Other state of the art to visit on
Last update: 20 July 2005
Plaen, M.D. Division of Neonatology
Box #45 Children's Memorial Hospital
Children's Memorial Research Center (Northwestern University)
2300 Children's plaza Chicago - IL 60614 Phone: 773-755-6379
Email address: email@example.com
Michael Caplan, M.D. Division of Neonatology
Evanston Northwestern Healthcare
2650 Ridge Avenue Evanston - IL 60201
Email address: firstname.lastname@example.org
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in the premature infant. Despite the recent advances of neonatal intensive care, it remains a major health concern in the intensive care nursery and an important cause of neonatal morbidity and mortality. In many cases, NEC affects apparently healthy premature infants who have no other medical problems or those who have recovered from their initial respiratory disease, look well and are feeding and growing. Early recognition of symptoms followed by immediate intervention is prudent, although no clear evidence has proven that early diagnosis can alter the outcome.
Although NEC is most commonly observed in premature infants, 10% of affected patients are born at term. Its incidence varies between 0.3 and 2.4 infants/1000 births and between 7-11% (range 3-22% in individual nursery data) amongst infants of less than 1500 g. Male and female are equally affected. There is a sharp decrease in its incidence around 35-36 weeks of post-conceptional age. The age at onset is inversely related to birth weight and gestational age (mean age of 3 weeks in the <30 weeks, 2 weeks for the 31-33 weeks and 5 days for >34 weeks, 2 days for full-term infant). NEC mortality varies between 9-28%.
Initial symptoms vary and may include feeding intolerance, abdominal distension, bloody stools, apnea, lethargy, temperature instability or hypoperfusion. Classically, increased amounts of gastric residual and abdominal distension are noted. Prior to any specific signs, the bedside nurse might have noted a decrease in the infant activity level or some temperature instability. A careful and meticulous abdominal exam might elicit localized tenderness. The speed of progression of the disease is quite variable. In some cases, the onset is sudden with little (if any) warning signs and is followed by a rapid clinical deterioration, such as severe apnea requiring intubation, persistent metabolic acidosis, decreased peripheral perfusion and hypotension requiring boluses of intravascular fluid and pressor therapy.
Infant with necrotizing enterocolitis.
1. Radiology: The abdominal Xray is the best diagnostic tool in the
evaluation of NEC. However, there is a wide range of inter-observer variability
in its interpretation. Pneumatosis intestinalis (air in the bowel wall), when
present, is diagnostic of NEC. It is thought to be due to the production of
gas from bacterial fermentation of substrate with a significant portion being
hydrogen gas. Portal venous air is seen in about 1/3 of the cases, and has been
associated with a worse prognosis in some studies. When evaluating an Xray for
possible NEC, it is important to look systematically for the presence of:
1. Pneumatosis intestinalis (diagnostic of NEC): Looking at the Xray from some distance (as with an impressionist painting) might be helpful - this might be localized to one loop of bowel. These changes might not be detectable on low-resolution digitalized images and a printed Xray film might be necessary.
2. Pneumoperitoneum (free air in the peritoneal cavity): - In a supine Xray, the air will collect anteriorly (near the umbilicus) and "a football sign" might be apparent. Air might outline the falciform ligament. - A cross-table lateral Xray might show the air collected outside the bowel loops just beneath the anterior abdominal wall. - A left lateral decubitus is an alternative to the cross-table lateral Xray. However, it is important to allow a few minutes after turning the infant and before doing the Xray for the air to migrate to the non-dependent area. Although free air in the abdominal cavity confirms it, bowel wall perforation might be present in the absence of free air in 1/3 of the cases.
3. Non specific radiological findings include a persistently abnormal gas pattern, such as a localized dilated loop of bowel seen on serial Xrays, thickened loops, ascites or a gasless abdomen.
Radiological aspect of NEC with Pneumatosis Intestinalis and portal air.
2. Laboratory evaluation:
Common laboratory abnormalities include thrombocytopenia, leukocytosis, electrolytes imbalance, metabolic acidosis, hypoxia or hypercapnia; therefore one should carefully monitor the complete blood count, electrolytes and blood gases. NEC is associated with bacteremia in approximately 30% of the cases, and a blood culture should be obtained before antibiotics are started. The fulminant form is more frequently associated with a positive blood culture.
3. Bell clinical staging:
Bell and coworkers have proposed a clinical staging classification to describe NEC severity:
- Stage I: Suspect: Infant with suggestive clinical signs but Xray non-diagnostic.
- Stage II: Definite: Infant with pneumatosis intestinalis. (IIA: mildly ill - IIB: moderately ill (acidosis, thrombocytopenia or ascites))
- Stage III: Advanced. (IIIA: Critical with impending perforation - IIIB: Critical with proven perforation)
Despite many years of research, its pathogenesis remains unknown. Several factors appear to play either a primary or a secondary role: infectious agents/toxins, enteral alimentation, mesenteric ischemia/tissue hypoxia and prematurity.
Occasional epidemics of NEC have occurred in some nurseries, and have been associated with Klebsiella, E. coli, Clostridia, coagulase negative Staphylococcus, rotavirus, and coronavirus. The newborn intestine is sterile at birth. In healthy term infants, harmonious colonization of the intestine with non-pathogenic flora occurs after birth and help to prevent bacterial overgrowth. This is facilitated by breastfeeding. The overgrowth of a single predominant stool organism has been implicated in NEC development. Bacterial products such as endotoxin trigger the inflammatory cascade and might play an important role in the pathogenesis of NEC.
NEC occurs mostly in fed infants (90%). This might be due to an increased metabolic demand of the intestine during nutrient absorption, leading to tissue hypoxia and subsequent mucosal injury. This also could be due to the availability of metabolic substrates, allowing bacterial overgrowth or to the production of food-induced toxic by-products that could alter the epithelial barrier. Breast milk is known to have some protective effects, and has been shown to reduce the incidence of NEC by 50% in some studies.
Mesenteric ischemia/tissue hypoxia:
A reduced or absent intrinsic ability of the neonatal intestine to regulate blood flow and oxygenation might contribute to intestinal necrosis as seen in NEC. In term infants, NEC has been associated with conditions that may compromise gastrointestinal oxygenation such as low Apgar scores, birth asphyxia, congenital heart disease, RDS, polycythemia, gastroschisis, umbilical vessel catheterizations, intrauterine growth retardation, exchange transfusion, and decreased in utero umbilical artery blood flow.
There is a sharp decrease in the incidence of NEC around 35-36 weeks of post-conceptional age. Many factors might contribute to the preponderance of disease in preterm infants, including impaired host defense, abnormal gut bacterial colonization, an exaggerated pro-inflammatory response, abnormal autoregulation of intestinal blood flow, depressed peristalsis, and unusual feeding patterns.
Inflammatory mediators: : The final common pathway probably involves the production of inflammatory mediators, such as Platelet-activating factor (PAF). PAF is a potent pro-inflammatory phospholipid and when given IV to rats, induces isolated bowel necrosis
Picture of acute bowel necrosis as seen in NEC, induced by an intravenous injection of PAF in a rat model.
NEC is probably the result of a complex interaction between mucosal injury caused by a variety of factors (ischemic, infectious, intraluminal) and host response to that injury (circulatory, immunologic and inflammatory).Treatment
Treatment should be undertaken without delay as soon as NEC is suspected:
1. Early bowel decompression by effective nasogastric tube suction.
2. Prompt intravenous broad spectrum antibiotic therapy (usually include ampicillin, an aminoglycoside and anaerobic bacterial coverage such as clindamycin).
3. Maintain volemia/ mesenteric perfusion. Often NEC is associated with significant third spacing of fluid into the mesentery, so intra-vascular volume supplementation is required to maintain mesenteric perfusion and to avoid worsening intestinal injury. The perfusion of the extremities (color, temperature, capillary refill time) should be carefully monitored as well as the urine output. Aiming for a urine output of 1-2 ml/kg/hour is a reasonable goal. Repeated boluses of 0.9% NaCl are often necessary over the first 72 hours to reach that goal. Low doses of dopamine (2-3 mcg/kg/min) are often helpful to improve mesenteric perfusion.
4. Except in the milder cases, because of respiratory failure and worsening acidosis, intubation mechanical ventilation is often necessary. If the infant is on CPAP, this should be discontinued and elective intubation performed to allow proper bowel decompression and to decrease the risk of apnea prompted by pain medications.
5. Pain control is essential in this extremely painful disease. In an intubated and ventilated baby, a fentanyl drip is often used at 2-4 mcg/kg/hour. Limiting the infant handling to the minimum and administering additional bolus doses of fentanyl prior to the necessary handling will keep the infant as comfortable as possible. Maintaining the infant on a radiant warmer allow close follow up of the infant while avoiding hypothermia.
6. Early parenteral nutrition with adequate protein/calories/lipid is essential in order to provide substrate for the bowel to heal.
7. Surgery: The surgical management of NEC remains controversial. Surgery is indicated if bowel perforation is suspected (pneumoperitoneum on Xray) or if progressive clinical deterioration occurs despite medical management. It is performed in 23-70% of the cases, depending on the series reported. Surgical options include laparotomy with resection and enterostomy or peritoneal drain placement, allowing abdominal decompression, with a subsequent open procedure required in only half of these patients. Neonatal surgeons do not agree on a clear standard of care in these situations. Based on a case series of successful treatment of unstable infants less than 1000 g with peritoneal drain placement, two prospective clinical trials comparing primary peritoneal drainage to laparotomy and bowel resection in premature infants with perforated NEC are currently under way. The importance of the peri-operative care can not be underestimated. Particular attention should be given to the maintenance of the temperature during surgery and transport to the surgical suite, to the intra-vascular volume, the hemoglobin concentration and the platelet count, adequate pain control, parenteral nutrition and close post-operative electrolyte monitoring.
Promising prophylactic intervention:
While initially thought to be promising in reducing the incidence of NEC, oral IgA or glutamine supplementation has not demonstrated consistent beneficial effects. While a randomized clinical trial involving 152 infants suggests that L-Arginine supplementation might significantly decrease the risk of developing NEC, a larger study is needed to confirm these findings. Prebiotics (non-digestible carbohydrates that provide substrates to selected bacteria) and probiotics might be beneficial to prevent NEC. Probiotics, such as Lactobacillus acidophilus and Bifidobacterium infantis given in conjunction with breast milk have been shown to reduce the incidence and severity of NEC in VLBW infants. The supplementation of formula with growth factors, such as epidermal growth factor, heparin-binding EGF-like growth factor (HB-EGF) has shown some promise in animal experiments. However, their beneficial effects in infants at risk for NEC will need to be demonstrated in a randomized clinical trial.
NEC mortality ranges from reported 9 to 28% and is due to refractory shock, disseminated intra-vascular coagulation, multiple organ failure, intestinal perforation, sepsis, extensive bowel necrosis and complication of short bowel syndrome. In a prospective study involving 194 infants with NEC, portal air was not associated with an increase risk of mortality. NEC complications include inadequate nutrition with failure to thrive, electrolytes and nutrient losses, complications due to prolonged total parenteral nutrition and central venous catheters (infections, thrombus,…), intestinal surgical complications (intestinal stricture in 25-35% of NEC survivors, complication related to the stoma,… ) and short bowel syndrome. Of utmost importance, surviving infants who required surgery for NEC were found to have significant growth delay and an increased incidence in adverse neurodevelopmental outcomes. These sobering data suggest that additional work is needed to improve the outcomes for this dreaded disease.
Acknowledgment: We would like to thank Mary Wyers, M.D. from the department of Medical Imaging at Children's Memorial Hospital for providing the Xray of infants with NEC.
1. Reber KM, Nankervis CA. Necrotizing enterocolitis: preventative strategies. Clin Perinatol. 2004 Mar;31(1):157-67. Review.
2. Caplan MS: "Pathogenesis and Prevention of Neonatal Necrotizing Enterocolitis" in: Fox and Polin, Eds, Fetal and Neonatal Physiology, 2004, Third Edition.
3. Stoll BJ. Epidemiology of Necrotizing Enterocolitis. Clinics in perinatology, 1994, 21(2): 205-218.
4. Kanto WP, Hunter JE, and Stoll BJ. Recognition and Medical management of necrotizing enterocolitis. Clinics in perinatology, 1994, 21(2): 335-346.
5. Morrison SC and Jacobson JM. The radiology of necrotizing enterocolitis. Clinics in perinatology, 1994, 21(2): 347-364.
6. Bell MJ, Ternberg JL, Feigin RD et al. Neonatal necrotizing enterocolitis. Therapeutic decision based upon clinical staging. Ann Surg 1978 187, 1-7.
7. Sato TT, Oldham KT. Abdominal drain placement versus laparotomy for necrotizing enterocolitis with perforation. Clin Perinatol. 2004 Sep;31(3):577-89.
8. Sharma R, Tepas JJ, Hudak ML, Wludyka PS, Mollitt DL, Garrison RD, Bradshaw JA, Sharma M. Portal venous gas and surgical outcome of neonatal necrotizing enterocolitis. J Pediatr Surg. 2005 Feb; 40(2):371-6.
9. Hintz SR, Kendrick DE, Stoll BJ, Vohr BR, Fanaroff AA, Donovan EF, Poole WK, Blakely ML, Wright L, Higgins R; NICHD Neonatal Research Network. Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics. 2005 Mar;115(3):696-703.
10. Rees CM, Hall NJ, Eaton S, Pierro A. Surgical strategies for necrotising enterocolitis: a survey of practice in the United Kingdom. Arch Dis Child Fetal Neonatal Ed. 2005 Mar;90(2):F152-5
11. Lin HC, Su BH, Chen AC, Lin TW, Tsai CH, Yeh TF, Oh W. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics. 2005 Jan;115(1):1-4.
12. Hsueh W, Caplan MS, Qu XW, Tan XD, De Plaen IG, Gonzalez-Crussi F. Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts. Pediatr Dev Pathol. 2003 Jan-Feb;6(1):6-23.
13. Amin HJ, Zamora SA, McMillan DD, Fick GH, Butzner JD, Parsons HG, Scott RB. Arginine supplementation prevents necrotizing enterocolitis in the premature infant. J Pediatr. 2002 Apr;140(4):425-31.