KEY POINTS
- 1.
Necrotizing enterocolitis (NEC) is a disease of premature infants that results in life-threatening intestinal ischemia and necrosis.
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Suspect NEC presents in a stable, formula-fed premature neonate who suddenly develops feeding intolerance and abdominal distention. Infants with suspected disease have abdominal distention, bilious emesis, and bloody stools but no specific radiographic features of NEC. Some of these infants may have temperature instability, apnea, bradycardia, or lethargy.
- 3.
In infants with definite NEC, bowel ischemia becomes detectable on abdominal radiography with the presence of pneumatosis. Many have abdominal tenderness, cellulitis, metabolic acidosis, and thrombocytopenia.
- 4.
Advanced NEC progresses to frank bowel wall necrosis causing intestinal perforation and pneumoperitoneum, peritonitis, septic shock, disseminated intravascular coagulation, and ultimately circulatory collapse.
- 5.
Advances in circulating biomarkers and imaging may help in earlier diagnosis of NEC.
- 6.
Medical management of NEC comprises bowel rest with gastrointestinal decompression, parenteral nutrition, careful administration of fluids, and broad-spectrum antibiotics.
- 7.
Surgery is indicated in infants with pneumoperitoneum and/or portal venous gas. Infants with rapidly increasing clinical instability with extensive intestinal disease, severe thrombocytopenia, anemia, or metabolic acidosis may also benefit from surgical exploration.
Introduction
Necrotizing enterocolitis (NEC) is a disease of premature infants that results in life-threatening intestinal ischemia and necrosis. Approximately 1 to 3 per 1000 infants born in the United States will develop NEC, , and NEC is the leading cause of death due to gastrointestinal pathology in premature infants. The incidence of NEC is inversely proportional to gestational age, making the disease relatively rare in full-term infants and more common in premature infants. The incidence is as high as 13% in infants born at or before 33 weeks’ gestation or weighing less than 2500 g. , Black and Hispanic infants also have higher incidence of and mortality from NEC, demonstrating that racial disparities exist for NEC care.
The average mortality risk for NEC is 20% to 30% but can approach 50% in patients with significant bowel injury. Infants who survive NEC are also at risk for serious long-term morbidity. Damage to the brain and bowel from NEC causes lasting neurocognitive injury in 30% to 50% of survivors. , Intestinal strictures from ischemic injury occur in 12% to 35% of infants. , Complications also arise from the surgical management of NEC, with significant bowel resections resulting in short bowel syndrome (SBS) (20%–35%) and growth delay (10%). ,
Risk Factors
The etiology of NEC remains an active area of investigation. However, clinical and experimental data implicate immature immune signaling and abnormal microbial colonization of the intestinal mucosa. These factors contribute to the characteristic intestinal necrosis and inflammation associated with NEC. ,
Clinically, the most significant risk factor for NEC is prematurity. , Formula feeding, blood transfusions, prolonged empiric antibiotics, and use of antacids are also known risk factors. From observational studies, maternal risk factors for NEC also exist and include prolonged rupture of membranes, maternal infection, Black race, preeclampsia, placental abruption, and intrauterine growth restriction.
No single genetic determinant has been implicated in NEC pathogenesis, however results of twin studies suggest a familial predisposition. As will be described in more detail below, NEC develops in response to the activation of the innate immune receptor, toll-like receptor 4 (TLR4), on the surface of the intestinal epithelium, which is expressed at high levels in premature compared with full-term infants.
TLR4 activation in the intestinal epithelium leads to enterocyte death by apoptosis and necroptosis and impaired healing via reduced proliferation and migration of enterocytes in the intestinal epithelium. , , The reason that TLR4 is expressed at high levels in the intestinal epithelium of premature infants is found in the nonimmune role that TLR4 plays in the regulation of normal intestinal development through its activation of Wnt and Notch. Thus in the presence of prematurity, when the intestinal lumen becomes colonized with microbes that express the TLR4 ligand lipopolysaccharide, TLR4 signaling switches from a developmental to an inflammatory role, and NEC develops. This “cross switching” hypothesis of NEC is fundamental to our understanding of disease pathogenesis and of our search for novel therapies.
In support of the clinical relevance of TLR4 signaling in the pathogenesis of NEC, mutations of the single immunoglobulin and toll-interleukin 1 receptor (SIGIRR) gene, an inhibitor of TLR4 activation, for instance, have been associated with NEC development. Other gene polymorphisms under study for their association with NEC are proinflammatory cytokines such as tumor necrosis factor α, interleukin (IL)–4 receptor α-chain, IL-6, IL-23 receptor and IL-17, and vascular endothelial growth factor.
The Five Clinical Presentations of NEC in Infants
NEC typically presents in a stable, formula-fed premature neonate who suddenly develops feeding intolerance and abdominal distention. NEC onset is dependent on an infant’s gestational age at birth. Extremely premature infants (born at ≤27 weeks’ gestation) typically develop NEC at 4 to 5 weeks of age, whereas NEC occurs within 2 weeks of age in full-term infants. The inverse relationship between gestational age and NEC onset is potentially explained by the increased expression of TLR4 in the premature intestine, the delayed microbial colonization and altered T-cell–mediated adaptive immune response of the premature gut, and the frequent use of broad-spectrum antibiotics in neonatal intensive care. ,
The presentation and progression of NEC is classically described by Bell’s staging criteria, which categorize disease severity into suspected NEC (stage I), moderate NEC (stage II), and advanced NEC (stage III) , ( Table 81.1 ). Infants with Bell’s stage I disease have abdominal distention, bilious emesis, and bloody stools but no specific radiographic features of NEC. Historically, high gastric residuals were also considered suspicious for NEC; however, this practice has fallen out of favor due to a lack of standardized protocols and frequent measurement error. Neonates with suspected NEC may also have systemic inflammatory signs such as temperature instability, apnea, bradycardia, or lethargy. When bowel ischemia from NEC becomes detectable on abdominal radiography with the presence of pneumatosis, infants are classified with Bell’s stage II disease. They may also have abdominal tenderness, cellulitis, metabolic acidosis, and thrombocytopenia. Finally, infants with Bell’s stage III disease have progressed to frank bowel wall necrosis causing intestinal perforation and pneumoperitoneum, peritonitis, septic shock, disseminated intravascular coagulation, and ultimately circulatory collapse. ,
| NEC Scenarios | Presentation | Labs and Imaging | Management | Operative Considerations |
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| Textbook NEC | Premature infant starts formula and develops sudden abdominal distention, emesis, bloody stools Textbook NEC follows the classic progression through Bell’s stages |
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| NEC with refractory, nonprogressive pneumatosis | A variant of textbook NEC where the disease progression halts at Bell’s stage II |
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| NEC with portal venous gas | A variant of textbook NEC that develops both pneumatosis and portal venous gas on abdominal radiograph |
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| Staccato NEC | An accelerated presentation compared with textbook NEC Staccato NEC presents within hours with a tense abdomen from severe ascites and rapid hemodynamic instability |
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| NEC totalis | An intraoperative finding of near-complete intestinal necrosis Can occur with any other NEC subtypes |
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Decades of clinical experience and a deeper understanding of the pathogenesis of NEC has taught us that NEC is not a homogeneous disease with a uniform clinical pattern but rather has several presentations that must be considered in order to appreciate a more complete understanding of how to successfully diagnose and treat this condition. We have recognized five presentations of NEC that include classic “textbook NEC,” NEC that fails to improve after medical management, NEC with portal venous air, NEC totalis , and “staccato NEC.”
Classic Textbook NEC
The classic “ textbook NEC ” presentation describes infants whose disease progression follows the classic Bell’s staging descriptions, developing intestinal inflammation, ischemia, and ultimately necrosis with free air, as manifest by the presence of pneumoperitoneum on x-ray, during a 24- to 48-hour window. Medical management can halt this progression in approximately 50% of infants, whereas the other half develop Bell’s stage III with intestinal perforation that mandates surgical intervention. However, many infants do not present with this classic “ textbook ” progression (see Table 81.1 ). The diagnosis of intestinal perforation is typically straightforward to establish, and surgical intervention is indicated after a period of resuscitation. We do not advocate delaying surgery while waiting for normalization of all lab values. It may be impossible to normalize the infant’s physiology without resection of the diseased intestine, resulting in delayed surgery, more extensive disease, and worse outcome.
NEC That Fails to Improve After a Period of Medical Therapy
One of the most challenging diagnostic instances that occur in patients with NEC involves the child with medical disease (typically but not always with persistent pneumatosis) who fails to respond to medical therapy. These infants will typically start with textbook NEC that progresses to pneumatosis on abdominal radiograph. However, unlike textbook NEC , the disease will neither progress to intestinal perforation nor improve with maximal medical management. Radiographs may show persistent pneumatosis , persistent ileus, ascites, or some combination of these signs in the absence of free air.
Clinically, the child will display persistent abdominal fullness, with slowly down-trending platelets and hemoglobin, requiring intermittent transfusions. Platelet consumption is an important sign of coagulative necrosis of the small bowel and can be missed in the setting of transfusions that artificially stabilize thrombocytopenia. , Other concerning signs of bowel necrosis in these patients include increasing abdominal distention and increasing ventilatory or vasopressor support. In these patients, it is important to “set a line in the sand” in collaboration with the neonatology team. If the child fails to improve within 48 hours or if the child shows greater needs for ventilatory or inotropic support, for example, then surgical exploration of the abdomen is indicated.
NEC in the Presence of Portal Venous Gas
Portal venous gas is an important sign of severe NEC. In the patient who has abdominal distention and tenderness, the presence of portal venous gas generally indicates the presence of significant intestinal necrosis and mandates early exploration. It is sufficient for the portal venous gas to be present on only a single film, because this finding may be fleeting despite the presence of extensive, irreversible intestinal damage, and therefore its absence on later plain films does not imply resolution of bowel injury from NEC. Infants with a single radiograph showing portal venous gas should be treated as equivalent to those with pneumoperitoneum in the setting of appropriate clinical findings.
Staccato NEC
This presentation is known to all clinicians who care for infants with NEC, and it describes the child who has an extremely rapid course of deterioration. In “ staccato NEC ,” patients manifest early deterioration as a reflection of progressive bowel necrosis. Within a few hours of presentation, infants with staccato NEC will have a tense abdomen from severe ascites, and abdominal radiographs will show some degree of pneumatosis with or without portal venous gas. Staccato NEC is associated with high mortality and is manifest by early hemodynamic instability, profound thrombocytopenia, and worsening respiratory distress due to progressive abdominal distention.
NEC Totalis
NEC totalis refers to the most severe form of NEC, in which there is near-complete intestinal necrosis. Historically, NEC totalis was an indication for palliative care, with both surgeons and neonatologists adopting a fatalistic approach. However, with the dramatic improvements in management of patients with SBS and the dramatic success in achieving enteral autonomy as well as improvements in intestinal transplantation, the presence of NEC totalis need not be an immediate death sentence for a patient. Rather, in the appropriate setting, including the absence of major comorbitidies and a family that can partner and is willing to provide ongoing complex medical care, patients with NEC totalis can be offered intestinal resection and be considered salvageable.
Differential Diagnoses
The initial presentation of NEC overlaps with other neonatal pathology, making early diagnosis a challenge. Signs of ileus and feeding intolerance seen at NEC onset are also present with anatomic intestinal obstructions (e.g., malrotation, intestinal atresia) or functional obstruction (e.g., Hirschsprung disease). Septic ileus can mimic the hemodynamic instability and abdominal distention seen in later stages of NEC. Other causes of intestinal ischemia occur with volvulus or cardiac and hematologic disorders. , A milk protein allergy can also mimic the signs and symptoms of NEC, including radiographic features of pneumatosis , although this is a diagnosis of exclusion.
NEC Versus Spontaneous Intestinal Perforation
It is especially important to distinguish NEC from spontaneous intestinal perforation (SIP), another disease of very low birth weight infants. SIP and NEC are different entities, although they overlap in presentation, and management strategies and prognoses markedly differ. SIP typically presents with sudden-onset pneumoperitoneum and peritonitis in the absence of bowel wall necrosis in a premature infant, usually within the first week of life.
SIP can be challenging to distinguish from NEC prior to laparotomy. However, there are distinct differences in the risk factors, physical exam findings, and timing of disease onset that help distinguish between SIP and NEC. Unlike NEC, SIP is not associated with feeding onset and instead has distinct risk factors of indomethacin and postnatal steroid exposure. Infants with SIP occasionally have a characteristic blue abdominal discoloration, whereas those with NEC classically have abdominal erythema and cellulitis. In comparison with NEC, SIP occurs earlier: between days 7 and 10 of life in extremely low birth weight infants. Patients with SIP do not display pneumatosis intestinalis.
Overall, distinguishing between NEC and SIP is imperative because patients with SIP can benefit from peritoneal drainage (PD) procedures whereas the ischemic bowel seen in NEC warrants surgical exploration and bowel resection. Outcomes of SIP are also better than those of NEC, and SIP does not result in long-term neurologic deficits. ,
Diagnosis
Imaging
Upon clinical suspicion for NEC, serial anteroposterior and lateral abdominal radiographs every 6 to 8 hours are helpful to assess for disease progression. Radiographs of early, suspected NEC frequently show nonspecific bowel distention. , As intestinal inflammation and ischemia develop, radiographs reveal focal distention of the bowel that progresses to bowel wall thickening and fixed intestinal loops. A paucity of abdominal gas is also concerning for NEC. ,
The hallmark diagnosis of NEC is radiographic evidence of pneumatosis intestinalis or portal venous gas ( Fig. 81.1A, B ). This extraluminal gas is a result of intestinal bacterial fermentation producing hydrogen gas, which then dissects the bowel wall and enters the portal venous system. , Pneumatosis and portal venous gas are highly specific (92%–100%) but poorly sensitive (34%–44%) for bowel injury that is due to NEC.
As mentioned above, pneumoperitoneum is another diagnostic feature of radiographic NEC that requires prompt surgical intervention (see Fig. 81.1C ). Secondary to bowel perforation from intestinal necrosis, pneumoperitoneum may present with a large radiolucency over the abdomen, called the “football sign,” or may be seen as air under the diaphragm. Although it has been reported that only approximately half of patients with perforated bowel from NEC have detectable pneumoperitoneum on imaging, this figure is probably an overstatement. The message, though, is that the absence of pneumoperitoneum does not exclude the presence of intestinal perforation.
During the past decade, abdominal ultrasound has gained popularity as an alternative imaging modality for NEC. Ultrasound enables visualization of early signs of NEC including decreased bowel peristalsis, intestinal wall thickening, and decreased bowel wall perfusion. A recent meta-analysis showed that similar to abdominal radiographs, bowel ultrasound for NEC has low sensitivity but high specificity and is a reasonable adjunct for an NEC diagnosis.
Biomarkers and Laboratory Parameters for the Diagnosis of NEC
There has been significant interest in identifying serum, fecal, and urine biomarkers that detect the intestinal inflammation and bowel wall injury seen in NEC. Increases in acute-phase reactants such as C-reactive protein, serum amyloid A, chemokines, cytokines, and interleukins are nonspecific findings seen with NEC, yet they have been correlated with NEC severity and with need for surgery. , Markers for intestinal injury, such as intestinal fatty acid-binding protein (I-FABP), , fecal calprotectin, and claudin-3, can also assist the evaluation of patients with NEC. Trends in these markers may be more useful than any individual marker in isolation.
I-FABP is an enterocyte intracellular protein that is released with mucosal injury, and elevated levels in the urine and plasma are specific (91%) but not sensitive (64%) for diagnosing NEC. , Infants with elevated I-FABP at birth and during their first feeding are also more likely develop NEC. Fecal calprotectin has high sensitivity (76%–100%) for bowel perforation and may have a role in differentiating Bell’s stage IIB from stage III. , , Urine claudin-3 is another potential biomarker for early detection of surgical NEC.
Despite these findings, systematic reviews consistently report limited evidence for the utility of biomarkers for screening and diagnosis of NEC. Therefore the current recommendation for NEC screening and management involves the evaluation of routine laboratory parameters in conjunction with imaging studies. Routine laboratory parameters assess disease severity and guide balanced fluid resuscitation in neonatal critical care. Leukocytosis or leukopenia, thrombocytopenia, metabolic acidosis, glucose instability, and elevated C-reactive protein are frequently observed in infants with NEC. , , Neutropenia, thrombocytopenia, and metabolic acidosis are associated with a poor prognosis and need for surgery, whereas a resolution of thrombocytopenia can indicate clinical improvement. , , Therefore trending complete blood counts (CBC), serum chemistries, lactate, and blood gases are useful adjuncts to detect bowel ischemia, metabolic acidosis, and electrolyte derangements in the setting of diagnosed or suspected NEC.
Management
There are two fundamental pillars of NEC management:
1.Minimize NEC progression with medical management to prevent the development of intestinal necrosis.
2.Quickly identify and resect intestinal necrosis to obtain source control and limit the systemic inflammatory response.
Surgical exploration for pneumoperitoneum remains an absolute operative indication for infants with NEC. However, infants with other presentations of NEC frequently require surgery ( Table 81.2 ). As mentioned previously, portal venous gas in the presence of the appropriate clinical findings should be treated as equivalent to pneumoperitoneum and be a clear operative indication. Infants with rapidly progressive s taccato NEC require early surgery for management of progressive clinical instability and extensive intestinal disease, even in the absence of other surgical indications. In the setting of severe thrombocytopenia, anemia, or metabolic acidosis, waiting to medically optimize these infants for surgery only results in worsening intestinal necrosis. , ,
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