key: cord-0005499-5lzj6rdd authors: Kulkarni, Anjali; Vigneswaran, R. title: Necrotizing enterocolitis date: 2001 journal: Indian J Pediatr DOI: 10.1007/bf02762112 sha: c75d2d950ae6e19e4145358006e86b8b6201887f doc_id: 5499 cord_uid: 5lzj6rdd Improvement in survival rates of low birth-weight infants particularly in the neonatal intensive care units of India appears to be accompanied by frequent recognition of Necrotizing enterocolitis (NEC) among early survivors. As the philosophy and practice of advanced care for tiny infants becomes more acceptable and affordable in the country, a steady increase in survival of such infants is predictable. However there is growing concern in India that NEC could become a significant contributor to morbidity and mortality in the future. NEC is currently regarded as the most common acquired gastrointestinal emergency in the newborn period, and the outcome of this disease is universally poor. Improved understanding of the pathophysiology and pathogenesis of this condition is required for formulating optimal principles of prevention and management. NEC was initially recognised as a disease primarily affecting premature babies in 1950s and 1960s. The first case with signs and symptoms similar to NEC was described by Genersich in 1891 in a 45 hour old premature infant who died within 24 hours. Since then there have been several case reports. However, it was recognised as a syndrome and described by Mizrahi et al. in 1965 in what is referred to as the landmark report. = As most of the studies published early on NEC were retrospective in nature, Ryder et al conducted a multicentre prospective case control study which was published in 1980. 2 The results of this study showed that incidence of NEC was 2% of all admissions to the neonatal intensive care units and several factors were found on multivariate analysis to be significantly associated with NEC. Low 5 minute apgar score, patent ductus arteriosus, maternal receipt of anaesthesia during delivery, enteral feeding on 10% dextrose, early gavage feeds and premature rupture of membranes were factors considered significant. Since then several studies have attempted to define the contribution of various aetiological factors precisely and they shall be referred to and discussed later. The incidence of NEC as reported from different parts of the world is comparable. 3.4 There is paucity of published data about the incidence of NEC in India. As expected, fewer cases of full blown NEC are seen in India because only a small proportion of VLBW population survives. A survey conducted by All India Institute of Medical Sciences over 16 Indian NICU's has reported an incidence Reprint requests : Dr. Anjali Kulkarni, 6 Ishwar Nagar Mathura Road, New Delhi 110065. E-mail : akulkarni58@rediffmail.com. Fax : 011-6328725 of 1.55% in pre-term babies. Prematurity and low birth weight, enteral feeding, gastrointestinal infection and compromised in-utero blood flow are some of the known predisposing factors for NEC. Greater than 90% of infants with NEC are preterm infants with low birth weight and the maturity of the gastro intestinal tract is considered to be an important factor in the aefiology of NEC. 4 Nearly all infants with NEC have history of enteral feeding, s Rapid increment in feeds of more than 20 ml/ kg/day, formula feeding as compared to breastfeeding, and hyperosmolar feeds are factors associated with development of NEC. s Epidemics of NEC are frequently reported from neonatal intensive care units. However, investigation of epidemics with standard techniques have not revealed any microbiological agent in affected infants. Association between reverse end diastolic flow in umbilical arteries and NEC have been reported . Histopathology of intestines has been characterised by coagulation necrosis indicative of ischaemia. The aetiology of NEC is multifactorial. Figure 1 gives a diagrammatic representation of aetiology and pathogenesis. 6 Preterm infants are at higher risk for NEC because they are vulnerable to tissue damage by toxins, nutrients, circulatory insufficiency, stasis and bacterial proliferation, and translocation of infecting organisms. Breast milk has been shown to reduce the risk of NEC in preterm infants. The particular properties of breast milk that account for its protective nature are immunological defence factors and non-immunological defence factors. In addition to IgA immune protection is believed to be provided by anti-inflammatory components, namely PAF acetylhydrolase, Vitamin E, B-carotene and ascorbic acid. Human milk lipids may be less toxic to the intestinal epithelium. Nutrients such as glutamine and nucleotides enhance gastrointestinal cell metabolism and function. Also breast milk contains many growth factors and hormones that may improve function and maturity. It is also understood that the cysts of pneumatosis contain methane + CO2 + hydrogen and bacterial fermentation is the only known source of hydrogen gas. Further evidence is provided by the decreased incidence of NEC following the use of oral antibiotics" Cohen has commented that the gastrointestinal pathology of NEC is consistent with the interaction of epithelial cells with bacterial toxins and one toxin that presents similar pathologic finding is the enterotoxin produced by C. perfringes type C, the causative agent of pigbel which is a disease seen in adults and children following a traditional pigfeast. Enteropathogenic viruses are believed to infect epithelial cells resulting in cell destruction, necrosis and intestinal perforation. There are, however, some indications that infection is not mandatory for development of NEC. Infectious agents are isolated only in 30 -35% cases, and there is no uniformity in pathogens isolated. Also same pathogens can be isolated from stools of healthy infants and sick babies with known gastrointestinal infection who do not develop NEC. It is arguable that infection may not be the initiating factor, but a permissive agent in the pathologic cascade leading to NEC. The link between circulatory disturbances and pathogenesis of NEC is based on the understanding that reduced mesenteric blood flow leads to ischaemia which in turn causes hypoxic cell damage and release of inflammatory mediators. These changes are associated with reperfusion followed by release of oxygen free radicals leading to loss of cellular integrity. Although decreased circulation is a significant factor, extensive physiological studies carried out recently dispute ischaemia as being the primary actiological agent. 9 Several clinical studies published in the recent times have shown that infants who developed NEC did not have low apgar scores and they showed no concomitant changes of hypoxia and ischaemia in other organs? ~ However, it is interesting to note that all these risk factors are significantly associated with development of NEC in term and near term babies, u Umbilical artery catheterisation and exchange transfusion have been shown to have an association with development of NEC in term or near term infants. 12 However, studies in Australian populations of preterm infants have not confirmed this relationship. Antenatal circulatory disturbances predispose the gut to damage by various agents. Moreover, these disturbances are associated with IUGR and VLBW and these factors may independantly contribute to the development of NEC. The pathological changes are probably a secondary event following mucosal injury. Endothelial injury causes altered nitric oxide production leading to vasoconstriction and ischaemia. The final common pathway in the development of NEC is believed to involve mediators like platelet activating factor, endotoxin lipopolysaccharide, tumour necrosis factor and other cytokines, prostaglandins and leukotrines. This theory has been supported by the fact that administration in experimental animals produced 'NEC' like lesions. Elevated levels of some of these have been documented in babies with 'NEC'. 13 Antenatal/ postnatal glucocorticoids are known to decrease incidence of NEC. ~4 Furthermore isolated thrombocytopenia and all the other haematological and circulatory disturbances seen in NEC are also explained on this basis. Clinical presentation of NEC may vary from subtle feeding intolerance and change in bowel pattern to catastrophic deterioration in general condition with severe abdominal distension and bloody stools. In general, infants demonstrate gastrointestinal dysfunction as reflected by the presence of abdominal distension, vomiting, bilious drainage from feeding tubes or blood stained bowel action, and systemic illness as reflected by temperature instability, apnoea, lethargy or hypotension. The age of onset is inversely related to gestational age at birth and preterm infants remain at risk until postconceptual age of 35 to 36 weeks or later. Clinicians must be extremely vigilant in assessing preterm infants for a protracted post natal period. Initially proposed by Bell and coworkers is and later modified by Walsh and Kliegman, ~6 these criteria provide a basis for a strategic plan of management. (Table 1 ). Stage 1. (Suspected NEC) is associated with non-specific clinical and radiological signs like temperature instability, mild abdominal distension, dilated bowel loops and bowel wall thickening on X-ray. Stage 2. (Definite NEC) is characterised by gross blood in stool, mild metabolic acidosis and thrombocytopenia along with radiological finding of intestinal pneumatosis. Typically there is a linear streak of gas within the bowel wall visualized in a single discrete portion of the small intestine. Rarely, it may extended throughout the small and large intestine. Sometimes a bubbly pattern is seen which is similar to that seen in newborn infants who retain meconiurn in the intestine. This is less specific for NEC than the linear pattern. Stage 3. (Advanced NEC) is characterised by hypotension, disseminated intravascular coagulation and sometimes signs of generalised peritonitis. Respiratory acidosis may be present due to elevation of diaphragm along with radiological features of intestinal perforation. Typically, free air is visualised on a cross-table lateral or lateral decubitus film. Diagnosis is mainly clinical supported by radiological features. Intra mural gas (pneumatosis intestinalis) is the hall mark of diagnosis. However, other radiological features which may be present are : ischaemia. Prone and decubitus position can help to differentiate from normal dilated intestine 3. Diminishing bowel gas -poor motility leads to filling with fluids and reduced gas 4. Intrahepatic portal-venous gas 5. Pneumoperitoneum best seen in lateral decubitus films No individual laboratory feature is diagnostic of NEC. Laboratory analysis is primarily used to confirm clinical diagnostic impressions and to assess progression of severity of disease. Peripheral haematological studies may reveal abnormally high or low leucocyte counts with a shift towards immature precursors. The classical triad of increasing thrombocytopenia, acidosis and hyponatremia is suggestive of severe NEC likely to progress towards surgical intervention. Thr0mbocytopenia is probably caused by increased peripheral destruction rather than diminished production of platelets. Hyponatremia is usually due to tissue sequestration of sodium. Metabolic acidosis is an indicator of sepsis with decreased tissue perfusion and arterial pH is frequently below 7.20. A recent study of magnetic resonance imaging (MRI) for non-invasive diagnosis of intestinal necrosis in NEC showed that it is a useful method of confirming necrosis in NEC and may aid the timing of surgical intervention in preterm infants with a clinical diagnosis of NEC. v Early Diagnosis : It is extremely important to diagnose this condition as early as possible to limit the morbidity and mortality. This can be achieved by the following . This diagnostic facility is based on a study carried out in the department of Radiology at University of California, San Francisco. Urine specimens from 22 neonates were obtained 8-12 hours after enteral administration of Iohexol. 12 of these had suspected {n=5} or definite {n=7} NEC. Routine upper gastrointestinal study was conducted on these and 13 control neonates who did not receive Iohexol. The attenuation coefficient of each urine specimen was determined with computerized tomography. The main CT attenuation coefficient in neonates with NEC was significantly higher than that in patients without NEC who underwent upper gastrointestinal study. Prognosis : The prognosis depends upon the clinical staging and some radiological and haematological parameters. The bad prognostic indicators are depicted in Table 2 . When the diagnosis of NEC is made, carefully planned medical management should be instituted. Staging of the disease is helpful in designing various components of therapy. The irffant requires cardiorespiratory monitoring, prompt cessation of enteral feeding and commencement of 2 hourly gastric suction as well as continuous open drainage. Intravenous fluid therapy should be commenced simultaneously. Broad spectrum antibiotics namely ampicillin and Gentamicin along with a loading dose of Metronidazole should be initiated. Close If progressive improvement is seen leading to full recovery from symptoms and signs within five days enteral feeding should be introduced gradually. When the diagnosis is certain enteral nutrition should be withdrawn until full recovery. The infant requires total parenteral nutrition during that time. Respiratory function of infants with established NEC becomes severely affected and the infant may require ventilatory support. Hypotension may require volume expansion with either albumin or normal saline or vasopressor agent namely dopamine or dobutamine. Anaemia may require correction and thrombocytopenia would require platelet transfusion. Coagulation disorders if present should be treated appropriately. Severe metabolic acidosis can be expected and treatment with sodium bicarbonate should be offered as necessary. Electrolyte disturbance should be watched for and appropriate changes to fluid management should be made. Antibiotic therapy already commenced may require reviewing in the light of culture reports and treatment with Metronidazole should be maintained. Serial radiological examinations (abdominal X-ray 6 hourly or when prompted by clinical changes) are necessary in the acute stage of the illness. It is recommended to do supine and lateral decubitus films in order to detect intestinal perforation early. Although NEC usually responds to intensive medical AnJali Kulkami and R. Vigneswaran treatment, between 30 to 50% of infants progress to the advanced stage III and develop complications requiring surgery. There is no consensus on either the indication of or the timing and type of surgery for infants with NEC. 19 Development of gangrenous bowel and perforation is considered to be the absolute indication for surgery. Pneumoperitoneum when present is a useful guide. Other clues to the development of intestinal gangrene are used as relative operative indications. They are : (1) Presence of a fixed dilated intestinal loop on serial X-rays. (2) Abdominal mass or an abscess secondary to localised perforation. (3) Clinical deterioration over 12-24 hours despite intensive medical support, as evidenced by persistent or worsening metabolic acidosis, persistent thrombocytopenia, increasing ventilatory status and deteriorating haematological parameters. The goals of surgical intervention are to remove non viable bowel and preserve all viable bowel. Surgical procedures adopted for treatment of NEC fall into four categories -(1) Resection of necrotic bowel and primary anastomosis. In stable infants with localised disease, it is the procedure of choice. Complications : Complications may be due to the disease or the management. These are listed in Table 3 OVERALL OUTCOME Based on the expanding knowledge of the pathogenesis of NEC several prophylactic strategies have been developed. These strategies cover two major aspects of pathogenesis namely microbial infection and immature intestines. ~ Enteral antibiotics have been tested for the prevention of NEC the results are conflicting and routine use is not recommended. 23 Although theoretically gastrointestinal acidification may inhibit bacterial colonisation of the gut its value in preventing NEC is far from proven. On immunological grounds exclusive expressed breast milk feeding should be expected to have protective effect on the gut of the preterm newborn infants. Although the results of a multicentre trial showed favourable results, the inappropriate study design casts uncertainty. Oral immunoglobulin administration showed a decrease in incidence of NEC and this particular strategy appears to be promising. Further confirmation is considered necessary before recommending for routine practice. Meta-analysis of 12 controlled trials of antenatal corticosteroid therapy showed that the risk of developing NEC was greatly reduced. The use of antenatal corticosteroids should therefore be encouraged, u The beneficial effects of early enteral feedings and slow increments while carefully monitoring tolerance have been recognised in strategies to prevent NEC. NEC is largely a disease of the immature infant and immaturity of the local host defenses of the gut is a factor. Also, immaturity of gut immunity causes susceptibility to specific infections and/or poorly regulated inflammatory responses, both of which can cause localised injury to the gut. The breast milk is believed to provide an array of specific and non specific immune factors that may protect from NEC. Experimentally systemic administration of proinflammatory cytokines have been shown to induce hemorrhagic intestinal necrosis that characterises NEC. Based on this phenomenon PAF acetylhydrolase has been used to alleviate bowel necrosis and many of the other features of NEC. Several gastrointestinal trophic factors that influence the pre and post natal growth and development of the gastrointestinal tract have been identified and are considered to be potentially effective when used therapeutically to enhance gastrointestinal maturation and repair followinginjury. 2s The value of enteral glutamine supplementation-for decreased gastrointestinal morbidity in new infants has been demonstrated. 26 Although no single strategy has been shown to be highly successful in preventing NEC, all the methods do have scientific merits and deserve consideration by clinicians in their efforts to decrease the incidence and/or severity of this disease. Scope for intervention in the future lies in the success of identification of a single pathogen or virulence factor, the viability of therapeutic use of gastrointestinal trophic factors for their protective value and on the value of inhibitors of inflammatory mediators in preventing and modifying the process of NEC. 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