cases, although this too may be a transient phenomenon (Fig. 2b). The presence of portal-vein gas usually signifies extensive necrosis and has been associated with a poor prognosis. The presence of free intra-abdominal air signifies intestinal perforation, but this may be difficult to visualize. The football sign, 17outlining of both sides of the falciform ligament (Fig. 2a) or the Doge's hat sign, TM a triangular lucency from air in the hepatorenal space, are two of the subtle signs of intestinal perforation in necrotizing enterocolitis. Dissatisfaction with the plain abdominal radiograph has led to the use of additional imaging modalities to improve the diagnosis of NEC. The detection of echogenic intravascular and hepatic microbubbles in infants with NEC was first reported as an incidental finding during echocardiography, and may be seen before any radiographic abnormalities are observed. D6ppler ultrasound has not, as yet, been able to predict the occurrence of NEC, though abnormalities in splanchnic perfusion have been seen in those at risk. 1~ In vitro evidence suggests that magnetic resonance imaging may be able to detect bowel ischaemia at an early stage. Phosphorus nuclear magnetic-resonance
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a
b
Fig 2 a) Intestinal perforation with air either side of falciform ligament (football sign); b) pneumatosis and portal vein gas
imaging correlated with the histological evidence of ischaemia in rats subjected to varying amounts of mesenteric ligation. The clinical application of both these techniques is limited by the size, availability and the cost of the equipment.
CLINICAL STAGING The severity of necrotizing enterocolitis ranges from a mild subclinical disease to frank necrosis and perforation. Bell et al classified their 48 cases of NEC into suspected, definite and advanced groups (Table 1). The British Association of Perinatal Paediatrics classification was based on features seen in 165 cases of necrotizing enterocolitis from 54 British centres. 2° Grade I cases have at least two of the following: abdominal distension; blood in faeces; hypotonia; lethargy or apnoea; or pneumatosis on an abdominal
radiograph. Grade II have, in addition, abdominal tenderness or rigidity, mucosal tissue in the stool, spontaneous bleeding, a white-cell count < 6 x 109/1, a platelet count < 100 x 109/1, radiological evidence of portalvein gas, or pneumoperitoneum. Cases are further subdivided into confirmed on the radiological presence of pneumatosis, portal-vein gas, pneumoperitoneum, or histological evidence from operation or post-mortem, and unconfirmed. An advantage of this classification is the recognition that pneumatosis is not a sine qua non for the diagnosis of necrotizing enterocolitis.
HISTOPATHOLOGY OF NEC NEC may affect any part of the gastrointestinal tract, although the duodenum and rectum are rarely involved, and may be either localized or extensive. Extensive involvement most commonly affects the
Table 1 Staging system for necrotizing enterocolitisI Stage I
Stage II
Stage III
Suspected signs AXR Definite signs AXR Advanced signs
temp instability, lethargy, apnoea, bradycardia poor feeding, gastric stasis, vomiting, abdo distension distension with mild ileus as above + tenderness + persistent occuR/overt GI blood loss intestinal distension and ileus pneumatosis intestinalis, portal vein gas as above + deterioration in vital signs septic shock, marked GI blood loss
An update on necrotizing enterocolitis 211 large bowel, while localized disease occurs most often in the terminal ileum and caecum. Diffuse involvement of almost the entire bowel, with patchy areas of gangrene and necrosis, are appropriately referred to as 'leopard spot' disease. Macroscopically at operation the bowel appears dilated and friable with areas of frank necrosis and intramural haemorrhage. Ulceration of the mucosa leads to thinning of the bowel wall, which may be composed of serosa only. Air bubbles may be seen in the bowel wall corresponding to the pneumatosis seen radiographically. An inflammatory mass may surround necrotic areas owing to attempts to localize the perforation. Microscopically the features progress from early coagulative necrosis of the mucosa, through superficial mucosal ulceration and submucosal haemorrhage, to full thickness necrosis.
MEDICAL TREATMENT The mainstays of medical or 'conservative' treatment of NEC are general supportive measures with intravenous fluid resuscitation, parenteral antibiotic therapy and the use of intermittent positive-pressure ventilation and inotropic support as necessary. As NEC is in all probability a spectrum of disease severity, the length of treatment will depend on the severity at the time of diagnosis. If symptoms are mild, 48 h bowel rest may be sufficient prior to refeeding, while more severe disease warrants 7-10 days of antibiotics and bowel rest. Surgical treatment Even though NEC has become the most common lifethreatening disorder to affect the gastrointestinal tract in the neonatal period, there is little consensus on the indications for, the timing of or the type of operation performed. Resection and primary anastomosis has been shown to be successful, avoiding the complications of stomas, such as prolapse and electrolyte loss, without excessive loss of bowel length compared to formation of stomas and their subsequent closure. Percutaneous drainage of the abdomen in extremely small neonates, originally advocated as a temporizing manoeuvre,2~has been adopted as definitive treatment in some centres, as up to 30% of neonates require no further intervention although another 30% continue to deteriorate and die.22
POST NECROTIZING ENTEROCOLITIS STRICTURE As the survival of infants with NEC improved, the sequelae of the condition became apparent. The reported incidence of stricture following non-operative management of NEC ranges from 9% to 44% with an average of around 20%. Strictures usually occur within 3 months of the acute phase, and can follow successful surgical or medical treatment. While the majority of symptomatic strictures have been treated by resection, successful balloon dilation under radiological control has been reported. PREVENTION The use of enterally administered antibiotics (kanamycin, vancomycin and gentamicin) have been used to reduce colonization and reports have suggested that the incidence of NEC has fallen. However, the emergence of resistant organisms or perceived lack of efficacy has limited their routine use. An alternative approach to reducing bacterial colonization of the gastrointestinal tract involves acidification of enteral feeds with hydrochloric acid to pH < 4 Immunoglobulins both oral and parenteral have also been recommended to prevent NEC, but again this is not widely accepted. CORTICOSTEROIDS The use of antenatal steroids in preterm labour is now well established. Most studies have concentrated on the decreased incidence of respiratory-distress syndrome, but there is also a significant reduction in incidence of NEC. Postnatal steroids also decrease the incidence of NEC, though it is also recognized that dexamethasone, used as part of the management of ventilator dependent infants, may result in isolated intestinal perforation of stomach or upper small bowel. Research into the aetiology of NEC is hampered by the lack of a reproducible animal model of the disease. Many of the reported models involve the direct manipulation of the mesenteric blood supply and the development of histological changes within hours of the insult and, as such, are models of ischaemia reperfusion injury rather than the complex pathophysiology of NEC, although this mechanism may play an important role. Other animal models have used some form of perinatal stress-to mimic the human situation, but have been difficult to reproduce consistently.
POSTOPERATIVE NEC PERSONAL PRACTICE NEC has been noted to occur postoperatively in patients with gastroschisis, long-segment oesophageal atresia and neural-tube defects. 23 It was also frequently seen post-cardiac catheterization in the sick newborn. Recurrence of NEC is again not uncommon, but why it should occur is not clear. 24
Prevention While we are happy to feed ventilated babies, even if paralysed, it is very important that feeds are not increased unless they are tolerated. This requires careful observation and monitoring of gastric residues.
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W h i l e 80% o f babies will o p e n their bowels in the first 48 h, the passage o f a c h a n g i n g stool gives m o r e reassurance as to the integrity o f bowel function. We often use suppositories, t h o u g h a c k n o w l e d g e that there is little p u b l i s h e d evidence for their use. I n those infants d e e m e d to be at risk we believe t h a t m i n i m a l enteral n u t r i t i o n is very i m p o r t a n t as t o o r a p i d an increase m a y well precipitate necrotizing N E C . We are w a r y o f the r a p i d increase in milk, often with a d d e d c a r b o h y d r a t e o r fat, in infants o f diabetic m o t h e r s o r those with low b l o o d sugars a n d feel it is safer to continue with difficult intravenous access t h a n to h o p e t h a t the infant will tolerate a large solute load. We d o n o t have access to b a n k e d b r e a s t m i l k b u t m a n a g e to start enteral n u t r i t i o n w i t h b r e a s t m i l k in a b o u t 80% o f infants, usually awaiting the arrival o f the b r e a s t m i l k before starting feeds. I f b r e a s t m i l k is unavailable we start feeds with a p r e t e r m formula.
2. 3.
4.
5. 6. 7. 8. 9.
Management O u r m a i n s t a y o f m e d i c a l t r e a t m e n t is intensive system s u p p o r t with e n d o t r a c h e a l i n t u b a t i o n a n d positivepressure o r h i g h - f r e q u e n c y oscillatory ventilation. H y p o t e n s i o n a n d a b n o r m a l c o a g u l a t i o n is m a n a g e d with F F P a n d i n o t r o p i c s u p p o r t . We still use first-line b r o a d - s p e c t r u m antibiotics, penicillin o r flucloxacillin with g e n t a m i c i n a n d m e t r o n i d a z o l e . We m o n i t o r the radiological progress with 12-24 h o u r l y a b d o m i n a l films. However, we no longer feel that perforation is an absolute indication for laparotomy, particularly in extremely low-birth-weight babies. A s w i t h m a n y surgical conditions, resuscitation a n d stabilization is p a r a m o u n t to a successful outcome. We use p e r i t o n e a l d r a i n a g e u n d e r local anaesthesia when a b d o m i n a l distension c o m p r o m i s e s ventilation in the extremely l o w - b i r t h - w e i g h t infant. S o m e o f these babies i m p r o v e a n d the decision to w a t c h a n d wait o r p e r f o r m l a p a r o t o m y at this stage is a difficult one. S o m e babies c o n t i n u e to d e t e r i o r a t e a n d die w i t h o u t l a p a r o t o m y , which, f r o m p a s t experience, does n o t influence the outcome. I n larger babies with f r a n k intestinal p e r f o r a t i o n the b a b y is stabilized a n d t r a n s p o r t e d to the o p e r a t i n g theatre for l a p a r o tomy. O u r preference is for resection o f f r a n k l y necrotic bowel a n d p r i m a r y a n a s t o m o s i s , avoiding the sequelae o f fluid a n d electrolyte loss f r o m stomas. We do n o t routinely p e r f o r m c o n t r a s t enemas on babies who have been successfully m a n a g e d conservatively, b u t await the d e v e l o p m e n t o f a b d o m i n a l distension o r intolerance o f enteral feeds in those infants who develop p o s t - N E C strictures. C o n t r a s t studies o f mucus fistulas are always d o n e p r i o r to re-anastomosis.
REFERENCES 1. Bell M J, Ternberg J L, Feigin R D, Keating J P, Marshall R, Barton L. Neonatal necrotizing enterocolitis. Therapeutic
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11. 12. 13. 14.
15. 16. 17. 18. 19.
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22. 23. 24.
decisions based upon clinical staging. Ann Surg 1978; 187: 1-7. Beeby P J, Jeffrey H. Risk factors for necrotising enterocolitis: the influence of gestational age. Arch Dis Child 1992; 67: 432.435. Hackett G A, Campbell S, Gamsu H, Cohen-Overbeek T, Pearce J M. Doppler studies in the growth retarded fetus and prediction of neonatal necrotising enterocolitis, haemorrhage, and neonatal morbidity. Br Med J 1987; 294: 13-16. Malcolm G, Ellwood D, Devonald K, Beilby R, HendersonSmart D. Absent or reversed end diastolic flow velocity in the umbilical artery and necrotising enterocolitis. Arch Dis Child 1991; 66: 805-807. Kempley S T, Gamsu H R, Vyas S, Nicolaides K. Effects of intrauterine growth retardation on postnatal visceral and cerebral blood flow. Arch Dis Child 1990; 65:115-118. Avila C G, Harding R, Rees S, Robinson P M. Small intestinal development in the growth retarded fetal sheep. J Pediatr Gastroenterol Nutr 1989; 8: 507-515. Lucas A, Cole T J. Breast milk and neonatal necrotising enterocolitis. Lancet 1990; 336: 1519-1523. Kosloske A M. A unifying hypothesis for pathogenesis and prevention of necrotizing enterocolitis. J Pediatr 1990; 117: $68 $74. Morecroft J A, Spitz L, Hamilton P A, Holmes S J K. Necrotizing enterocolitis - multisystem organ failure of the newborn? Acta Paediatrica 1994; 396 Suppl: 21~3. Morecroft J A, Spitz L, Hamilton P A, Holmes S J K. Plasma interleukin-6 and tumour necrosis factor levels as predictors of disease severity and outcome in necrotizing enterocolitis. J Pediatr Surg 1994; 29:798 800. Morecroft J A, Spitz L, Hamilton P A, Holmes S J K. Plasma cytokine levels in necrotizing enterocolitis. Acta Paediatrica 1994; 396 Suppl: 18-20. Lloyd J R. The etiology of gastrointestinal perforations in the newborn. J Pediatr Surg 1969; 4: 77-84. Nagaraj H S, Sandhu A S, Cook L N, Buchino J J, Groff D B. Gastrointestinal perforation following indomethacin therapy in very low birthweight infants. J Pediatr Surg 1981; 16:1003 1007. Coombs R C, Morgan M E I, Durbin G M, Booth I W, McNeish A S. Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin. Arch Dis Child 1990; 65: 67-71. Williams R A, Brown E F, Hurst D et al. Transfusion of infants with activation of erythroeyte T antigen. J Pediatr 1989; 115: 949-953. Squire R, Kiely E, Drake D, Lander A. Intravascular haemolysis in association with necrotising enterocolitis. J Pediatr Surg 1992; 27: 808-810. Miller R E. Perforated viscus in infants. A new roentgen sign. Radiology 1960; 74: 65. Brill P W, Olson S R, Winchester R Neonatal necrotizing enterocolitis: air in Morison pouch. Radiology 1990; 174: 469-471. Coombs R C, Morgan M E I, Durbin G M, Booth I W, McNeish A S. Abnormal gut blood flow velocities in neonates at risk of necrotising enterocolitis. J Pediatr Gastroenterol Nutr 1992; 15: 13-19. British Association for Perinatal Paediatrics and Public Health Laboratory Service Communicable Disease Surveillance Centre. Surveillance of necrotising enterocolitis 1981-2. Br Med J 1983; 287: 824.826. Ein S H, Shandling B, Wesson D, Filler R M. A 13-year experience with peritoneal drainage under local anesthesia for necrotizing enterocolitis perforation. J Pediatr Surg 1990; 25: 1034-1037. Morgan L J, Shochat S J, Hartman G E. Peritoneal drainage as primary management of perforated NEC in the very low birth weight infant. J Pediatr Surg 1994; 29:310-315. Shanbhogue L K R, Tam P K H, Lloyd D A. Necrotizing enterocolitis following operation in the neonatal period. Br J Surg 1991; 78: 1045-1047. Stringer M D, Brereton R J, Drake D P, Kiely E M, Capps S N J, Spitz L. Recurrent necrotizing enterocolitis. J Pediatr Surg 1993; 28: 979-981.
Mini-symposium: Gastroenterology
An update on necrotizing enterocolitis
J. A. Morecroft, R. C. Coombs
Neonatal necrotizing enterocolitis (NEC) is an inflammatory condition of the bowel that is characterized by abdominal distension, intolerance of enteral feeds, the passage of blood per rectum and pneumatosis intestinalis and predominantly affects premature babies. The reported incidence ranges from 0.4 to 14 per 1000 live births and affects up to 5% of admissions to neonatal intensive care units. A recent UK survey revealed around 300 cases per year while OPCS data show NEC caused or contributed to death in between 70 and 100 cases annually. There is also considerable short-term morbidity from stricture formation and from liver failure as a result of prolonged total parenteral nutrition. Despite familiarity with the condition, little has changed in the management of these patients since Bell et al rationalized the treatment of NEC according to clinical staging.1 In this review we highlight some of the more important advances or observations, review management, staging and the indications for surgery, and speculate a little on where future advances may come from.
severe asphyxia or exchange transfusion. In more mature infants (30-40 weeks) NEC is often associated with significant growth retardation? INTRAUTERINE GROWTH RETARDATION AND ABSENT END DIASTOLIC FLOW
Abnormal flow patterns in the umbilical artery or fetal descending aorta detected by D6ppler ultrasound have been associated with intrauterine growth retardation and perinatal asphyxia, and several studies have reported an incidence of NEC up to 50% in these high-risk babies. 3,4 The antenatal ultrasound finding of bright or echogenic bowel also seems to be associated with growth retardation, sticky meconium, delayed tolerance of oral feed and the development of NEC. Kempley et al reported significantly lower bloodflow velocity in the superior mesenteric artery in very low birth-weight growth-retarded infants compared to weight and gestation matched controls, and this was most marked in those babies with absent end diastolic flow documented on antenatal scans? There are very little data on the histological characteristics of the preterm human gut because of rapid autolysis. However, in an ovine model of intrauterine growth retardation the small intestine shows a significant decrease in villus height and both crypt and villus density, characteristics of a more immature gut. This might explain the association between growth retardation and NEC. 6
W H O IS AT RISK?
While prematurity has always been recognized as an important factor, it has not proved a good predictor for those at risk. NEC is mainly seen in infants under 30 weeks' gestation increasing in incidence as age decreases to 10% at 25 weeks. It is uncommon in term infants, when it is associated with events such as
AGE AT O N S E T James A. Morecroft MA, MChir, FRCS(Paed), Paediatric Surgery
In many reported series, there is an inverse relationship between the age at onset of symptoms and birth weight, with larger more mature infants presenting early, possibly reflecting a predictable response to a
Unit, Sheffield Children's Hospital. Robert C. Coombs BSe, MRCP, Neonatal Intensive Care Unit, Jessop Hospital for Women, Leavygreave Road, Sheffield $3 7RE, UK. Correspondence and requests for offprints to RCC.
207
208
Current Paediatrics 50 o
40 o ,,, 30 Z "O
20 .
r=-041
10 0 501
- -~- ~O ° °Oo" ' ~• I
1500
" 0 0 " 0 ~ I
2500
0 I
3500
: I
4500
birth weight (g)
Fig. 1. Age at onsetof necrotizingenterocolitisrelatedto birth weightin a seriesof 55 patients.
recognized insult (Fig. 1). The development of NEC also depends on what the infant is fed, with several studies demonstrating a protective effect of breast milk. Lucas and Cole found a threefold increase in incidence of NEC in those babies fed formula over those fed with breast milk2
AETIOLOGY OF NECROTIZING ENTEROCOLITIS Attempts to explain the pathogenesis of this devastating neonatal condition have focused on three separate areas: mucosal injury secondary to mesenteric ischaemia occurring during perinatal stress, the role of bacteria and viruses, and the importance of enteral feeding, particularly with infant formulas. Attempts to integrate these three concepts into a unified hypothesis on a quantitative basis have proved unsatisfactory as 95% of neonates exposed to the same perinatal stress, colonized with the same organisms and fed the same formula do not develop NEC, suggesting that other factors, such as host susceptibility, play an important role) While the gastrointestinal tract has been the primary focus of attention with regard to the clinical manifestation, aetiology and treatment of NEC, little note has been taken of failure in other organ systems. The development of renal failure, coagulopathy and disseminated intravascular coagulation, hepatic dysfunction and the need for respiratory or circulatory support are seen as a result of secondary sepsis rather than part of a primary multisystem disorder. Multisystem organ failure is a well characterized syndrome of sequential organ failure, often related to gram-negative sepsis or trauma, in which inflammatory mediators, such as cytokines, oxygen derived free radicals, platelet activating factor, leukotrienes, thromboxane and complement play an important role. Cytokines, such as tumour necrosis factor c~(TNF) and interleukin 6 (IL-6), play an important role in the
pathogenesis of multisystem organ failure following septic shock and have recently been implicated in NEC. The development of anti-cytokine therapy and monoclonal antibodies offers promise for the treatment of multisystem organ failure associated with septic shock and may also be appropriate for the treatment of necrotizing enterocolitis, /f these cytokines can be shown to be active in the clinical disease. A review of 46 infants treated for NEC revealed evidence of respiratory failure in 42 (91%), renal failure in 39 (85%), cardiovascular failure in 38 (83%), haematological failure in 37 (80%), microvascular failure in 15 (33%) and hepatic failure in 7 (15%).9While such high rates of failure are not unexpected, in view of the life threatening nature of the disease, failure of other systems occurred in over 50% of infants before NEC became clinically apparent, raising the possibility that it is not simply a disorder of the gastrointestinal tract. In a prospective study of 24 infants with NEC, TNF was detected in the plasma of 79% of the patients, but at levels which were considerably lower than those previously reported in neonatal septic shock?° The initial plasma TNF concentration was neither helpful as an indicator of disease severity nor as a predictor of outcome? z IL-6 was detected in the plasma of 75% of the patients and was significantly higher in those infants with advanced disease that required surgery. A persistently raised IL-6 was a sensitive indicator of such advanced disease, but the wide range of initial plasma levels resulted in IL-6 being a poor predictor of outcome.
MUCOSAL INJURY As histological evidence of mucosal injury is one of the predominant features of NEC, it is not surprising that direct or indirect injury to the mucosa has been suggested as the cause of NEC. Direct injury from hyperosmolar feeds and indirect injury by cellular hypoxia from asphyxia, hypovolaemia, hypothermia, umbilical artery catheters, exchange transfusions and indomethacin have all been proposed as the initiating event. While there are some data on time to first stool in the neonatal population, there is little information on time to changing stool. This is often delayed in the preterm or growth-retarded infant resulting in the retention of undigested food, such as lactose, that can facilitate bacterial overgrowth and possible subsequent mucosal injury.
ASPHYXIA With the development of special care baby units in the 1960s, necrotizing enterocolitis became widely recognized. Many of these early series highlighted prematurity and perinatal stress, particularly birth asphyxia, as factors which might be important in the
An update on necrotizing enterocolitis development of NEC. Lloyd's review of 87 infants with gastrointestinal perforations suggested over 80% had experienced perinatal asphyxia? 2 Following Scholander's description of the diving reflex, they suggested that after a perinatal episode of hypoxia or cooling, ischaemia of the bowel wall leads to loss of mucosal integrity with invasion by gas-forming organisms. INDOMETHACIN Indomethacin is a prostaglandin synthetase inhibitor used in the treatment of symptomatic patent-ductus arteriosus. Nagaraj et al reported an increased incidence of NEC following indomethacin treatment compared to primary ligation or fluid restriction and diuretics. 13 Infants with patent-ductus arteriosus, characteristically, have absent or retrograde diastolic flow in the superior mesenteric artery suggesting a compromised flow. A rapid and profound fall in superior mesenteric artery peak systolic velocity further compromising the mucosa occurs after bolus administration of indomethacin and can be prevented by slow intravenous infusion. 14 CLINICAL PRESENTATION NEC presents, initially, with non-specific symptoms such as lethargy, refusal of feeds, temperature instability and episodes of bradycardia and apnoea. The symptoms of intestinal obstruction, namely bile stained vomiting or nasogastric aspirate and abdominal distension, develop later followed by evidence of gastrointestinal bleeding with the passage of blood stained stools. Examination may reveal an unresponsive child with abdominal distension and visible loops of bowel. An umbilical flare progressing to erythema of the abdominal wall indicates parietal inflammation. Rarely, a mass may be palpable as the result of localized intra-abdominal inflammation. Intra-abdominal crepitus from extensive pneumatosis is a late feature of advanced disease.
HAEMATOLOGICAL ASPECTS OF NEC Neutropenia is frequently seen and thrombocytopaenia may be the first indication of unhealthy bowel in an otherwise well neonate. There may be evidence of disseminated intravascular coagulation with prolonged thrombin and partial thromboplastin times, decreased plasma fibrinogen, elevated fibrin-split products and markedly reduced antithrombin-III.
THOMSEN-FRIEDENREICH CRYPTANTIGEN The Thomsen-Friedenreich cryptantigen, (T anti-gen) is a naturally occurring antigen on the surface of red
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cells that is normally concealed by a N-acetylneuraminic-acid residue. Neuraminidase, produced by Clostridia, Bacteroides and Streptococcus pneumoniae, can remove the N-acetylneuraminic acid to expose the cryptantigen and render the red cells susceptible to haemolysis by anti-T-antigen antibodies, that are present in human plasma from the age of 6 months onwards and develop in the same way as anti-A and anti-B isohaemagglutinins. The presence of T-activation can be detected, by a rapid agglutination test using peanut lectin, in up to 11% of babies with NEC compared to 0.1% for all other neonatal admissions. '5 Exchange transfusion has been advocated prior to surgery in infants with established haemolysis using saline-adenine-glucose-mannitol (SAGM blood)? 6 Many units do not see this haemolysis, possibly because of their use of SAGM blood for routine neonatal top-up transfusions.
RADIOLOGICAL FEATURES The hallmark of NEC is the presence of intramural gas (Fig. 2b), which is distinct from a more benign form, pneumatosis cystoides intestinalis, found in adults with chronic obstructive airways disease in which air tracks from the mediastinum via the aortic adventitia to the mesenteric vessels and out into the subserosa. Pneumatosis may be linear (subserosal) or cystic (submucosal), is notably transient and may be difficult to distinguish from air mixed with meconium. In 20%-30% of cases pneumatosis may not be seen. Absorption of the intramural gas into the portal venous system may lead to its detection within the extrahepatic or intrahepatic portal vein in up to 25% cases, although this too may be a transient phenomenon (Fig. 2b). The presence of portal-vein gas usually signifies extensive necrosis and has been associated with a poor prognosis. The presence of free intra-abdominal air signifies intestinal perforation, but this may be difficult to visualize. The football sign, 17outlining of both sides of the falciform ligament (Fig. 2a) or the Doge's hat sign, TM a triangular lucency from air in the hepatorenal space, are two of the subtle signs of intestinal perforation in necrotizing enterocolitis. Dissatisfaction with the plain abdominal radiograph has led to the use of additional imaging modalities to improve the diagnosis of NEC. The detection of echogenic intravascular and hepatic microbubbles in infants with NEC was first reported as an incidental finding during echocardiography, and may be seen before any radiographic abnormalities are observed. D6ppler ultrasound has not, as yet, been able to predict the occurrence of NEC, though abnormalities in splanchnic perfusion have been seen in those at risk. 1~ In vitro evidence suggests that magnetic resonance imaging may be able to detect bowel ischaemia at an early stage. Phosphorus nuclear magnetic-resonance
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a
b
Fig 2 a) Intestinal perforation with air either side of falciform ligament (football sign); b) pneumatosis and portal vein gas
imaging correlated with the histological evidence of ischaemia in rats subjected to varying amounts of mesenteric ligation. The clinical application of both these techniques is limited by the size, availability and the cost of the equipment.
CLINICAL STAGING The severity of necrotizing enterocolitis ranges from a mild subclinical disease to frank necrosis and perforation. Bell et al classified their 48 cases of NEC into suspected, definite and advanced groups (Table 1). The British Association of Perinatal Paediatrics classification was based on features seen in 165 cases of necrotizing enterocolitis from 54 British centres. 2° Grade I cases have at least two of the following: abdominal distension; blood in faeces; hypotonia; lethargy or apnoea; or pneumatosis on an abdominal
radiograph. Grade II have, in addition, abdominal tenderness or rigidity, mucosal tissue in the stool, spontaneous bleeding, a white-cell count < 6 x 109/1, a platelet count < 100 x 109/1, radiological evidence of portalvein gas, or pneumoperitoneum. Cases are further subdivided into confirmed on the radiological presence of pneumatosis, portal-vein gas, pneumoperitoneum, or histological evidence from operation or post-mortem, and unconfirmed. An advantage of this classification is the recognition that pneumatosis is not a sine qua non for the diagnosis of necrotizing enterocolitis.
HISTOPATHOLOGY OF NEC NEC may affect any part of the gastrointestinal tract, although the duodenum and rectum are rarely involved, and may be either localized or extensive. Extensive involvement most commonly affects the
Table 1 Staging system for necrotizing enterocolitisI Stage I
Stage II
Stage III
Suspected signs AXR Definite signs AXR Advanced signs
temp instability, lethargy, apnoea, bradycardia poor feeding, gastric stasis, vomiting, abdo distension distension with mild ileus as above + tenderness + persistent occuR/overt GI blood loss intestinal distension and ileus pneumatosis intestinalis, portal vein gas as above + deterioration in vital signs septic shock, marked GI blood loss
An update on necrotizing enterocolitis 211 large bowel, while localized disease occurs most often in the terminal ileum and caecum. Diffuse involvement of almost the entire bowel, with patchy areas of gangrene and necrosis, are appropriately referred to as 'leopard spot' disease. Macroscopically at operation the bowel appears dilated and friable with areas of frank necrosis and intramural haemorrhage. Ulceration of the mucosa leads to thinning of the bowel wall, which may be composed of serosa only. Air bubbles may be seen in the bowel wall corresponding to the pneumatosis seen radiographically. An inflammatory mass may surround necrotic areas owing to attempts to localize the perforation. Microscopically the features progress from early coagulative necrosis of the mucosa, through superficial mucosal ulceration and submucosal haemorrhage, to full thickness necrosis.
MEDICAL TREATMENT The mainstays of medical or 'conservative' treatment of NEC are general supportive measures with intravenous fluid resuscitation, parenteral antibiotic therapy and the use of intermittent positive-pressure ventilation and inotropic support as necessary. As NEC is in all probability a spectrum of disease severity, the length of treatment will depend on the severity at the time of diagnosis. If symptoms are mild, 48 h bowel rest may be sufficient prior to refeeding, while more severe disease warrants 7-10 days of antibiotics and bowel rest. Surgical treatment Even though NEC has become the most common lifethreatening disorder to affect the gastrointestinal tract in the neonatal period, there is little consensus on the indications for, the timing of or the type of operation performed. Resection and primary anastomosis has been shown to be successful, avoiding the complications of stomas, such as prolapse and electrolyte loss, without excessive loss of bowel length compared to formation of stomas and their subsequent closure. Percutaneous drainage of the abdomen in extremely small neonates, originally advocated as a temporizing manoeuvre,2~has been adopted as definitive treatment in some centres, as up to 30% of neonates require no further intervention although another 30% continue to deteriorate and die.22
POST NECROTIZING ENTEROCOLITIS STRICTURE As the survival of infants with NEC improved, the sequelae of the condition became apparent. The reported incidence of stricture following non-operative management of NEC ranges from 9% to 44% with an average of around 20%. Strictures usually occur within 3 months of the acute phase, and can follow successful surgical or medical treatment. While the majority of symptomatic strictures have been treated by resection, successful balloon dilation under radiological control has been reported. PREVENTION The use of enterally administered antibiotics (kanamycin, vancomycin and gentamicin) have been used to reduce colonization and reports have suggested that the incidence of NEC has fallen. However, the emergence of resistant organisms or perceived lack of efficacy has limited their routine use. An alternative approach to reducing bacterial colonization of the gastrointestinal tract involves acidification of enteral feeds with hydrochloric acid to pH < 4 Immunoglobulins both oral and parenteral have also been recommended to prevent NEC, but again this is not widely accepted. CORTICOSTEROIDS The use of antenatal steroids in preterm labour is now well established. Most studies have concentrated on the decreased incidence of respiratory-distress syndrome, but there is also a significant reduction in incidence of NEC. Postnatal steroids also decrease the incidence of NEC, though it is also recognized that dexamethasone, used as part of the management of ventilator dependent infants, may result in isolated intestinal perforation of stomach or upper small bowel. Research into the aetiology of NEC is hampered by the lack of a reproducible animal model of the disease. Many of the reported models involve the direct manipulation of the mesenteric blood supply and the development of histological changes within hours of the insult and, as such, are models of ischaemia reperfusion injury rather than the complex pathophysiology of NEC, although this mechanism may play an important role. Other animal models have used some form of perinatal stress-to mimic the human situation, but have been difficult to reproduce consistently.
POSTOPERATIVE NEC PERSONAL PRACTICE NEC has been noted to occur postoperatively in patients with gastroschisis, long-segment oesophageal atresia and neural-tube defects. 23 It was also frequently seen post-cardiac catheterization in the sick newborn. Recurrence of NEC is again not uncommon, but why it should occur is not clear. 24
Prevention While we are happy to feed ventilated babies, even if paralysed, it is very important that feeds are not increased unless they are tolerated. This requires careful observation and monitoring of gastric residues.
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W h i l e 80% o f babies will o p e n their bowels in the first 48 h, the passage o f a c h a n g i n g stool gives m o r e reassurance as to the integrity o f bowel function. We often use suppositories, t h o u g h a c k n o w l e d g e that there is little p u b l i s h e d evidence for their use. I n those infants d e e m e d to be at risk we believe t h a t m i n i m a l enteral n u t r i t i o n is very i m p o r t a n t as t o o r a p i d an increase m a y well precipitate necrotizing N E C . We are w a r y o f the r a p i d increase in milk, often with a d d e d c a r b o h y d r a t e o r fat, in infants o f diabetic m o t h e r s o r those with low b l o o d sugars a n d feel it is safer to continue with difficult intravenous access t h a n to h o p e t h a t the infant will tolerate a large solute load. We d o n o t have access to b a n k e d b r e a s t m i l k b u t m a n a g e to start enteral n u t r i t i o n w i t h b r e a s t m i l k in a b o u t 80% o f infants, usually awaiting the arrival o f the b r e a s t m i l k before starting feeds. I f b r e a s t m i l k is unavailable we start feeds with a p r e t e r m formula.
2. 3.
4.
5. 6. 7. 8. 9.
Management O u r m a i n s t a y o f m e d i c a l t r e a t m e n t is intensive system s u p p o r t with e n d o t r a c h e a l i n t u b a t i o n a n d positivepressure o r h i g h - f r e q u e n c y oscillatory ventilation. H y p o t e n s i o n a n d a b n o r m a l c o a g u l a t i o n is m a n a g e d with F F P a n d i n o t r o p i c s u p p o r t . We still use first-line b r o a d - s p e c t r u m antibiotics, penicillin o r flucloxacillin with g e n t a m i c i n a n d m e t r o n i d a z o l e . We m o n i t o r the radiological progress with 12-24 h o u r l y a b d o m i n a l films. However, we no longer feel that perforation is an absolute indication for laparotomy, particularly in extremely low-birth-weight babies. A s w i t h m a n y surgical conditions, resuscitation a n d stabilization is p a r a m o u n t to a successful outcome. We use p e r i t o n e a l d r a i n a g e u n d e r local anaesthesia when a b d o m i n a l distension c o m p r o m i s e s ventilation in the extremely l o w - b i r t h - w e i g h t infant. S o m e o f these babies i m p r o v e a n d the decision to w a t c h a n d wait o r p e r f o r m l a p a r o t o m y at this stage is a difficult one. S o m e babies c o n t i n u e to d e t e r i o r a t e a n d die w i t h o u t l a p a r o t o m y , which, f r o m p a s t experience, does n o t influence the outcome. I n larger babies with f r a n k intestinal p e r f o r a t i o n the b a b y is stabilized a n d t r a n s p o r t e d to the o p e r a t i n g theatre for l a p a r o tomy. O u r preference is for resection o f f r a n k l y necrotic bowel a n d p r i m a r y a n a s t o m o s i s , avoiding the sequelae o f fluid a n d electrolyte loss f r o m stomas. We do n o t routinely p e r f o r m c o n t r a s t enemas on babies who have been successfully m a n a g e d conservatively, b u t await the d e v e l o p m e n t o f a b d o m i n a l distension o r intolerance o f enteral feeds in those infants who develop p o s t - N E C strictures. C o n t r a s t studies o f mucus fistulas are always d o n e p r i o r to re-anastomosis.
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