Pathophysiology 21 (2014) 3–12
Neonatal necrotizing enterocolitis: Clinical challenges, pathophysiology and management Shehzad Huda a , Shabnum Chaudhery b , Hassan Ibrahim c , Arun Pramanik c,∗ a
Department of Neonatal-Perinatal Medicine, University of Alabama at Birmingham, Birmingham, AL, United States b Department of Pathology, LSU-Health, Shreveport, LA, United States c Department of Pediatrics, LSU-Health, Shreveport, LA, United States
Abstract NEC remains a major concern for neonatologists, surgeons, and gastroenterologists due to its high morbidity and mortality. These infants often have poor developmental outcome, and contribute to significant economic burden resulting in marked stress in these families. By developing and adhering to strict feeding protocols, encouraging human milk feeding preferably from the infant’s mother, use of probiotics, judicious antibiotic use, instituting blood transfusion protocols, the occurrence of NEC may possibly be reduced. However, because of its multifactorial etiology, it cannot be completely eradicated in the NICUs, particularly in the extremely premature infants. Ongoing surveillance of NEC and quality improvement projects may be beneficial. © 2014 Published by Elsevier Ireland Ltd. Keywords: Necrotizing enterocolitis; Preterm infant; Prevention
1. Introduction The first case report of necrotizing enterocolitis (NEC) probably dates back to 1823 when Charles Billard used the term “gangrenous enterocolitis” or “malignant enteritis” to describe necrosis and inflammation of the intestinal tract in a small infant. This was followed by a report of 25 patients with “gangrenous enterocolitis” in 1850 [1]. During the early part of 20th century, there were more reports of peritonitis with ileal perforation due to what was then called “infectious enteritis”. In 1953, Schmidt and Quaiser coined the term “Newborn NEC” [2]. However, the clinical and radiological features of NEC as currently used were first described in 21 such infants by Berndon from New York Babies hospital in 1964 [3]. Necrotizing enterocolitis, an inflammatory bowel disease of newborn infants attributed to multifactorial etiology often presents unexpectedly in the Neonatal Intensive Care Unit
∗ Corresponding author at: Department of Pediatrics, Louisiana State University Health, PO Box 33932, Shreveport, LA 71115, United States. E-mail address: [email protected] (A. Pramanik).
0928-4680/$ – see front matter © 2014 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.pathophys.2013.11.009
(NICU). It is the commonest gastrointestinal emergency with high morbidity and mortality, particularly in extremely premature infants. The terminal ileum and the proximal colon are the most commonly affected sites although any segment of the small or large intestine may be involved. In a subset of patients it has a rapid and fulminating course wherein the entire bowel is irreversibly damaged which has been termed as ‘NEC totalis’. The exact mechanism initiating the inflammation and injury to the gut is poorly understood despite extensive clinical and basic research on NEC in the last few decades. The lack of clinically significant progress, and the unchanged prevalence rate of NEC have been attributed to a variety of factors which include: increased survival of smaller and sicker premature infants at higher risk of NEC with the advent of modern NICU practices, our inability to differentiate this disease early from ‘feeding intolerance’, alterations in gut flora with use of antibiotics and feeding practices, a possible risk of increased NEC due to blood transfusions during feeding, and our inability to create an animal model closely simulating human disease. NEC is estimated to affect approximately one out of 10 premature infants with birth weights less than 1000 g and results in significant morbidity and mortality, particularly in extremely premature infants.
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Fig. 1. Pathophysiological risk factors for necrotizing enterocolitis.
In premature infants, it usually presents several weeks after birth and the age of onset is inversely proportional to the gestational age at birth, with an exponential increase in its rate in infants weighing less than 1000 g. Because NEC has not been described in a fetus, several investigators have suggested that postnatal factors likely contribute to its etiology. More than 90% of neonates were enterally fed prior to the onset of NEC. NEC may occur in full term infants in whom it clinically presents earlier in life due to a variety of underlying disease states listed below under epidemiology. Although the exact mechanism of gut injury remains controversial, factors that have been attributed in infants at greater risk are: immature gut mucosal and barrier function or dysmotility, tissue ischemia secondary to underlying diseases, excessive pro-inflammatory cytokines, enteral feeding or medications altering gut flora, and enhanced inflammatory response (Fig. 1). Tissue hypoxia of the affected intestine may further decrease gut motility, and with continuation of feeding gut flora are possibly altered and overgrowth resulting in gut mucosal damage which may be followed by translocation of gut bacteria into the systemic circulation with resulting
septicemia in up to 30% of NEC patients [4]. Here we will review the epidemiology, clinical features, pathophysiology, management and prevention of NEC.
2. Epidemiology NEC prevalence varies amongst NICUs. In a report from the NICHD Neonatal Research Network, NEC had a mean prevalence of 7% in infants with birth weight less than 1500 g, rising to 15% in infants weighing less than 750 g, with 50% of them receiving surgical intervention [5]. Overall, NEC results in significant morbidity [6–8], and the mortality rates range from 5 to 24% [9–13]. On rare occasions, NEC may occur in infants born at near-term or term gestation in whom it presents earlier. These term infants may have asphyxia, congenital heart disease, polycythemia, exchange transfusion or underlying surgical condition (e.g. Hirschprung’s disease) suggesting a different mechanism of gut injury.
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Table 1 Stage
Clinical
Laboratory
Radiological
Management
Ia
Temperature instability, apnea, bradycardia, ↓ SaO2 , ↑ gastric residuals, abdominal distension, stool-occult blood +ve Same as above
Unremarkable
Unremarkable
Asses frequently to rule out if due to prematurity, CPAP or sepsis, hold feeds if green tinged, increase feeds cautiously
Same as above + bloody stools
Unremarkable
Above + rule out fissures. Consider antibiotics to be discontinued in 2 days if CRP and blood cultures are normal NPO, gastric decompression, X-ray abdomen q 6–8 h including left lateral decubitus, inform surgeons. Start antibiotics × 7–10 days after sepsis work-up Same as above + supportive treatment
Ib
IIa
Stage I + decreased or absent bowel sound, guarding
Mild metabolic acidosis, mild thrombocytopenia
Dilated bowel loops, sentinel loops, pneumatosis intestinalis
IIb
Metabolic acidosis, thrombocytopenia, hyponatremia
IIA + portal venous gas shadows
IIIa
Stage I & IIa + absent bowel sounds, marked guarding, abdominal wall discoloration or cellulitis, Rt. lower quadrant mass Stage I & II + hypotension, DIC
Stage II + ascites
Same as above + insure adequate coverage for gram negative bacteria and anaerobes
IIIb
Same as above
Respiratory acidosis, metabolic acidosis, neutropenia, increased PT/PTT/INR, D-dimer, increase CRP Same as above
Stage II & IIIa + pneumoperitoneum
Above + emergency surgery
In 1978 Bell et al. [14] suggested staging of NEC depending on its severity, which was subsequently modified by Walsh and Kliegman [15]. Table 1 lists the staging along with suggested management strategies. Feeding intolerance is a common presentation of NEC which is also observed in premature infants with septicemia, decreased gut motility, use of caffeine or indomethacin, and gastro-esophageal reflux, thus resulting in over-diagnosis of stage I NEC. In
order to diagnose NEC early, a high index of suspicion should be maintained in premature infants, particularly those with birth weights less than 1 kg, and in infants with unstable perinatal events who should be monitored closely. Non-specific laboratory findings reported in NEC patients are: neutropenia, leukocytosis, thrombocytopenia [16,17], hyponatremia, acidosis or hyperglycemia. Radiological findings of fixed dilated bowel loops or ‘sentinel loop sign’ (Fig. 2), pneumatosis intestinalis (white arrows: Fig. 3), portal venous gas shadow (black arrows: Fig. 3) and pneumoperitoneum which
Fig. 2. X-rays KUB with markedly dilated sausage shaped loop (white arrow) and umbilical venous catheter in place.
Fig. 3. X-rays KUB with black arrow depicts portal venous gas shadow and white arrow depicts pneumatosis intestinalis.
3. Clinical features
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Fig. 4. Football sign – black arrow depicts free air under the diaphragm and white arrow depicts falciform ligament.
may present as ‘football sign’ (Fig. 4; white arrows: free air, black arrows: falciform ligament) are helpful in diagnosis of NEC. In some patients, pneumatosis, portal venous gas and pneumoperitoneum are seen in advanced stage of NEC with gut necrosis or ‘NEC totalis’ with poor prognosis. Pneumoperitoneum represents bowel perforation and is a surgical emergency. Isolated spontaneous intestinal perforation (SIP) is also occasionally seen in premature infants who have received postnatal corticosteroids, indomethacin, or were hypotensive, and these patients have a relatively better prognosis. The diagnosis of SIP is difficult to make without laparotomy, and thus some epidemiological studies may have overestimated the prevalence of NEC. High resolution ultrasonography has been used to asses gut injury, wherein echogenic dots or dense granular echogenic spots are seen in the bowel wall [18], and color Doppler imaging has been used to diagnose pneumatosis [19], but these techniques have not received wide acceptance. Some investigators believe that due to our failure to diagnose NEC early, infants have serious adverse outcome with enormous impact on their families who have to make frequent hospital visits, care for a handicapped infant and deal with financial burden [20]. Hence many NICUs adhere to strict feeding protocols, which have been considered to possibly decrease the occurrence of NEC. However, randomized, prospective studies with adequate statistical power to control for multiple factors in the extremely premature infants, particularly those with fetal compromise
Fig. 5. Congested, discolored and thickened bowel due to edema and inflammation.
and/or critically ill at birth are lacking. Therefore, we suggest a conservative approach in these high-risk infants by encouraging breast milk feeding (total or partial), to cautiously increase feeds and frequently assess them to minimize the occurrence of NEC, and diagnose NEC earlier when it does occur.
4. Pathology (gross and histopathology) NEC commonly affects the terminal ileum followed by colon and other segments of the small intestine [21,22]. Since pathological specimens are obtained from surgery or during autopsy, early stages of NEC are not usually accessible for pathological examination. On gross examination, as the disease process continues, the intestines appear congested, discolored and thickened (Fig. 5) due to edema and in advanced cases gas-filled cysts may be visible. These areas can progress to appear dark, gray and gangrenous (Fig. 6) and may perforate. Intestinal pneumatosis, the formation of gas bubbles within the intestinal wall is a characteristic finding seen in most patients with NEC, likely resulting from fermentation and gas production by bacteria. The intestinal wall perforates when the disease is severe with transmural involvement.
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5.1.1. Decrease in mucin production In NEC, the onset of the inflammatory process may be gradual, but may have a rapid progression, thus making it difficult to ascertain the time of its origin. Since most premature infants do not develop NEC despite immature intestines, it has been suggested that there may be genetic predisposition with fewer mucin-producing goblet cells in some infants. The goblet cells are expressed as early as 9 weeks of gestation, with peak expression at 23 weeks of gestation. The developmental expression of mucin goes through various stages of maturation with adult pattern layer observed between 23 and 27 weeks of gestation. Mucin protects the intestinal epithelial lining and prevents the translocation of the gut microbes into the circulation [6,25–28].
Fig. 6. Dark, gray gangrenous bowel with hemorrhagic foci.
Microscopic examination shows early changes of microvascular thrombi, submucosal gas-filled cysts (intestinal pneumatosis), vascular congestion, edema and a variable inflammatory infiltrate in the mucosal and submucosal areas. The inflammatory component may appear relatively less compared to the degree of necrosis. Late changes include coagulation necrosis with hemorrhage and gangrenous bowel wall susceptible to perforation [23] (Fig. 7a–e). Although there is no histological grading of NEC in humans, using an animal model, Jilling et al. have described grading from 0 to 4 with grade 0 representing intact morphology, grade 1 showing sloughing of the tip of villi, grade 2 with mild necrosis of villi, grade 3 with loss of villi, and grade 4 representing complete destruction of the intestinal mucosa [24].
5. Pathophysiology 5.1. Mechanism of injury This has been described in other chapters. We have summarized some of the salient features below.
5.1.2. Cytokines and chemokines The role of cytokines and chemokines in inflammation leading to gut injury in NEC has been extensively studied. The initial process of inflammation in gut injury likely begins with ischemia leading to the dysmotility of the intestine followed by excessive distension leading to the damage of the intestinal mucosal epithelial cells leading to the proliferation of proinflammatory bacteria. Lipopolysaccharide (LPS) [29–31] (an endotoxin present in the outer wall of the gram negative bacteria) may trigger the activation of the inflammatory cascade by engaging the toll like receptors (TLR), leading to the release of various cytokines and chemokines, e.g. interferon gamma, Interleukin-6, interleukin-8, interleukin-12, interleukin-18, tumor necrosis factor-alpha. These cytokines and chemokines are regulated by the transcription factor nuclear factor-kB, which regulates the leukocyte adhesion molecules. The role of cytokines and toll receptors has been discussed in other chapters in this issue. 5.1.3. Role of endothelium Several researchers have proposed that NEC is an ischemia–reperfusion injury with significant reduction in intestinal blood flow leading to inflammation followed by cellular necrosis. With compromised blood flow, the tissue is deprived of oxygen and nutrients. Endothelium, which lines the microvessels plays a pivotal role in controlling the blood flow to the intestinal tissues via regulation of endothelin-1 (ET-1) and endothelial nitric oxide (eNO). ET-1 is a potent vasoconstrictor [32], which acts via binding with ETA receptor and eNO, a potent vasodilator, which acts via ETB receptor. Nankervis and Nowicki postulated that this results from imbalance between vasoconstriction and vasodilatation properties of the endothelin leading to ischemia of the affected tissue causing NEC [33]. Thus vascular endothelial cells also play a major role in inflammatory cascade and acts as an immunomodulator. 5.1.4. Role of feeding Although NEC has never been reported in a fetus, Nanthakumar et al. found evidence suggesting gut inflammation in aborted fetuses [34]. They postulated that because of
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Fig. 7. (a) H&E-stained histological sections of a macroscopically unaffected segment, showing early signs of epithelial degeneration at villous tips and thrombus formation (arrow head) in an underlying vessel, hematoxylin–eosin stain, 100×. (b) Pathologic findings in NEC. Histologic sections of small bowel showing early stage of intestinal injury with hyperemia of mucosa and loss of epithelial cells at the villus tips (1). Intramural gas is seen as rounded bubbles in the submucosa (arrows), hematoxylin–eosin stain, 100×. (c) Here the bowel is affected much more severely. There is necrosis of the mucosa and submucosa with intraluminal necrotic debris on the mucosal side of the bowel wall (m) and loss of villi. The histologic characteristics of NEC include coagulative necrosis (1), bacterial overgrowth with inflammatory cell infiltration (2), mucosal edema and ulceration (3), hematoxylin–eosin stain, 100× with insert at 400×. (d) High magnification of a histological section of the necrotic small bowel mucosa showing characteristic vascular thrombi (arrowhead) and necrosis (arrow), hematoxylin–eosin stain, 200×. (e) Transmural necrosis of mucosa, submucosa, and muscularis propria extending to serosa with potential for perforation. s = serosal surface of bowel wall.
excessive cytokine production, immature human enterocytes may be prone to necrosis. In more than 90% of patients, NEC occurs in neonates who received enteral feeds. Although there is lack of consensus amongst neonatologists regarding the timing of initiation and the rate of increase of enteral feedings in premature infants, most physicians administer trophic feeds which are increased cautiously in extremely premature infants, particularly those who had absent diastolic flow in fetal period, had hypotension or severe intrauterine growth retardation. Also, it has been suggested that in utero, these infants produce meconium by swallowing amniotic fluid, which possibly has protective chemicals with a role in preventing intestinal injury after birth. Christensen et al. fed
a small group of 10 very low birth weight infants weighing 750–1250 g with formula having composition similar to the amniotic fluid and found no significant adverse effects in all these VLBW infants [35]. They suggested that amniotic fluid contents including erythropoietin and granulocyte-colony stimulating factor have antiapoptotic effects. Feeding practices in many NICUs are dependent on the clinician caring for the infant. However many neonatologists consider that if the infant does not have a large Patent Ductus Arteriosus or hypotension requiring vasopressors, minimal enteral nutrition, i.e. trophic feedings should be initiated once the infant is stable. This concept of priming the gut epithelium and develop adaptability may also help in decreasing feeding
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intolerance. Clinical trials have been conducted by keeping these infants Nil Per Os (NPO) for a week followed by introduction of the feeds with no differences observed in the incidence of NEC in infants weighing greater than750 g at birth. The Cochrane Systematic Review evaluating 9 trials does not suggest that the practice of minimal enteral nutrition either increases (or decreases) the risk of definite NEC, with a typical relative risk of 1.07 (95% confidence interval 0.67, 1.70); typical risk difference of 0.01 (95% confidence interval −0.04, 0.05) [36]. Premji et al. reviewed data from seven different trials in 571 infants on the effectiveness of continuous feedings in premature infants weighing less than 1500 g and concluded that there was no significant difference in the time to achieve the full feeds, somatic growth and the incidence of the NEC [37]. A consensus should be developed amongst neonatologists regarding the postnatal age to start trophic feeds, and the rate of increase of enteral feeds in various subgroups of premature infants. Although studies have been conducted on rapidity of increasing enteral feeds in premature infants, there is paucity of data in infants with birth weight of less than 750 g, and in those with varying degrees of illness. Since VLBW have a poor gut barrier and motility, they are prone to develop feeding intolerance. Under such circumstances, with an increase in gastric residuals even an experienced neonatologist may miss the early signs of NEC and although radiological evidence to support the diagnosis [38,39] and other criteria listed in table have been used, they are not definitive. 5.1.5. Infant formula and breast milk The next question is which form of enteral nutrition should be used, i.e. cow milk-based infant formula or human milk (either mother’s breast milk or donor breast milk)? The American Academy of Pediatrics endorses the use of human milk [40]. With the use of human milk, a decrease in the incidence of the NEC has been reported [41–44]. Lactoferrin, an iron-binding protein is suggested to be an important factor providing protective barrier and boosting the immune system by stimulating the infant’s innate immunity [4]. It is highest in colostrum (7 g/dL) compared to mature milk (1 g/dL) and is lowest in the mid-lactation milk (0.1 g/dL) [45–47]. Although in the fetus the gut is sterile, it is colonized by variety of microbes in the post-natal period. Gut microbiota is also altered by the type of feeding the newborn infant receives, i.e. breast fed infants get lactobacilli or bifidobateria in comparison to formula fed infants that are colonized with enterobacteria and other gram negative organisms [48]. In a double-blind placebo controlled randomized trial conducted at eleven tertiary care NICUs involving 472 very low birth weight infants (VLBW) infants who were given bovine lactoferrin (BLF) and BLF plus Lactobacillus rhamnosus GG (LGG) from birth to 30 days of life, Manzoni et al. concluded that BLF supplementation alone or in combination with LGG reduced the incidence of a first episode of late onset sepsis in VLBW neonates [49]. Additionally, with the use of prolonged use of antibiotics and/or H2-blockers, the gut loses its
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normal flora and may develop resistant microbes which may result in NEC and sepsis [34]. Carrion and Egan reported that by maintaining an acidic gastric pH less than 3.0 in breast milk, PM 60/40 and PF20, the incidence of NEC decreased, in contrast to higher gastric enteric bacterial colony counts which strongly correlated with gastric pH greater than 4.0 [50]. It is unclear whether the absence of harmful contents, or the presence of anti-inflammatory factors in the human milk prevents NEC. It is also postulated that unknown proinflammatory substances in artificial formula milk aggravate gut injury in infants with a genetic predisposition. Several probiotic strains have been used by researchers including: Bifidobacterium bifidus, breve, infantis, lactis and longus; Lactobacillus acidophilus, casei, rhamnosus GG, plantarum and sporogenes; Streptococcus thermophillus and Saccharomyces boulardii. Although clinical trials have demonstrated favorable result with use of probiotics treatment, several concerns remain, such as their side effects, optimal organism, dosages and the immature immune response of premature infants. Since, the actual dosage of pre, pro and postbiotics are unknown, complications may occur which could be dose related [1,51]. Rationale for the use of prebiotics and postbiotics in preventing NEC has been discussed by Dr. Panigrahi and Dr. Denning in this issue. 5.1.6. Transfusion associated gut injury Agwu et al. in 2005 in a case report suggested that blood transfusion may be a risk factor in inducing gut injury in premature infants leading to NEC. Subsequently several studies documented an increase in NEC among premature infants receiving enteral feeding during transfusion [52–56]. Stritzke et al. in 2013 conducted a retrospective chart review of 927 patients with NEC and reported an association of transfusion associated NEC (TANEC). They noted that 5.5% of patients received transfusion two days prior to the diagnosis of NEC. Majority of these TANEC patients were critically ill during their initial hospital admission, and developed NEC between 23 and 37 days of life [57]. 5.2. Long-term outcome The prevalence of NEC varies amongst NICUs. Ladd et al. conducted a retrospective study of 249 NEC patients who underwent surgery to analyze the factors possibly impacting long-term survival and growth. They reported that survivors were more mature, increased birth weight and postnatal age at the time of surgery. There were 112 deaths with 36% having NEC totalis, and an additional 30% died of septicemia. The average postoperative survival was 46.9 ± 91.5 days. Significant mortality was observed in neonates ≤30 weeks gestation (53%). In NEC, those patients who received surgical intervention had longer hospital stays in comparison to medical NEC. All such babies go through prolonged periods of parenteral nutrition but the majority are on enteral nutrition at the time of discharge. Although
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duration of prolonged parenteral nutrition duration depends on the intact ileocecal valve, it is also dependent on the length of the intestine resected. In general, those in whom >20 cm has been resected, go through prolong parenteral nutrition [58]. These infants go through a prolonged period of intestinal rehabilitation, depending on the size of viable gut remaining. The consequences of short gut have been discussed by Dr. Peter Minneci in this issue of the journal. Growth and development remains a major concern in infants surviving NEC. Sonntag et al. reported significant neurodevelopmental delay at 12 and 20 months in a small group of VLBW survivors of NEC [59]. Salhab et al. reported similar findings with neurodevelopmental assessment done at 18–22 months [60]. In a large NICHD study cohort, Hintz et al. hypothesized that ELBW infants with surgically managed NEC are at greater risk for poor neurodevelopmental and growth outcomes than in NEC patients managed medically and those infants did not have NEC. They evaluated 2948 infants at 18–22 months. Amongst them, 124 survived after surgery of NEC, and 121 managed medically. Infants with NEC who had surgery had more cystic periventricular leukomalacia, bronchopulmonary dysplasia and stunted growth in comparison to those in whom the NEC was managed with medical therapy and those who did not develop NEC [61]. Whereas Schulzke et al. after reviewing eleven non-randomized studies including 5 with matched control patients reported similar neurodevelopmental impairment in the NEC survivors requiring surgical intervention compared to those requiring medical therapy [62]. 5.3. Management Patients with NEC managed medically should be NPO along with gastric decompression (using large-bore Repogle tube), given total parenteral nutrition, receive appropriate antibiotic coverage (to cover anaerobic, gram negative and positive organisms), and receive close clinical and laboratory monitoring with serial abdominal X-rays (antero-posterior and left lateral decubitus views) done every 6–8 h to detect intestinal perforation. Emergency surgical intervention is undertaken in all cases of pneumoperitoneum, and in some patients with abdominal cellulitis (i.e. peritonitis), and in those with persistent thrombocytopenia suggesting necrotic bowel. Whether infection is the primary cause or occurs secondary to the ischemic gut initiating the inflammatory cascade remains controversial. Cole et al. reported that patients with NEC had late onset sepsis [63]. There are no clinical features or diagnostic tests which enable the clinician to halt the inflammatory process which leads to gut injury and necrosis. When pneumoperitoneum is detected, gangrenous changes in the intestines may have occurred in some instances, hence surgeons must be consulted in all suspected patients with NEC to minimize the time to surgery after pneumoperitoneum is diagnosed (Fig. 4). In addition, surgical intervention is also indicated if the infant is clinically deteriorating despite maximal medical treatment, if abdominal
mass is detected, has signs of persistent intestinal obstruction, sepsis, or has intestinal stricture. Relative indications for surgery are: increased abdominal tenderness, distension, discoloration, or the persistence of portal vein gas [64]. Surgical interventions include primary peritoneal drainage, laparotomy with resection and enterostomy, resection with primary anastomosis, proximal diverting jejunostomy, and “Clip and Drop” technique. Najaf et al. reported that 24% of their 124 infants with >Stage II NEC developed bowel perforation with a median interval of 1 day from the appearance of the symptoms [65]. In another review of 147 patients with NEC, Kosloske concluded that in addition to pneumoperitoneum which remains the definitive indication for surgery, portal venous gas and greater than 0.5 mL of brown fluid and/or bacterial growth in the fluid at paracentesis, surgical intervention should be considered [66]. Dr. Moss has elaborated on the surgical management of patients with NEC in this issue.
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S. Huda et al. / Pathophysiology 21 (2014) 3–12 [15] M.C. Walsh, R.M. Kliegman, Necrotizing enterocolitis: treatment based on staging criteria, Pediatr. Clin. North Am. 33 (1986) 179–201. [16] J.J. Hutter, W.E. Hathaway, E.R. Wayne, Hematologic abnormalities in severe neonatal necrotizing enterocolitis, J. Pediatr. 88 (6) (1976) 1026–1031. [17] M.C. Sola, A. Del Vecchio, L.M. Rimsza, Evaluation and treatment of thrombocytopenia in the neonatal intensive care unit, Clin. Perinatol. 27 (3) (2000) 655–679. [18] W.Y. Kim, W.S. Kim, I.O. Kim, et al., Sonographic evaluation of neonates with early-stage necrotizing enterocolitis, Pediatr. Radiol. 35 (11) (2005) 1056–1061. [19] R. Faingold, A. Daneman, G. Tomlinson, et al., Necrotizing enterocolitis: assessment of bowel viability with color Doppler US, Radiology 235 (2) (2005) 587–594. [20] J.A. Bisquera, T.R. Cooper, C.L. Berseth, Impact of necrotizing enterocolitis on length of stay and hospital charges in very low birth weight infants, Pediatrics 109 (3) (2002) 423–428. [21] T.V. Santulli, J.N. Schullinger, W.C. Heird, R.D. Gongaware, J. Wigger, B. Barlow, W.A. Blanc, W.E. Berdon, Acute necrotizing enterocolitis in infancy: a review of 64 cases, Pediatrics 55 (1975) 376–387. [22] W.A. Ballance, B.B. Dahms, N. Shenker, R.M. Kliegman, Pathology of neonatal necrotizing enterocolitis: a ten year experience, J. Pediatr. 117 (1990) S6–S13. [23] S. Silverberg, Surgical Pathology and Cytopathology, 4th ed., Churchill Livingston Elsevier, Philadelphia, 2006, pp. 1397–1398. [24] T. Jilling, J. Lu, M. Jackson, M. Caplan, Intestinal epithelial apoptosis initiates gross bowel necrosis in an experimental rat model of neonatal necrotizing enterocolitis, Pediatr. Res. 55 (4) (2004) 622–629. [25] M.P. Buisine, L. Devisme, T.C. Savidge, et al., Mucin gene expression in human embryonic and fetal intestine, Gut 43 (1998) 519–524. [26] J. Neu, W.A. Walker, Necrotizing enterocolitis, N. Engl. J. Med. 364 (3) (2011) 255–264. [27] C.M. Young, S.D. Kingma, J. Neu, Ischemia–reperfusion and neonatal intestinal injury, J. Pediatr. 158 (Suppl. 2) (2011) e25–e28. [28] E.C. Claud, W.A. Walker, Hypothesis: inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis, FASEB J. 15 (8) (2001) 1398–1403. [29] F. Gonzalez-Crussi, W. Hsueh, Experimental model of ischemic bowel necrosis. The role of platelet-activating factor and endotoxin, Am. J. Pathol. 112 (1983) 127–135. [30] R. Sharma, J.J. Tepas, M.L. Hudak, et al., Neonatal gut barrier and multiple organ failure: role of endotoxin and proinflammatory cytokines in sepsis and necrotizing enterocolitis, J. Pediatr. Surg. 42 (2007) 454–461. [31] N.A. Essani, G.M. McGuire, A.M. Manning, et al., Endotoxin-induced activation of the nuclear transcription factor kappa B and expression of E-selectin messenger RNA in hepatocytes, Kupffer cells, and endothelial cells in vivo, J. Immunol. 156 (1996) 2956–2963. [32] M. Yanagisawa, H. Kurihara, S. Kimura, Y. Tomobe, M. Kobayashi, A novel potent vasoconstrictor peptide produced by the vascular endothelium, Nature 332 (1988) 411–413. [33] P. Nowicki, C. Nankervis, P. Giannone, et al., Endothelin-1 in human intestine resected for necrotizing enterocolitis, J. Pediatr. 146 (6) (2005) 805–810. [34] N.N. Nanthakumar, R.D. Fusunyan, I. Sanderson, et al., Inflammation in the developing human intestine: a possible pathophysiologic contribution to necrotizing enterocolitis, Proc. Natl. Acad. Sci. U. S. A. 97 (11) (2000) 6043–6048. [35] R.D. Christensen, T. Havranek, D.R. Gerstmann, D.A. Calhoun, Enteral administration of a simulated amniotic fluid to very low birth weight neonates, J. Perinatol. 25 (2005) 380–385. [36] S. Bombell, W. McGuire, Early trophic feeding for very low birth weight infants, Cochrane Database Syst. Rev. 3 (2009) CD000504. [37] D.M. Hans, M. Pylipow, J.D. Long, et al., Nutritional practices in the neonatal intensive care unit: analysis of a 2006 neonatal nutrition survey, Pediatrics 123 (1) (2009) 51–57.
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[38] S.S. Premji, L. Chessell, Continuous nasogastric milk feeding versus intermittent bolus milk feeding for premature infants less than 1500 grams, Cochrane Database Syst. Rev. (11) (2011) CD001819. [39] B.A. Cobb, W.A. Carlo, N. Ambalavanan, Gastric residuals and their relationship to necrotizing enterocolitis in very low birth weight infants, Pediatrics 113 (1 Pt 1) (2004) 50–53. [40] G. Terrin, A. Passariello, R.B. Canani, et al., Minimal enteral feeding reduces the risk of sepsis in feed-intolerant very low birth weight newborns, Acta Paediatr. 98 (1) (2009) 31–35. [41] Section on Breastfeeding, Breastfeeding and the use of human milk, Pediatrics 129 (3) (2012) e827–e841. [42] G. Henderson, M.Y. Anthony, W. McGuire, Formula milk versus maternal breast milk for feeding preterm or low birth weight infants, Cochrane Database Syst. Rev. (4) (2007) CD002972. [43] M.A. Quigley, G. Henderson, M.Y. Anthony, et al., Formula milk versus donor breast milk for feeding preterm or low birth weight infants, Cochrane Database Syst. Rev. (4) (2007) CD002971. [44] J. Meinzen-Derr, B. Poindexter, L. Wrage, et al., Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death, J. Perinatol. 29 (1) (2009) 57–62. [45] P.M. Sisk, C.A. Lovelady, R.G. Dillard, et al., Early human milk feeding is associated with a lower risk of necrotizing enterocolitis in very low birth weight infants, J. Perinatol. 27 (7) (2007) 428–433. [46] P.L. Masson, J.F. Heremans, Lactoferrin in milk from different species, Comp. Biochem. Physiol. 39B (1971) 119–129. [47] P.F. Hennart, D.J. Brasseur, J.B. Delogne-Desnoeck, M.M. Dramaix, C.E. Robyn, Lysozyme, lactoferrin, and secretory immunoglobulin A content in breast milk: influence of duration of lactation, nutrition status, prolactin status, and parity of mother, Am. J. Clin. Nutr. 53 (1991) 32–39. [48] L. Sanchez, P. Aranda, M.D. Perez, M. Calvo, Concentration of lactoferrin and transferrin throughout lactation in cow’s colostrum and milk, Biol. Chem. Hoppe Seyler 369 (1988) 1005–1008. [49] S.E. Balmer, P.H. Scott, B.A. Wharton, Diet and fecal flora in the newborn: casein and whey proteins, Arch. Dis. Child. 64 (1989) 1674–1678. [50] P. Manzoni, M. Rinaldi, S. Cattani, L. Pughi, et al., Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low birth neonates, JAMA 302 (13) (2009) 1421–1428. [51] V. Carrion, E.A. Egan, Prevention of neonatal necrotizing enterocolitis, J. Pediatr. Gastroenterol. Nutr. 11 (3) (1990) 317–323. [52] T. Ravindranath, T. Yoshioka, M. Goto, et al., Endotoxemia following enteral refeeding in children, Clin. Pediatr. (Phila.) 36 (9) (1997) 523–528. [53] J.C. Agwu, H. Narchi, In a preterm infant, does blood transfusion increase the risk of necrotizing enterocolitis? Arch. Dis. Child. 90 (2005) 102–103. [54] A. Short, A. Gallagher, M. Ahmed, Necrotising enterocolitis following blood transfusion, Arch. Dis. Child. 90 (2005) 102–103 (14 April, Letter). [55] P. Mally, S.G. Golombek, R. Mishra, S. Nigam, K. Mohandas, H. Depalhma, E.F. LaGamma, Association of necrotizing enterocolitis with elective packed red blood cell transfusions in stable, growing, premature neonates, Am. J. Perinatol. 23 (2006) 451–458. [56] R.D. Christensen, D.K. Lambert, E. Henry, S.E. Wiedmeier, G.L. Snow, et al., Is “transfusion-associated necrotizing enterocolitis” an authentic pathogenic entity? Transfusion 50 (2010) 1106–1112. [57] A.I. Stritzke, J. Smyth, A. Synnes, S.K. Lee, P. Shah, Transfusionassociated necrotizing enterocolitis in neonates, Arch. Dis. Child. Fetal Neonatal Ed. 98 (2013) F10–F14, http://dx.doi.org/10.1136/ fetalneonatal-2011-301282. [58] A.P. Ladd, J. Frederick, W.W. Karen, et al., Long-term follow up after bowel resection for necrotizing enterocolitis: factors affecting outcome, J. Pediatr. Surg. 33 (7) (1998) 967–972. [59] J. Sonntag, I. Grimmer, T. Scholz, B. Metze, J. Wit, M. Obladen, Growth and neurodevelopmental outcome of very low birth weight infants with necrotizing enterocolitis, Acta Pediatr. 89 (2000) 528–532.
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[60] W.A. Salhab, J.M. Perlman, L. Silver, R.S. Broyles, Necrotizing enterocolitis and neurodevelopmental outcome in extremely low birth weight infants
Neonatal necrotizing enterocolitis: Clinical challenges, pathophysiology and management Shehzad Huda a , Shabnum Chaudhery b , Hassan Ibrahim c , Arun Pramanik c,∗ a
Department of Neonatal-Perinatal Medicine, University of Alabama at Birmingham, Birmingham, AL, United States b Department of Pathology, LSU-Health, Shreveport, LA, United States c Department of Pediatrics, LSU-Health, Shreveport, LA, United States
Abstract NEC remains a major concern for neonatologists, surgeons, and gastroenterologists due to its high morbidity and mortality. These infants often have poor developmental outcome, and contribute to significant economic burden resulting in marked stress in these families. By developing and adhering to strict feeding protocols, encouraging human milk feeding preferably from the infant’s mother, use of probiotics, judicious antibiotic use, instituting blood transfusion protocols, the occurrence of NEC may possibly be reduced. However, because of its multifactorial etiology, it cannot be completely eradicated in the NICUs, particularly in the extremely premature infants. Ongoing surveillance of NEC and quality improvement projects may be beneficial. © 2014 Published by Elsevier Ireland Ltd. Keywords: Necrotizing enterocolitis; Preterm infant; Prevention
1. Introduction The first case report of necrotizing enterocolitis (NEC) probably dates back to 1823 when Charles Billard used the term “gangrenous enterocolitis” or “malignant enteritis” to describe necrosis and inflammation of the intestinal tract in a small infant. This was followed by a report of 25 patients with “gangrenous enterocolitis” in 1850 [1]. During the early part of 20th century, there were more reports of peritonitis with ileal perforation due to what was then called “infectious enteritis”. In 1953, Schmidt and Quaiser coined the term “Newborn NEC” [2]. However, the clinical and radiological features of NEC as currently used were first described in 21 such infants by Berndon from New York Babies hospital in 1964 [3]. Necrotizing enterocolitis, an inflammatory bowel disease of newborn infants attributed to multifactorial etiology often presents unexpectedly in the Neonatal Intensive Care Unit
∗ Corresponding author at: Department of Pediatrics, Louisiana State University Health, PO Box 33932, Shreveport, LA 71115, United States. E-mail address: [email protected] (A. Pramanik).
0928-4680/$ – see front matter © 2014 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.pathophys.2013.11.009
(NICU). It is the commonest gastrointestinal emergency with high morbidity and mortality, particularly in extremely premature infants. The terminal ileum and the proximal colon are the most commonly affected sites although any segment of the small or large intestine may be involved. In a subset of patients it has a rapid and fulminating course wherein the entire bowel is irreversibly damaged which has been termed as ‘NEC totalis’. The exact mechanism initiating the inflammation and injury to the gut is poorly understood despite extensive clinical and basic research on NEC in the last few decades. The lack of clinically significant progress, and the unchanged prevalence rate of NEC have been attributed to a variety of factors which include: increased survival of smaller and sicker premature infants at higher risk of NEC with the advent of modern NICU practices, our inability to differentiate this disease early from ‘feeding intolerance’, alterations in gut flora with use of antibiotics and feeding practices, a possible risk of increased NEC due to blood transfusions during feeding, and our inability to create an animal model closely simulating human disease. NEC is estimated to affect approximately one out of 10 premature infants with birth weights less than 1000 g and results in significant morbidity and mortality, particularly in extremely premature infants.
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Fig. 1. Pathophysiological risk factors for necrotizing enterocolitis.
In premature infants, it usually presents several weeks after birth and the age of onset is inversely proportional to the gestational age at birth, with an exponential increase in its rate in infants weighing less than 1000 g. Because NEC has not been described in a fetus, several investigators have suggested that postnatal factors likely contribute to its etiology. More than 90% of neonates were enterally fed prior to the onset of NEC. NEC may occur in full term infants in whom it clinically presents earlier in life due to a variety of underlying disease states listed below under epidemiology. Although the exact mechanism of gut injury remains controversial, factors that have been attributed in infants at greater risk are: immature gut mucosal and barrier function or dysmotility, tissue ischemia secondary to underlying diseases, excessive pro-inflammatory cytokines, enteral feeding or medications altering gut flora, and enhanced inflammatory response (Fig. 1). Tissue hypoxia of the affected intestine may further decrease gut motility, and with continuation of feeding gut flora are possibly altered and overgrowth resulting in gut mucosal damage which may be followed by translocation of gut bacteria into the systemic circulation with resulting
septicemia in up to 30% of NEC patients [4]. Here we will review the epidemiology, clinical features, pathophysiology, management and prevention of NEC.
2. Epidemiology NEC prevalence varies amongst NICUs. In a report from the NICHD Neonatal Research Network, NEC had a mean prevalence of 7% in infants with birth weight less than 1500 g, rising to 15% in infants weighing less than 750 g, with 50% of them receiving surgical intervention [5]. Overall, NEC results in significant morbidity [6–8], and the mortality rates range from 5 to 24% [9–13]. On rare occasions, NEC may occur in infants born at near-term or term gestation in whom it presents earlier. These term infants may have asphyxia, congenital heart disease, polycythemia, exchange transfusion or underlying surgical condition (e.g. Hirschprung’s disease) suggesting a different mechanism of gut injury.
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Table 1 Stage
Clinical
Laboratory
Radiological
Management
Ia
Temperature instability, apnea, bradycardia, ↓ SaO2 , ↑ gastric residuals, abdominal distension, stool-occult blood +ve Same as above
Unremarkable
Unremarkable
Asses frequently to rule out if due to prematurity, CPAP or sepsis, hold feeds if green tinged, increase feeds cautiously
Same as above + bloody stools
Unremarkable
Above + rule out fissures. Consider antibiotics to be discontinued in 2 days if CRP and blood cultures are normal NPO, gastric decompression, X-ray abdomen q 6–8 h including left lateral decubitus, inform surgeons. Start antibiotics × 7–10 days after sepsis work-up Same as above + supportive treatment
Ib
IIa
Stage I + decreased or absent bowel sound, guarding
Mild metabolic acidosis, mild thrombocytopenia
Dilated bowel loops, sentinel loops, pneumatosis intestinalis
IIb
Metabolic acidosis, thrombocytopenia, hyponatremia
IIA + portal venous gas shadows
IIIa
Stage I & IIa + absent bowel sounds, marked guarding, abdominal wall discoloration or cellulitis, Rt. lower quadrant mass Stage I & II + hypotension, DIC
Stage II + ascites
Same as above + insure adequate coverage for gram negative bacteria and anaerobes
IIIb
Same as above
Respiratory acidosis, metabolic acidosis, neutropenia, increased PT/PTT/INR, D-dimer, increase CRP Same as above
Stage II & IIIa + pneumoperitoneum
Above + emergency surgery
In 1978 Bell et al. [14] suggested staging of NEC depending on its severity, which was subsequently modified by Walsh and Kliegman [15]. Table 1 lists the staging along with suggested management strategies. Feeding intolerance is a common presentation of NEC which is also observed in premature infants with septicemia, decreased gut motility, use of caffeine or indomethacin, and gastro-esophageal reflux, thus resulting in over-diagnosis of stage I NEC. In
order to diagnose NEC early, a high index of suspicion should be maintained in premature infants, particularly those with birth weights less than 1 kg, and in infants with unstable perinatal events who should be monitored closely. Non-specific laboratory findings reported in NEC patients are: neutropenia, leukocytosis, thrombocytopenia [16,17], hyponatremia, acidosis or hyperglycemia. Radiological findings of fixed dilated bowel loops or ‘sentinel loop sign’ (Fig. 2), pneumatosis intestinalis (white arrows: Fig. 3), portal venous gas shadow (black arrows: Fig. 3) and pneumoperitoneum which
Fig. 2. X-rays KUB with markedly dilated sausage shaped loop (white arrow) and umbilical venous catheter in place.
Fig. 3. X-rays KUB with black arrow depicts portal venous gas shadow and white arrow depicts pneumatosis intestinalis.
3. Clinical features
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Fig. 4. Football sign – black arrow depicts free air under the diaphragm and white arrow depicts falciform ligament.
may present as ‘football sign’ (Fig. 4; white arrows: free air, black arrows: falciform ligament) are helpful in diagnosis of NEC. In some patients, pneumatosis, portal venous gas and pneumoperitoneum are seen in advanced stage of NEC with gut necrosis or ‘NEC totalis’ with poor prognosis. Pneumoperitoneum represents bowel perforation and is a surgical emergency. Isolated spontaneous intestinal perforation (SIP) is also occasionally seen in premature infants who have received postnatal corticosteroids, indomethacin, or were hypotensive, and these patients have a relatively better prognosis. The diagnosis of SIP is difficult to make without laparotomy, and thus some epidemiological studies may have overestimated the prevalence of NEC. High resolution ultrasonography has been used to asses gut injury, wherein echogenic dots or dense granular echogenic spots are seen in the bowel wall [18], and color Doppler imaging has been used to diagnose pneumatosis [19], but these techniques have not received wide acceptance. Some investigators believe that due to our failure to diagnose NEC early, infants have serious adverse outcome with enormous impact on their families who have to make frequent hospital visits, care for a handicapped infant and deal with financial burden [20]. Hence many NICUs adhere to strict feeding protocols, which have been considered to possibly decrease the occurrence of NEC. However, randomized, prospective studies with adequate statistical power to control for multiple factors in the extremely premature infants, particularly those with fetal compromise
Fig. 5. Congested, discolored and thickened bowel due to edema and inflammation.
and/or critically ill at birth are lacking. Therefore, we suggest a conservative approach in these high-risk infants by encouraging breast milk feeding (total or partial), to cautiously increase feeds and frequently assess them to minimize the occurrence of NEC, and diagnose NEC earlier when it does occur.
4. Pathology (gross and histopathology) NEC commonly affects the terminal ileum followed by colon and other segments of the small intestine [21,22]. Since pathological specimens are obtained from surgery or during autopsy, early stages of NEC are not usually accessible for pathological examination. On gross examination, as the disease process continues, the intestines appear congested, discolored and thickened (Fig. 5) due to edema and in advanced cases gas-filled cysts may be visible. These areas can progress to appear dark, gray and gangrenous (Fig. 6) and may perforate. Intestinal pneumatosis, the formation of gas bubbles within the intestinal wall is a characteristic finding seen in most patients with NEC, likely resulting from fermentation and gas production by bacteria. The intestinal wall perforates when the disease is severe with transmural involvement.
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5.1.1. Decrease in mucin production In NEC, the onset of the inflammatory process may be gradual, but may have a rapid progression, thus making it difficult to ascertain the time of its origin. Since most premature infants do not develop NEC despite immature intestines, it has been suggested that there may be genetic predisposition with fewer mucin-producing goblet cells in some infants. The goblet cells are expressed as early as 9 weeks of gestation, with peak expression at 23 weeks of gestation. The developmental expression of mucin goes through various stages of maturation with adult pattern layer observed between 23 and 27 weeks of gestation. Mucin protects the intestinal epithelial lining and prevents the translocation of the gut microbes into the circulation [6,25–28].
Fig. 6. Dark, gray gangrenous bowel with hemorrhagic foci.
Microscopic examination shows early changes of microvascular thrombi, submucosal gas-filled cysts (intestinal pneumatosis), vascular congestion, edema and a variable inflammatory infiltrate in the mucosal and submucosal areas. The inflammatory component may appear relatively less compared to the degree of necrosis. Late changes include coagulation necrosis with hemorrhage and gangrenous bowel wall susceptible to perforation [23] (Fig. 7a–e). Although there is no histological grading of NEC in humans, using an animal model, Jilling et al. have described grading from 0 to 4 with grade 0 representing intact morphology, grade 1 showing sloughing of the tip of villi, grade 2 with mild necrosis of villi, grade 3 with loss of villi, and grade 4 representing complete destruction of the intestinal mucosa [24].
5. Pathophysiology 5.1. Mechanism of injury This has been described in other chapters. We have summarized some of the salient features below.
5.1.2. Cytokines and chemokines The role of cytokines and chemokines in inflammation leading to gut injury in NEC has been extensively studied. The initial process of inflammation in gut injury likely begins with ischemia leading to the dysmotility of the intestine followed by excessive distension leading to the damage of the intestinal mucosal epithelial cells leading to the proliferation of proinflammatory bacteria. Lipopolysaccharide (LPS) [29–31] (an endotoxin present in the outer wall of the gram negative bacteria) may trigger the activation of the inflammatory cascade by engaging the toll like receptors (TLR), leading to the release of various cytokines and chemokines, e.g. interferon gamma, Interleukin-6, interleukin-8, interleukin-12, interleukin-18, tumor necrosis factor-alpha. These cytokines and chemokines are regulated by the transcription factor nuclear factor-kB, which regulates the leukocyte adhesion molecules. The role of cytokines and toll receptors has been discussed in other chapters in this issue. 5.1.3. Role of endothelium Several researchers have proposed that NEC is an ischemia–reperfusion injury with significant reduction in intestinal blood flow leading to inflammation followed by cellular necrosis. With compromised blood flow, the tissue is deprived of oxygen and nutrients. Endothelium, which lines the microvessels plays a pivotal role in controlling the blood flow to the intestinal tissues via regulation of endothelin-1 (ET-1) and endothelial nitric oxide (eNO). ET-1 is a potent vasoconstrictor [32], which acts via binding with ETA receptor and eNO, a potent vasodilator, which acts via ETB receptor. Nankervis and Nowicki postulated that this results from imbalance between vasoconstriction and vasodilatation properties of the endothelin leading to ischemia of the affected tissue causing NEC [33]. Thus vascular endothelial cells also play a major role in inflammatory cascade and acts as an immunomodulator. 5.1.4. Role of feeding Although NEC has never been reported in a fetus, Nanthakumar et al. found evidence suggesting gut inflammation in aborted fetuses [34]. They postulated that because of
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Fig. 7. (a) H&E-stained histological sections of a macroscopically unaffected segment, showing early signs of epithelial degeneration at villous tips and thrombus formation (arrow head) in an underlying vessel, hematoxylin–eosin stain, 100×. (b) Pathologic findings in NEC. Histologic sections of small bowel showing early stage of intestinal injury with hyperemia of mucosa and loss of epithelial cells at the villus tips (1). Intramural gas is seen as rounded bubbles in the submucosa (arrows), hematoxylin–eosin stain, 100×. (c) Here the bowel is affected much more severely. There is necrosis of the mucosa and submucosa with intraluminal necrotic debris on the mucosal side of the bowel wall (m) and loss of villi. The histologic characteristics of NEC include coagulative necrosis (1), bacterial overgrowth with inflammatory cell infiltration (2), mucosal edema and ulceration (3), hematoxylin–eosin stain, 100× with insert at 400×. (d) High magnification of a histological section of the necrotic small bowel mucosa showing characteristic vascular thrombi (arrowhead) and necrosis (arrow), hematoxylin–eosin stain, 200×. (e) Transmural necrosis of mucosa, submucosa, and muscularis propria extending to serosa with potential for perforation. s = serosal surface of bowel wall.
excessive cytokine production, immature human enterocytes may be prone to necrosis. In more than 90% of patients, NEC occurs in neonates who received enteral feeds. Although there is lack of consensus amongst neonatologists regarding the timing of initiation and the rate of increase of enteral feedings in premature infants, most physicians administer trophic feeds which are increased cautiously in extremely premature infants, particularly those who had absent diastolic flow in fetal period, had hypotension or severe intrauterine growth retardation. Also, it has been suggested that in utero, these infants produce meconium by swallowing amniotic fluid, which possibly has protective chemicals with a role in preventing intestinal injury after birth. Christensen et al. fed
a small group of 10 very low birth weight infants weighing 750–1250 g with formula having composition similar to the amniotic fluid and found no significant adverse effects in all these VLBW infants [35]. They suggested that amniotic fluid contents including erythropoietin and granulocyte-colony stimulating factor have antiapoptotic effects. Feeding practices in many NICUs are dependent on the clinician caring for the infant. However many neonatologists consider that if the infant does not have a large Patent Ductus Arteriosus or hypotension requiring vasopressors, minimal enteral nutrition, i.e. trophic feedings should be initiated once the infant is stable. This concept of priming the gut epithelium and develop adaptability may also help in decreasing feeding
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intolerance. Clinical trials have been conducted by keeping these infants Nil Per Os (NPO) for a week followed by introduction of the feeds with no differences observed in the incidence of NEC in infants weighing greater than750 g at birth. The Cochrane Systematic Review evaluating 9 trials does not suggest that the practice of minimal enteral nutrition either increases (or decreases) the risk of definite NEC, with a typical relative risk of 1.07 (95% confidence interval 0.67, 1.70); typical risk difference of 0.01 (95% confidence interval −0.04, 0.05) [36]. Premji et al. reviewed data from seven different trials in 571 infants on the effectiveness of continuous feedings in premature infants weighing less than 1500 g and concluded that there was no significant difference in the time to achieve the full feeds, somatic growth and the incidence of the NEC [37]. A consensus should be developed amongst neonatologists regarding the postnatal age to start trophic feeds, and the rate of increase of enteral feeds in various subgroups of premature infants. Although studies have been conducted on rapidity of increasing enteral feeds in premature infants, there is paucity of data in infants with birth weight of less than 750 g, and in those with varying degrees of illness. Since VLBW have a poor gut barrier and motility, they are prone to develop feeding intolerance. Under such circumstances, with an increase in gastric residuals even an experienced neonatologist may miss the early signs of NEC and although radiological evidence to support the diagnosis [38,39] and other criteria listed in table have been used, they are not definitive. 5.1.5. Infant formula and breast milk The next question is which form of enteral nutrition should be used, i.e. cow milk-based infant formula or human milk (either mother’s breast milk or donor breast milk)? The American Academy of Pediatrics endorses the use of human milk [40]. With the use of human milk, a decrease in the incidence of the NEC has been reported [41–44]. Lactoferrin, an iron-binding protein is suggested to be an important factor providing protective barrier and boosting the immune system by stimulating the infant’s innate immunity [4]. It is highest in colostrum (7 g/dL) compared to mature milk (1 g/dL) and is lowest in the mid-lactation milk (0.1 g/dL) [45–47]. Although in the fetus the gut is sterile, it is colonized by variety of microbes in the post-natal period. Gut microbiota is also altered by the type of feeding the newborn infant receives, i.e. breast fed infants get lactobacilli or bifidobateria in comparison to formula fed infants that are colonized with enterobacteria and other gram negative organisms [48]. In a double-blind placebo controlled randomized trial conducted at eleven tertiary care NICUs involving 472 very low birth weight infants (VLBW) infants who were given bovine lactoferrin (BLF) and BLF plus Lactobacillus rhamnosus GG (LGG) from birth to 30 days of life, Manzoni et al. concluded that BLF supplementation alone or in combination with LGG reduced the incidence of a first episode of late onset sepsis in VLBW neonates [49]. Additionally, with the use of prolonged use of antibiotics and/or H2-blockers, the gut loses its
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normal flora and may develop resistant microbes which may result in NEC and sepsis [34]. Carrion and Egan reported that by maintaining an acidic gastric pH less than 3.0 in breast milk, PM 60/40 and PF20, the incidence of NEC decreased, in contrast to higher gastric enteric bacterial colony counts which strongly correlated with gastric pH greater than 4.0 [50]. It is unclear whether the absence of harmful contents, or the presence of anti-inflammatory factors in the human milk prevents NEC. It is also postulated that unknown proinflammatory substances in artificial formula milk aggravate gut injury in infants with a genetic predisposition. Several probiotic strains have been used by researchers including: Bifidobacterium bifidus, breve, infantis, lactis and longus; Lactobacillus acidophilus, casei, rhamnosus GG, plantarum and sporogenes; Streptococcus thermophillus and Saccharomyces boulardii. Although clinical trials have demonstrated favorable result with use of probiotics treatment, several concerns remain, such as their side effects, optimal organism, dosages and the immature immune response of premature infants. Since, the actual dosage of pre, pro and postbiotics are unknown, complications may occur which could be dose related [1,51]. Rationale for the use of prebiotics and postbiotics in preventing NEC has been discussed by Dr. Panigrahi and Dr. Denning in this issue. 5.1.6. Transfusion associated gut injury Agwu et al. in 2005 in a case report suggested that blood transfusion may be a risk factor in inducing gut injury in premature infants leading to NEC. Subsequently several studies documented an increase in NEC among premature infants receiving enteral feeding during transfusion [52–56]. Stritzke et al. in 2013 conducted a retrospective chart review of 927 patients with NEC and reported an association of transfusion associated NEC (TANEC). They noted that 5.5% of patients received transfusion two days prior to the diagnosis of NEC. Majority of these TANEC patients were critically ill during their initial hospital admission, and developed NEC between 23 and 37 days of life [57]. 5.2. Long-term outcome The prevalence of NEC varies amongst NICUs. Ladd et al. conducted a retrospective study of 249 NEC patients who underwent surgery to analyze the factors possibly impacting long-term survival and growth. They reported that survivors were more mature, increased birth weight and postnatal age at the time of surgery. There were 112 deaths with 36% having NEC totalis, and an additional 30% died of septicemia. The average postoperative survival was 46.9 ± 91.5 days. Significant mortality was observed in neonates ≤30 weeks gestation (53%). In NEC, those patients who received surgical intervention had longer hospital stays in comparison to medical NEC. All such babies go through prolonged periods of parenteral nutrition but the majority are on enteral nutrition at the time of discharge. Although
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duration of prolonged parenteral nutrition duration depends on the intact ileocecal valve, it is also dependent on the length of the intestine resected. In general, those in whom >20 cm has been resected, go through prolong parenteral nutrition [58]. These infants go through a prolonged period of intestinal rehabilitation, depending on the size of viable gut remaining. The consequences of short gut have been discussed by Dr. Peter Minneci in this issue of the journal. Growth and development remains a major concern in infants surviving NEC. Sonntag et al. reported significant neurodevelopmental delay at 12 and 20 months in a small group of VLBW survivors of NEC [59]. Salhab et al. reported similar findings with neurodevelopmental assessment done at 18–22 months [60]. In a large NICHD study cohort, Hintz et al. hypothesized that ELBW infants with surgically managed NEC are at greater risk for poor neurodevelopmental and growth outcomes than in NEC patients managed medically and those infants did not have NEC. They evaluated 2948 infants at 18–22 months. Amongst them, 124 survived after surgery of NEC, and 121 managed medically. Infants with NEC who had surgery had more cystic periventricular leukomalacia, bronchopulmonary dysplasia and stunted growth in comparison to those in whom the NEC was managed with medical therapy and those who did not develop NEC [61]. Whereas Schulzke et al. after reviewing eleven non-randomized studies including 5 with matched control patients reported similar neurodevelopmental impairment in the NEC survivors requiring surgical intervention compared to those requiring medical therapy [62]. 5.3. Management Patients with NEC managed medically should be NPO along with gastric decompression (using large-bore Repogle tube), given total parenteral nutrition, receive appropriate antibiotic coverage (to cover anaerobic, gram negative and positive organisms), and receive close clinical and laboratory monitoring with serial abdominal X-rays (antero-posterior and left lateral decubitus views) done every 6–8 h to detect intestinal perforation. Emergency surgical intervention is undertaken in all cases of pneumoperitoneum, and in some patients with abdominal cellulitis (i.e. peritonitis), and in those with persistent thrombocytopenia suggesting necrotic bowel. Whether infection is the primary cause or occurs secondary to the ischemic gut initiating the inflammatory cascade remains controversial. Cole et al. reported that patients with NEC had late onset sepsis [63]. There are no clinical features or diagnostic tests which enable the clinician to halt the inflammatory process which leads to gut injury and necrosis. When pneumoperitoneum is detected, gangrenous changes in the intestines may have occurred in some instances, hence surgeons must be consulted in all suspected patients with NEC to minimize the time to surgery after pneumoperitoneum is diagnosed (Fig. 4). In addition, surgical intervention is also indicated if the infant is clinically deteriorating despite maximal medical treatment, if abdominal
mass is detected, has signs of persistent intestinal obstruction, sepsis, or has intestinal stricture. Relative indications for surgery are: increased abdominal tenderness, distension, discoloration, or the persistence of portal vein gas [64]. Surgical interventions include primary peritoneal drainage, laparotomy with resection and enterostomy, resection with primary anastomosis, proximal diverting jejunostomy, and “Clip and Drop” technique. Najaf et al. reported that 24% of their 124 infants with >Stage II NEC developed bowel perforation with a median interval of 1 day from the appearance of the symptoms [65]. In another review of 147 patients with NEC, Kosloske concluded that in addition to pneumoperitoneum which remains the definitive indication for surgery, portal venous gas and greater than 0.5 mL of brown fluid and/or bacterial growth in the fluid at paracentesis, surgical intervention should be considered [66]. Dr. Moss has elaborated on the surgical management of patients with NEC in this issue.
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