Lakkundi, Anil

Phad, Nilkant

Todd, David

Trivedi, Amit

Journal of Neonatal Surgery

The Australian National University

 Journal of Neonatal Surgery 2014;3(4):44   EL-MED-Pub Publishers.                   * Corresponding Author  ORIGINAL ARTICLE   Intestinal Strictures Post-Necrotising Enterocolitis: Clinical Profile       and Risk Factors  Nilkant Phad1, Amit Trivedi1,* David Todd2, Anil Lakkundi3 1 Grace Centre for Newborn Care, Children’s Hospital at Westmead, Westmead, NSW, Australia 2 The Canberra Hospital, Garran, ACT, Australia  3 John Hunter Children’s Hospital, New Lambton Heights, NSW, Australia   ABSTRACT  Background: Intestinal stricture is an important complication of necrotising enterocolitis (NEC). We aimed to describe clinical profile and identify the risk factors for post-NEC intesti-nal strictures.  Method: A retrospective study of infants with NEC over 10 year period.  Results: Of the 61 infants with NEC, 18 (29.5%) developed intestinal strictures. Leucocyto-sis and longer length of bowel resection during acute stage of NEC was associated with a later diagnosis of intestinal stricture. Infants with NEC who did not develop stricture had non-specific intestinal dilatation on abdominal x-ray during acute NEC. Intestinal strictures were diagnosed at a median interval of 34 days after NEC. Majority of strictures (67%) oc-curred in the colon. A significant proportion (77%) of infants with intestinal stricture had as-sociated co-morbidities. No mortality occurred in infants with intestinal strictures.  Conclusion:  The incidence of post-NEC intestinal stricture is high but development of stric-ture is difficult to predict. Leucocytosis during NEC and length of bowel resected at surgery may be associated with development of post-NEC intestinal stricture. A substantial number of infants with post-NEC intestinal stricture fail to thrive, have co-morbidities and need pro-longed hospitalisation. Key words: Necrotising enterocolitis, Intestinal strictures   INTRODUCTION Neonatal necrotising enterocolitis (NEC) is one of the most common surgical emergencies in neonatal intensive care units (NICU) with a re-ported incidence of 2.6% to 6.6%, depending on the gestational age of infant at birth [1,2].  Most cases of NEC are managed conservatively and surgical intervention is required in infants with intestinal perforation or deteriorating clinical or laboratory parameters despite optimum medi-cal treatment [3,4]. With improved survival of many seriously ill infants with NEC, a sub-stantial number of infants present with inter-mediate or long-term  sequelae [5]. Intestinal stricture following NEC is a well-known complication of the healing process that follows ischaemic injury to the in-ner muscular layer of the intestine, during the acute episode [6].  Intestinal strictures develop irrespective of the mode of management of the acute episode of NEC and tend to have a strong preference for the left colon (splenic flexure, descending and sigmoid colon) [3]. Strictures manifest at a variable period after the acute NEC. Several studies have described significant mortality and morbidity secondary to intestinal strictures [3,5,7]. However, there is paucity of recent literature describing the natural history of intestinal strictures following NEC [8].    Intestinal Strictures Post-Necrotising Enterocolitis: Clinical Profile and Risk Factors   Journal of Neonatal Surgery Vol. 3(4); 2014                  The aim of this study was to describe clinical profile, complications and outcomes of post-NEC intestinal strictures in a surgical neonatal unit over a period of 10 years and to identify potential risk factors during the acute NEC episode that could predict development of post-NEC intestinal stricture. MATERIALS AND METHODS This was a retrospective study of infants who were treated for NEC in a neonatal unit of a children’s hospital from 1st January 2000 to 31st December 2010. All infants admitted to the neonatal unit during the study period with a diagnosis of NEC were eligible for inclusion. The study population was identified from the hospital’s electronic database by quizzing the database with search terms “Necrotising Enter-ocolitis”, “NEC” “Stricture” and “Intestinal Ste-nosis”. The infants with congenital anomalies and infants who died during acute NEC were not included in the study.  The electronic medical records and discharge summaries were reviewed. Demographic infor-mation, clinical indicators of severity of NEC such as haematological investigations, findings on abdominal x-ray, mode of management of the acute episode of NEC, length of bowel re-sected at surgery and histopathology of re-sected bowel segment were collected. All the abdominal X-rays were reported by a paediatric radiologist. The infants were classified into Stage I, Stage II or Stage III NEC using the modified Bell’s criteria.  For the infants who had post-NEC strictures, age at the diagnosis of stricture, time interval since diagnosis of acute NEC, weight at diagno-sis of stricture, signs at presentation, results of intestinal contrast study, number and site of strictures, complications attributable to stric-tures, mode of management of the stricture, time required to attain full enteral feeds and the length of hospital stay were recorded. All Infants with NEC were followed up in the hos-pital’s outpatient clinic until at least 3 months of corrected age.   Ethical approval was granted by the local Hu-man Research Ethics Committee. After the da-tabase was accessed and the medical records examined, de-identified study data were rec-orded electronically and password protected by the primary investigator. Statistical Analysis:  Data was analysed using SPSS software (IBM SPSS statistics for window, release 20.0.0) Chicago, IL, USA. Chi Square test, Fisher’s Exact test and Mann Whitney test were used as appropriate. A p-value of <0.05 was considered statistically significant. RESULTS We identified 72 infants with NEC during the study period. 11 infants died due to NEC and were excluded. 61 infants (28 male and 33 fe-male) with NEC were included in the study.  The baseline characteristics of infants with or without strictures were similar (Table 1). Modi-fied Bell’s stage I NEC occurred in 15/61 (24.5%) infants, Stage II in 22/61 (36%) and Stage III in 24/61 (39.5%) infants. Surgical in-tervention was required in 28/61 (46%) infants and 33/61 infants (54%) were managed conser-vatively. Intestinal strictures developed in 18/61 (29.5%) infants. The incidence of stric-ture was 35.5% (10/28) in the surgically man-aged subgroup and 24% (8/33) in the conser-vatively treated subgroup.  Table 1: Baseline characteristics Variable  Stricture (n=18) No stricture (n=43) P value  Mean gestational age in weeks  29.0 weeks 28.0 weeks 0.86 Male Gender  8 (44.4%) 20 (46.5%) 1.00 Mean birth weight  1199 grams 1065 grams 0.88 Median age at diagnosis of NEC 18.5 days 13 days 0.30 Use of Inotropes  6 (33.3%) 7 (16.3%) 0.18 Positive Blood Culture  5 (27.8%) 11(25.6%) 1.00 Patent Ductus Arteriosus  4 (22.2%) 14 (32.6%)  0.62 Surgical management of acute NEC 10 (55.6%)  18 (41.9%)  0.49  Intestinal Strictures Post-Necrotising Enterocolitis: Clinical Profile and Risk Factors   Journal of Neonatal Surgery Vol. 3(4); 2014                  Table 2: Haematological investigations   Variable  Stricture (n=18) No- stricture (n=43) P value  High C reactive protein 9 /10 (90%) 18/23 (78.5%) 0.64 High total white cell count  10 (58.8%) 9 (20.9%) 0.01 Thrombocytopenia  15 (83.3%) 31(72.1%) 0.52 Metabolic acidosis  13 (72.2%) 19(44.2%) 0.09  Lactic acidosis 13 (76.5%) 24 (55.8%) 0.23 Low serum bicarbonate 7 (38.9%) 12 (27.9%) 0.59  High base excess  8 (47.1%) 11 (25.6%) 0.19  The infants who developed intestinal strictures were more likely to have an elevated white cell count (> 25000/cmm) at the time of acute epi-sode of NEC (p = 0.01) (Table 2). Infants with Bell’s stage I disease and non-specific intestinal dilation on x-ray were less likely to develop a stricture (p = 0.05 and 0.02 respectively) (Table 3). Of the intestinal perforations during acute NEC (17/61 infants) caecal perforation posed a borderline risk for development of strictures (P=0.05). In infants that required surgical inter-vention for NEC, longer length of resected bowel was significantly associated with development of strictures (p=0.02) (table 3). In our series of 18 infants with intestinal strictures, the median time interval between NEC and diagnosis of the intestinal stricture was 34 days (range 27.5-62 days).  In 7/18 (39%) infants the strictures were diagnosed by the routine contrast study prior to reversal of stomas to re-establish gastro-intestinal conti-nuity. The remaining 11 infants had symptoms of intestinal obstruction and the diagnosis of intestinal strictures was established on a con-trast study. In 12/18 (67%) infants the strictures were lo-cated in the colon and in 6/18 (33%) the site was small bowel. Amongst the isolated colonic strictures, four were located in the transverse and descending colon each and one in the as-cending colon. Three infants had strictures in-volving more than one segment of colon. In six infants with stricture of the small bowel, five were located in the terminal ileum and one in the proximal ileum.  All small bowel strictures were isolated.  The complications noted in infants with intesti-nal strictures were intestinal perforation (2/18) bacterial sepsis (2/18), severe electrolyte im-balance in (4/18), hypoalbuminemia requiring albumin transfusion (8/18) and significant cholestasis in (9/18). Seven infants with intes-tinal stricture had growth failure with weight that dropped two major centile lines to well be-low 10th centile between the diagnosis of acute NEC and the diagnosis of stricture. Median time required to attain full enteral feeds after repair of stricture was 25 days (range 14-67.7 days) and the median duration of hospitalisa-tion for stricture and related issues was 33 days (range 21-81days). No deaths occurred in the infants with strictures in our cohort. DISCUSSION  Intestinal strictures following NEC in neonates were first reported by Rabinowitz et al in 1968.[9] There is paucity of studies looking at risk factors for post-NEC intestinal strictures [8]. With improved perinatal care in the last 20 years we sought to evaluate the pattern of post-NEC intestinal strictures. Our study had a sizeable number (18) of infants with intestinal stricture in comparison to the previous studies [5-11].  Our findings of the incidence of stricture, the median time to diagnosis of stricture since the acute episode of NEC, location of strictures and lack of significant association between devel-opment of post-NEC stricture and mode of management of acute NEC were similar of the previous reports [5,7,11-15].   The intestinal strictures result from collagen deposition, fibrosis and wound contraction over a variable period following an episode of acute inflammation. We examined various markers of inflammation and severity of illness at the time of acute NEC. We observed significant associa-tion between presence of high white cell count during acute NEC and length of bowel resected at NEC surgery and the occurrence of intestinal strictures.    Intestinal Strictures Post-Necrotising Enterocolitis: Clinical Profile and Risk Factors   Journal of Neonatal Surgery Vol. 3(4); 2014                   Table 3: Severity of NEC and abdominal x-ray findings  Variable  Stricture (n=18) No- stricture (n=43) P- value  Bell Stage I disease  1(5.6%) 14 (32.6%) 0.05 Bell Stage II disease  7 (38.9%) 15 (34.9%) 0.99 Bell Stage III disease 10 (55.6%)  14 (32.6%) 0.16 Non-specific dilatation of intestinal loops 1 (5.6%) 17 (39.5%)  0.02  Pneumatosis alone  7 (38.9%) 12 (27.9%) 0.59 Portal venous gas alone 0 (0%) 2 (4.7%) 0.86 Pneumatosis and Portal venous Gas  2 (11.1%) 1 (2.3%) 0.42 Pneumoperitoneum  6 (33.3%) 11 (25.6%) 0.76 Fixed dilated loops 2 (11.1%) 0 0.15 Ileal perforation  2 (33.3%) 5 (45.5%) 0.55 Caecal perforation  2 (33.3%) 1 (9.1%)  0.05  Ascending Colon perforation  0 2 (18.2%) 0.13 Sigmoid perforation  0 1 (9.1%)  0.54 Multiple perforations  2 (33.3%) 2 (18.2%) 0.34 Median Length of bowel resected at NEC surgery in  cm (quartile range) 19 (13-27) 5 (4-13.5) 0.02  These findings have not been described in the literature previously. They could be of prognos-tic significance and are biologically plausible. We hypothesize that presence of large number of white cells resulting in heightened immune mediator response locally may precede devel-opment of stricture and more length resection to be marker of more extensive disease. Con-trastingly, level of C- reactive protein (CRP) that has been reported as a part of a scoring system to predict development of stricture did not at-tain prognostic relevance in our study [16]. Thrombocytopenia and metabolic acidosis at the time of acute NEW were not predictors of later strictures.  Growth failure and life threatening complica-tions of strictures such as intestinal perforation and sepsis are well described in literature [3,5]. We found severe electrolyte abnormalities, hy-poalbuminemia, significant derangement of liver functions as associated morbidities in in-fants with intestinal stricture. Our observation of morbidity associated with intestinal stricture (in more than three fourths of infants) was higher than that reported by Janik et al (30%) [7]. This difference may be due to more varia-bles studied in our study population and com-paratively larger infants in the report by Janik et al. Mortality ranging from 8-25%, secondary to intestinal stricture related problems such as intestinal perforation, aspiration pneumonia and sepsis in the peri-operative period, has been reported in the literature [3’7]. We did not observe any mortality in infants with strictures.  Intestinal Strictures Post-Necrotising Enterocolitis: Clinical Profile and Risk Factors   Journal of Neonatal Surgery Vol. 3(4); 2014                  This difference could be due to improved neo-natal care in the last two decades.  This is a retrospective study from single neo-natal unit with a relatively small sample size and might not be powered to detect small dif-ferences between the study groups. Infants in-cluded in this study were referred from other neonatal units for surgical evaluation and could represent the severe end of NEC spec-trum making the observations not applicable to perinatal settings that medically manage in-fants with NEC. CONCLUSION Our study offers a recent insight into the im-pact of improved care on the clinical profile and outcomes of post-NEC strictures. The overall incidence of intestinal strictures has remained high and similar irrespective of the mode of management of NEC. Prediction of development of intestinal stricture following NEC is difficult. However, leucocytosis during acute NEC and the length of bowel resected at surgery could be potential predictors of post-NEC stricture. A substantial number of infants with strictures failed to thrive; the majority had morbidity and required prolonged hospitalisation.  Implications for current Practice All infants with confirmed NEC should be ob-served closely and investigated for stricture in the presence of any symptom of persistent gas-trointestinal disturbance irrespective of initial mode of management. Physical growth, liver functions and serum electrolyte levels of infants with post NEC strictures should be closely monitored and nutrition proactively managed. REFERENCES 1. Kliegman RM, Fanaroff AA. Necrotizing enterocolitis. N Engl J Med. 1984;310 :1093 -103.   2. Luig M, Lui K, NSW & ACT NICUS Group. Epidemiology of necrotising enterocolitis –part I: Changing regional trends.  J Paediatr Child Health. 2005; 41:169-73.  3. Hartman GE, Drugas GT, Shochat SJ. Post – necrotising enterocolitis strictures presenting with sepsis or perforation: risk of clinical observation. J Pediatr Surg. 1988; 23:562-6. 4. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. 2011; 364:255-64. 5. Bell MJ, Ternberg JL, Askin FB, McAlister W, Shackelford G. 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Born M, Holgersen LO, Shahrivar F, Stanley-Brown E, Hilfer C. Routine contrast enemas for diagnosis and managing strictures following non operative treatment of necrotising enterocolitis. J Pediatr Surg. 1985; 20:461-3. 12. Kosloske AM, Brustein J, Bartow SA. Intestinal obstruction due to colonic stricture following neonatal necrotising enterocolitis. Ann Surg. 1980; 192:202-7. 13. Reid WD, Shannon MP. Necrotizing enterocolitis: A medical approach to treatment. Can Med Assoc J. 1973; 108:573-6. 14. O’ Neil Jr JA, Holcomb Jr GW G. Surgical experience with neonatal necrotising enterocolitis (NNE). Ann Surg. 1979; 189:612-8.  15. Costin BS, Singleton EB. Bowel stenosis as a late complication of acute necrotising enterocolitis. Radiology. 1978; 128:435-8.  16. Evrard J, Khamis J, Rausin L, Legat C, Bertrand JM, Battisti O, et al. A scoring system in predicting the risk of intestinal stricture in necrotising enterocolitis. Eur J Pediatr. 1991;150:757-60. Address for correspondence A Trivedi. FRACP,  Locked Bag 4001, The Children’s Hospital at Westmead, Westmead NSW 2145, Australia E mail: Amit.Trivedi@health.nsw.gov.au Submitted on: 08-10-2014 Accepted on:   11-10-2014 Conflict of interest: None  Source of Support: Nil 

Intestinal Structures Post-Necrotising Enterocolitis: Clinical Profile and Risk Factors

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