Surgical therapy for necrotizing enterocolitis: bringing evidence to the bedside

Seminars in Pediatric Surgery (2005) 14, 181-190

Surgical therapy for necrotizing enterocolitis: bringing evidence to the bedside Marion C. W. Henry, MD, and R. Lawrence Moss, MD From the Section of Pediatric Surgery, Yale University School of Medicine, New Haven, Connecticut. INDEX WORDS Necrotizing enterocolitis; Laparotomy; Peritoneal drainage; NEC totalis; Evidence-based practice

Necrotizing enterocolitis is the most common surgical emergency in the neonatal intensive care unit. Despite decades of research that have led to a growing knowledge base about this disease, NEC continues to challenge the pediatric surgeon. In this review, we will examine the development of surgical therapy for NEC in the context of the supportive evidence, or lack thereof, for treatment approaches. We will discuss issues of indications for surgical intervention, primary peritoneal drainage versus laparotomy, enterostomy versus primary anastamosis and issues surrounding NEC totalis. © 2005 Elsevier Inc. All rights reserved.

Necrotizing enterocolitis (NEC) is the most common surgical emergency in the neonatal intensive care unit (NICU).1,2 Three decades after its initial description, despite a growing knowledge base supported by hundreds of laboratory and clinical research studies, NEC continues to challenge the pediatric surgeon. The incidence of NEC is increasing with improved survival rates for small premature infants,3 and the mortality rate remains between 20% and 50%.4,5 Investigators continue to examine the pathogenesis for NEC, while the clinical management continues to generate debate. The evolution of surgical treatment for NEC has occurred in the same manner as most treatment paradigms in children’s surgery have evolved. Surgeons were faced with a critical life-threatening illness for which there was no effective medical therapy. The disease was rare enough that it was only seen 10 to 20 times per year in a large children’s hospital and seen only a few times per year by an individual surgeon. Innovative surgeons, striving to do something for

Address reprint requests and correspondence: R. Lawrence Moss, MD, Section of Pediatric Surgery, 333 Cedar Street, FMB 132, P.O. Box 208062, New Haven, CT 06520-8062. E-mail address: [email protected].

1055-8586/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2005.05.007

these desperately ill infants, developed a variety of approaches which were sometimes successful. Individual surgeons and groups then tended to follow the basic tenet of surgery best stated by Dr. John Raffensperger: “we did what surgeons always do, we based our management on the experience of our last case.” (Raffensperger JG. Personal communication.) This resulted in each surgeon or group of surgeons learning how to treat NEC by trial and error; striving to do their best in interpreting their personal results in a small number of patients. Despite the dedication and effort on the part of surgeons, a consistent effective approach to surgical care could not evolve with surgical centers functioning as islands rather than as a community of investigators working together to answer questions. Recent advances are slowly allowing this paradigm to change. Investigators are beginning to work across institutional and geographic boundaries to address common issues. In this review, we will examine the development of surgical therapy for NEC in the context of the supportive evidence, or lack of it, for our treatment approaches. The diagnosis of NEC relies on the signs and symptoms of sepsis and intestinal ischemia in the neonate. These include feeding intolerance, gastric residuals, apnea and

182 bradycardia, abdominal distention, abdominal tenderness, and gastrointestinal bleeding. As isolated findings, these clinical signs have little specificity. However, if these signs manifest in a premature infant at risk and occur in the absence of an alternative source of sepsis, NEC should be seriously considered. Physical examination findings of a fixed abdominal mass and erythema of the abdominal wall are the most predictive of NEC when present, with nearly 100% specificity.6 However, these signs are typically present only in very advanced disease when the optimal time for surgical intervention may have passed. To aid in clinical diagnosis, Bell and colleagues in 1978 developed a clinical staging system that combines physical findings, laboratory data, and radiographic evidence of NEC. This scale remains in wide use today for defining the presence and stratifying the severity of NEC.7 Once the diagnosis of NEC has been made, initial management consists of aggressive fluid resuscitation and hemodynamic support, bowel rest, broad-spectrum antibiotic coverage, and close monitoring for the earliest signs of perforation. While many infants with NEC can be successfully managed medically, one-third to one-half8-10 will develop intestinal necrosis or perforation. These infants will require operative intervention in the acute setting. An operation will most commonly be required in very low birth weight (VLBW) infants but may be necessary at all gestational age babies, including term infants.11,12

Seminars in Pediatric Surgery, Vol 14, No 3, August 2005 ficity, positive predictive value, negative predictive value, and prevalence for 12 proposed criteria.6 Using data from 147 infants with documented NEC, 94 of whom had gangrene, Kosloske was able to separate the 12 criteria into best indicators, good indicators, fair indicators, and poor indicators based on their specificity, positive predictive value, and prevalence.6 The study was limited by its retrospective design, its relatively small sample size, and the fact that all patients were from a single institution treated with a uniform management style. Nevertheless, it represents one of the few attempts to evaluate therapy using a rigorous evidence-based approach. The best indicators were defined as having specificity and positive predictive value approaching 100% and a prevalence of more than 10%. Three indications achieved these parameters: pneumoperitoneum, positive paracentesis, and portal venous gas on radiograph.6 A positive paracentesis has also been reviewed as an indicator by Ricketts and colleagues who reported 94% sensitivity and 100% specificity among 36 infants with intestinal gangrene.19 Portal venous gas (PVG) on abdominal radiograph has been proposed as an indicator for operation, although this sign is not universally accepted as a surgical indication (Figure 1).14 Several studies have suggested that PVG is associated with a poor prognosis, and, therefore, should be considered an indication for operative intervention. In a

Indications for surgical intervention In 1975, O’Neill and coworkers proposed that the absolute indications for surgical intervention in the setting of NEC included intestinal perforation and relative indications included physiologic deterioration despite medical treatment.13 Since then, the only universally accepted absolute indication for operation in NEC is still evidence of intestinal perforation.6,7,14-17 Pneumoperitoneum seen on an abdominal radiograph is the most definitive evidence for perforation and the most common indication for operative treatment. Kosloske introduced the technique of paracentesis with examination of the peritoneal fluid for bile or bacteria as an adjunct in cases where perforation was suspected despite the absence of free air on radiographs.18 In theory, the optimal timing for exploration would be after severe ischemia had developed but just before perforation had occurred. This would avoid operation in babies destined to recover with medical therapy but result in necessary intervention before complications of advanced intraperitoneal sepsis ensue. Identifying this “window of opportunity” has proven to be extremely challenging. Multiple retrospective analyses have been unable to offer significant insight into our understanding of why some babies with NEC recover uneventfully, while others develop fulminant disease. In an attempt to at least identify better indicators of intestinal gangrene, Kosloske tested the sensitivity, speci-

Figure 1 Radiograph demonstrating portal venous air. (Color version of figure is available online.)

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Surgical Therapy for NEC

review of 101 infants requiring surgery for NEC, Cikrit and colleagues found that PVG was the only radiographic finding that was associated with a poor prognosis, having a 71% mortality rate.14 In a subsequent analysis of another 53 cases, they also found that PVG was associated with a significant increase in mortality, which led them to conclude that PVG should be considered an indication for early surgical intervention.20 Molik and colleagues reviewed their experience with infants with NEC who had portal venous gas on radiographs to reevaluate the prognostic importance of this indicator. Thirty-one of the 40 infants with PVG underwent laparotomy, and 14 survived for a 46% survival rate. Nine patients were treated expectantly and 3 survived for 33% survival. Additionally, 10 of the 40 patients (25%) had advanced, extensive disease noted at laparotomy. Based on their findings, these authors conclude that PVG is a poor prognostic indicator and suggest that patients with PVG on x-ray should undergo surgical intervention.21 Rowe and colleagues have also reported two series in which 93% of infants with PVG had full-thickness bowel necrosis, and 71% of extremely low birth weight (ELBW) infants with PVG had pan-involvement. Their conclusions were that PVG should be a definite indication for urgent operation, particularly in the ELBW infant.11 In Kosloske’s study, portal venous gas was 100% specific for and 100% predictive of intestinal gangrene, thus achieving status as a good indicator for surgery in that study.6 Numerous other studies have reported that patients with portal venous gas may recover without operation.10,16 Three indicators reached specificities and positive predictive values close to 100%, although their prevalence was less than 10%. These three indicators were termed “good indications” for surgery by Kosloske and include fixed loop on radiograph, erythema of the abdominal wall, and palpable abdominal mass. Their usefulness is limited by their limited prevalence.6 In addition all are subjective variables which may not prove nearly as useful prospectively as they seemed to be in this retrospective study. Indicators which were not considered indications for surgery, since they had specificities less than 90% and positive predictive values less than 80%, included clinical deterioration, platelet count less than 100,000/mm3, severe gastrointestinal hemorrhage, abdominal tenderness, and a gasless abdomen. In summary, after 30 years of study by retrospective and case series analyses, we have learned little more than we knew at the outset. Perforation is an absolute indication for operation. Abdominal radiographs are specific but not very sensitive in the diagnosis of perforation. Relative indications for operation include severe clinical deterioration, abdominal wall erythema, and perhaps portal venous gas and extensive pneumatosis. We have essentially no ability to predict which patients with NEC will respond to medical therapy and which will not. Further progress in this area is sorely needed.

183

Primary peritoneal drainage versus laparotomy Once the decision to operate has been made, the preferred method of surgical management is controversial. The two commonly used methods of treatment for NEC with perforation are laparotomy (LAP) or primary peritoneal drainage (PPD). Both of these methods have been used for more than 20 years, and both are considered “standard of care” depending on what institution or which surgeon is caring for the infant. The controversy between these two treatments illustrates an important lesson in the use of evidence in pediatric surgery to answer a clinical question. The data on PPD has evolved in the following manner (see Table 1 for summary). In 1977 Ein and colleagues first reported the use of PPD for perforation in VLBW infants.22 The patients in this report were deemed “too unstable” for laparotomy. PPD was not used as an alternative to laparotomy in these patients but rather as an innovative desperate attempt to do something for babies who were felt to be likely to die without some attempt at intervention. In this anecdotal report, three of the five patients surprisingly survived, and the two that died were found to have intact gastrointestinal (GI) tracts at autopsy. The success of PPD in this initial report was notable since conventional wisdom would suggest that intestinal necrosis and perforation must be treated with resection and enterostomy creation. However, the authors specified that they meant for PPD to be used only as a temporizing measure to stabilize the infant until formal laparotomy could be performed. Janik and Ein and colleagues updated their experience in 1980, at which time they described 15 patients who were treated with PPD.23 Overall survival was 46%. Despite the fact that PPD was intended as a “temporizing measure,” 40% of this group improved to the point that a laparotomy was never performed.23 Following these initial, small, anecdotal reports, additional investigators started reporting on their experiences with primary peritoneal drainage. Cheu and colleagues reported on 92 patients treated by either PPD or LAP.24 Those patients treated by PPD were smaller and had more comorbid conditions and lower pH, but their survival was identical. Furthermore, 2/3 of the PPD patients did not get a planned subsequent laparotomy.24 Other observational series followed, claiming PPD as effective therapy for perforated NEC. Takamatsu and colleagues reported on the survival of 4 infants weighing less than 1000 g who were treated with PPD and had resolution of their intraabdominal sepsis as well as return of gastrointestinal continuity and function.25 However, Horwitz and colleagues found, in a retrospective review of patients treated over a 10-year time period, that the 48 patients who underwent PPD had a 56% survival compared with 75% survival in the 204 patients who underwent laparotomy.26 Additionally, they found a significant increase in the complications among VLBW infants treated with PPD versus LAP (82% versus 38%). The au-

184 Table 1

Seminars in Pediatric Surgery, Vol 14, No 3, August 2005 Comparison of type of operation, gestational age, birth weight, and survival with perforated NEC published data PPD

LAP

Study

Year

No.

GA

BW

Subs. Lap n (%)

Survival n (%)

No.

GA

BW

Survival n (%)

Ein22 Janik23 Cheu24 Ein61 Takamatsu25 Morgan28 Horwitz26 Azarow27 Snyder12 Lessin29 Ahmed62 Rovin63 Downard64 Dimmitt30 Ehrlich65 Noble66 Camberos31 Demestre32 Gollin67 Sharma68

1977 1980 1988 1990 1992 1994 1995 1997 1997 1998 1998 1999 2000 2000 2001 2001 2002 2002 2003 2004

5 15 51 37 4 29 48 44 12 9 23 18 24 17 22 8 — 44 29 32

— — 29 — 27 27 — 28 29 25 27 28 26 25 25 25 — — 25 26

— — 1158 — 808 994 — 1100 1134 615 910 1118 794 677 697 728 — — 721 827

1 — — — — 6 19 — — — 19 12 — — 4 6 — 16 7 8

3 (60) (46) 18 (35) 21 (56) 4 (100) 23 (79) 27 (56) 27 (61) 3 (25) 6 (67) 10 (43) 16 (89) 19 (79) 7 (41) 14 (63) 4 (50) — 33 19 (66) 17 (53)

— — 41 40 — 20 204 42 91 — 22 10 9 9 48 32 35 36 — 46

— — 32 — — 32 — 31 31 — 35 29 30 26 26 27 26 31 — 27

— — 1875 — — 1854 — 1700 1628 — 2271 1274 1510 807 756 946 741 1461 — 937

— — 31 — — 18 154 24 52 — 19 9 7 5 36 26 26 22 — 26

thors do state that infants were selected for treatment in a nonrandomized fashion, but the specific criteria for selection were not elucidated any further than “the drainage patients were considered too unstable to undergo primary laparotomy.”26 In follow-up to Cheu’s comparative study, Azarow and colleagues treated two “comparable” but not randomized groups with either laparotomy or PPD. In contrast to Horwitz, they found that, for the group of infants ⬍1000 g, survival was 69% with PPD versus 22% with laparotomy.27 As the “evidence” for PPD grew, some authors began to advocate PPD as primary treatment for infants with perforated NEC. Morgan and coworkers reported treatment of 29 patients ⬍1500 g with PPD and showed good survival (79%) with no incidences of short bowel syndrome. Additionally, in 17 patients (74%) PPD alone provided definitive surgical treatment.28 Lessin treated 9 patients under 750 g all with PPD. Their survival rates were improved compared with historical controls. The authors’ recommendations noted that clinical improvement often occurred slowly, so not to rush to laparotomy.29 Dimmitt and coworkers reported that patients treated with PPD who clinically deteriorated did less well with “salvage laparotomy” than a comparable but nonrandomized group treated simply with continued drainage.30 In 2002 the clinical question regarding the relative merits of PPD versus LAP still plagued pediatric surgeons, and the absence of sound evidence was apparent in 2 conflicting reports that were published in 2 subsequent months in the same journal. In one, Camberos and colleagues treated 35 patients all with laparotomy with good survival rates and mortality that was gestational age-dependent. Therefore,

(20)

(21) (40)

(83) (67) (18) (75) (36) (24) (25)

(76) (90) (75) (57) (57) (86) (90) (78) (56) (75) (81) (74) (61) (57)

they concluded that laparotomy should be primary therapy.31 In the next issue of the Journal of Pediatric Surgery, Demestre and colleagues published a report on 47 patients treated all by PPD. Their survival was also good, and mortality was also gestational age-dependent. Their conclusions and recommendations were that PPD should be primary therapy.32 In an attempt to clarify conflicting reports regarding surgical treatment, one can turn to the technique of metaanalysis. Meta-analysis is a field of statistics developed to attempt to combine the results of prospective randomized trials and create a “consensus” estimate of the effect of a particular treatment. Meta-analysis was not developed to combine nonrandomized uncontrolled data but has been used to do this where nonrandomized data are the only data available. This is just such a situation. A review of the published experience of the use of PPD for perforated NEC revealed that patients undergoing PPD were significantly smaller and more premature than patients treated with laparotomy.33 These authors collected a large series of unpublished cases and found that selection bias occurred here as well. The authors concluded that, because of this marked bias and the lack of available information as to why patients were assigned to PPD versus laparotomy, the effectiveness of the two techniques could not possibly be determined using meta-analysis techniques. A more rigorous study methodology than simple case review was clearly necessary. As PPD appeared to be utilized in those patients with greater mortality, and then this “sicker” group did better, the question arose of whether PPD may be superior to laparotomy for the treatment of perforated NEC. This question is currently under assessment in randomized controlled trials

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in both the United States (Moss: NECSTEPS trial) and the United Kingdom (Pierro: NET trial). The NECSTEPS trial is a randomized clinical trial on surgery for NEC in human infants. It is a 14-site multicenter clinical trial. The trial is funded by the NICHD and run in collaboration with the NICHD neonatal network. The specific aims of the trial are threefold: (1) to determine whether PPD improves survival in infants ⬍1500 g; (2) to determine whether PPD decreases morbidity (GI, neurodevelopmental); and (3) to determine whether PPD decreases length of stay or hospital cost. The inclusion criteria consist of infants with a birth weight less than 1500 g and a gestational age ⬍34 weeks. There must be evidence of bowel perforation and no evidence of GI anomaly or prior abdominal operation. Exclusion criteria are failure to meet the inclusion criteria, bilateral grade IV intraventricular hemorrhage, or family refusal of randomization. A sample size of 130 patients was determined using 80% power and the hypothesis of lowering mortality from 50% to 25% in one group. After accrual of 69 patients, the data safety monitoring board performed an interim review and found that overall mortality was expected, mortality difference did not mandate early termination of the trial, and there was a high likelihood of clinically relevant findings. Enrollment in the trial should be concluded in 2005. The NET trial is a randomized clinical trial also comparing PPD with laparotomy for NEC or isolated perforation. This trial is including extremely low birth weight infants defined as those weighing ⱕ1000 g. Criteria for eligibility include evidence of free air on abdominal x-ray. Exclusion criteria include bilateral grade IV intraventricular hemorrhage, previous NEC, previous laparotomy or peritoneal drain, or presence in a NICU without pediatric surgical support. The main outcomes of interest in this study are survival at both 1 and 6 months. Secondary outcomes being studied include hospital stay, intestinal absorptive function, intestinal complications, respiratory function, intraventricular hemorrhage, time to death, and cause of death. The study is slated to have 208 patients and is scheduled to continue enrolling patients until December of 2006.34

Enterostomy versus primary anastomosis The objectives of laparotomy as treatment for NEC are to remove gangrenous bowel and to preserve as much bowel length as possible. There are several surgical options available that meet these objectives, including resection with enterostomy, resection with primary anastomosis, proximal diversion, “clip and drop” technique, and “patch, drain, and wait.” Laparotomy with surgical resection and enterostomy formation has traditionally been considered the safest approach to managing perforated NEC in the neonate. Resection of gangrenous bowel reduces bacterial translocation, and formation of enterostomies allows for resolution of peritonitis

185 and further disease before reestablishing continuity of the intestine. Furthermore, given the presence of peritonitis, inflammation, and potentially compromised bowel, conditions are unfavorable for healing an anastomosis.35 In 1979 Kosloske noted that primary anastomoses led to high rates of breakdown, sepsis, and stricture formation.36 Subsequently, several investigators have advocated resection with primary anastomosis, citing the high incidence of complications with enterostomies and the difficulties of achieving adequate enteral feeding in the presence of enterostomies.3,37-41 Although the initial reports advocated this technique for patients with only focal disease, it has also been suggested for patients with severe NEC and multifocal disease.3 Several small single-institution retrospective case series have been reported advocating intestinal resection with primary anastomosis. In 1979 Kiesewetter and colleagues described the management of 9 infants with primary anastomosis, 8 of whom survived (89%).37 This series, however, appears to be a very selective group of infants treated in this manner, as there were 55 other infants treated surgically for NEC during the same time period who had either simple explorations or resections with enterostomy formation. The authors do not clarify in their report how the 9 infants treated by primary anastomosis differed from the other surgical patients; however, by their descriptions, the infants treated with primary anastomosis appear to have very focal disease. Harberg and colleagues also report on a personal selected series of 27 neonates they treated with resection and primary anastomosis for complications of acute NEC.38 In this group of patients, they achieved 89% survival and had no incidences of postoperative strictures. These patients had a mean gestational age of 32 weeks and a mean birth weight of 1629 g. In this small series of patients, primary anastomosis was performed when there was both single and multiple areas of disease and regardless of the amount of peritoneal contamination. It is not clear, however, from the report how many of these patients had only a single perforation and how many had more extensive disease. Griffiths and colleagues report on a retrospective series of 50 infants treated surgically for NEC, of whom 29 had a primary anastomosis.39 They describe in their discussion that they preferentially use primary anastomosis unless an infant has total NEC or the ends of the bowel are not thought to be viable. Their patient groups who had stoma formation and who underwent primary anastomosis did not differ by gestational age, birth weight, age at onset of NEC, preoperative risk factors, or long-term outcomes. Twentytwo (76%) of their patients who underwent primary anastomosis survived, and only 3 (10%) patients developed anastomotic complications. Given these results, these authors advocate primary anastomosis “provided the ends [are] viable.”39 Ade-Ajayi and colleagues describe their experience treating 26 patients who underwent surgical intervention for NEC.40 Eight of these children had resection with enteros-

186 tomies, while 18 were treated with primary anastomosis. Sixteen of the 18 infants undergoing primary anastomosis survived (89%), with 4 (22%) developing recurrent NEC and 3 (17%) developing postoperative strictures. Only 3 of the 8 children treated with enterostomy formation survived. However, these 8 children differed considerably from the 18 treated by primary anastomosis. The mean gestational age of the enterostomy group was 28 weeks as compared with 31 weeks for the primary anastomosis group, and the mean birth weight was 879 g versus 1494 g. Furthermore, the authors describe that 5 of these 8 infants underwent high jejunostomy as a primary procedure for extensive distal disease, a subgroup of patients with known higher mortality rates.40 Fasoli and colleagues reported on 83 patients with Bell stage II or III NEC treated surgically over 11 years: 25 with isolated lesions, 46 with multi-focal disease, and 12 with pan-intestinal necrosis.8 Of these patients, 44 neonates underwent resection with primary anastomosis. This report does not indicate how the patients were allocated to various treatments. Of those patients with isolated NEC, there were 16 of 18 (89%) survivors for those who had primary anastomosis as compared with an 86% survival among the 7 patients who underwent enterostomy. Twenty-two of the 26 (85%) patients treated by primary anastomosis for multifocal disease survived compared with 10 of 20 (50%) treated with enterostomy formation. Of the patients treated with primary anastomosis, only 4 had small bowel anastomoses, while the other 22 had ileocolic or colocolic anastomoses. Of the patients who had enterostomies, 7 had no intestinal resection, with 2 high diverting jejunostomies, 3 ileostomies, and 2 colostomies. These details suggest that there may have been some significant differences between the patients selected for primary anastomosis and those selected for enterostomy. Based on their results, these authors conclude that resection and primary anastomosis is a valid option in the treatment of neonates with both isolated and multi-focal NEC.8 In each of these case series, selection bias must be considered when comparing the outcomes in treatment groups. All of these reports appear to have very significant differences among their treatment groups and thus valid comparisons between the surgical techniques cannot be made. The anecdotal data did suggest the possibility that primary anastomosis may be an option in highly selected patients. Pokorny and colleagues also report on a series of neonates with NEC who were treated either by resection with primary anastomosis or by enterostomy formation.9 Although these two groups were similar in regards to birth weight and site of bowel involvement, the authors take care to note that the patients who underwent enterostomy formation were chosen for this procedure because they had more extensive disease and were sicker in general than those who underwent primary anastomosis. Therefore, their results must be assessed with these selection biases in consider-

Seminars in Pediatric Surgery, Vol 14, No 3, August 2005 ation. These investigators report 25 of 28 (89%) survival in patients undergoing a primary anastomosis for acute NEC compared with 15 of 24 (63%) survival in those who underwent resection with a diverting ileostomy. They conclude that resection and primary anastomosis is safe in carefully selected patients with localized disease and who are in overall good condition.9 Cooper and colleagues reviewed their experience with operative NEC and enterostomy versus primary resection.42 They found 27 patients treated by primary anastomosis out of 143 who received operative treatment for NEC. These 27 patients, they commented, had been “carefully selected by the senior operating surgeon . . . based on the limited and apparently discrete nature of the disease found at laparotomy.”42 Despite this careful selection of patients, these investigators found only 13 of these 27 (48%) patients survived compared with 83 of 116 (72%) of patients treated with a proximal enterostomy. When looking at only the later time period (1977-1986) when resection with enterostomy had become established as standard therapy, there was a 64% survival in the 14 patients treated with primary anastomosis versus 79% survival in the 86 patients treated with an enterostomy. Half of the nonsurvivors from the primary anastomosis group underwent postmortem examination, and leaks were present in 2 of the 7 with a clearly gangrenous anastomosis in a third. Furthermore, microscopic disease was found to be present at the surgical margins in all of these cases, despite the fact that the bowel had appeared viable at the time of anastomosis, suggesting that even senior surgeons may not be able to adequately assess bowel viability in the case of NEC. Based on their results, these authors conclude that resection with primary anastomosis is not a safe alternative for treating neonates with NEC.42 Given the lack of unbiased evidence for primary anastomosis, it is difficult to evaluate the effectiveness of this treatment in comparison to resection with enterostomy formation. Further studies in which patients are randomly distributed between the two treatments could further clarify the potential advantages of one or the other of these approaches.

NEC totalis When massive intestinal necrosis is encountered at laparotomy (NEC totalis), the surgeon faces both clinical and ethical challenges. Simple closure of the abdomen followed by supportive care is associated with nearly 100% mortality.43 Extensive resection, however, leads to severe shortgut syndrome. Several techniques have been suggested with the aim of allowing time for supportive critical care and antibiotic treatment while the GI tract might have some possibility of healing. In 1980 Martin and Neblett first suggested the option of high diverting jejunostomy without resection of bowel. In 3 infants treated in this manner, this technique allowed for recovery from acute NEC so that it

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was possible to salvage functional distal bowel that would have otherwise been resected.44 Sugarman and Kiely report their experience treating another 10 children in this manner. Eight of 10 (80%) survived long enough for a second-look procedure after 6 to 8 weeks, with 5 (50%) achieving longterm survival.45 Vaughan and colleagues suggested an alternative technique for extensive bowel necrosis termed the “Clip and Drop-Back” technique.46 They report on five infants treated for extensive bowel necrosis, three from NEC and two from midgut volvulus, in whom rather than attempting a high enterostomy or performing multiple stomas, areas of obvious necrosis were resected and the bowel ends were clipped and dropped back in the abdomen. A second-look procedure was then performed 48 to 72 hours later, at which time intestinal continuity was established with anastomoses or the bowel was partially resected, clipped, and dropped back for an anastomosis at a third-look procedure. Using this procedure, all five infants survived without anastomotic complications.46 This method helps in preserving bowel length and avoids stoma formation. Another novel technique for use in extensive NEC has been proposed by Moore and is called “Patch, Drain and Wait.”47 The basic principles of this technique involve no bowel resection and no enterostomies. Instead, using either laparotomy or laparoscopy, the bowel is inspected and the extent of necrosis is evaluated. Intestinal decompression is then accomplished both through a gastrostomy and through any perforations. The peritoneal cavity is then irrigated clear and patching of perforations is performed. The most important part of the procedure, as described by the author, is the placement of small Penrose drains from the undersurface of both diaphragms down both sides of the peritoneal cavity to exit sites at stab wounds in the lower quadrants of the abdomen. These drains capture any fecal fistulas and create de-facto enterostomies. Waiting is a key part of this procedure and further laparotomy should not be performed before 14 days. Additionally, the drains are not removed until fecal drainage stops, which generally happens before 2 months. In treating 23 patients in this manner, there were no deaths in the first 60 days postoperatively and 16 of 23 patients (70%) had spontaneous closure of their fecal fistulas, never requiring a second operation.47 There are no other reports of other investigators or centers using this technique. Lessin and colleagues also have reported on their experience in using a new technique in treating two patients with extensive NEC that also avoids multiple stomas, maximizes bowel length, and eliminates nonviable bowel.48 In one patient, they performed a diverting jejunostomy and mucous fistula. An 8 french feeding tube was then passed through the multiple segments of bowel left after necrotic sections were resected and the ends were brought out through puncture sites in the abdominal wall. The second patient had a repogle suction catheter placed into the proximal jejunum through the abdominal wall during laparotomy. The intervening segments of small bowel that remained after resec-

187 tion were placed over the tube with single sutures orienting the mesenteries. The tube was then brought out through the appendix and out the abdominal wall. Contrast studies in both patients showed that the bowel auto-anastomosed over these tubes and the tubes were able to subsequently be removed.48 All four of these techniques suggest promising results in the care of the most critical NEC patients. However, as all of these reports are anecdotal and most patients with extensive NEC die, further investigation into these techniques is warranted. Given that these patients usually face extremely high morbidity and mortality (45-90%),11,49,50 the management decision can be particularly difficult for the pediatric surgeon and can involve difficult ethical choices. These choices must be made within an ethical framework which considers the ethical principles guiding both the pediatric surgeon and the parents. Glover and Caniano describe the dual principles of balancing possible benefits and harms as well as respecting the values of the patient and the family.51 Thus, in making decisions about how to proceed in the face of extensive intestinal necrosis, the surgeon must consider what can be done, how likely it is to help the infant, what harm is associated, and what will the infant have to go through to receive any benefit. Additionally, they must consider the wishes of the family and how these wishes impact the actions of the surgeons. However, these wishes must be balanced with keeping the infant from harm. The case discussion that Glover and Caniano present with the ethical framework within which decision making takes place illustrates that, at times, surgical decision making goes beyond the evidence of what can be done and must involve the merging of these data with ethical principles.51

Evidence-based practice The practice of evidence-based surgery involves using the best available evidence to answer a clinical question. When considering the evidence, there is a generally accepted hierarchy of research design, with the randomized clinical trial the “gold standard” and the pinnacle of the hierarchy. Figure 2 illustrates the hierarchy of research design. In pediatric surgery, however, the randomized clinical trial is rare. In fact, over 99% of the evidence found in the pediatric surgical literature is retrospective, observational data.52,53 This is for many reasons. Randomized trials at currently anathema to the manner in which surgeons are taught to solve clinical problems. Trials are expensive and time consuming. Furthermore, many clinical questions are not appropriate for a trial and better addressed by other methods of study. It is clear, however, that physicians caring for children with NEC must advance the field of clinical research in this disease beyond its current state. We must do clinical trials where appropriate, and use multi-center prospective data collection for our observational studies whenever possible.

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Seminars in Pediatric Surgery, Vol 14, No 3, August 2005

Figure 2

The hierarchy of trial design.

Even when we do retrospective case-series analysis, we must at the very least report these accurately and in a manner that allows the reader to truly assess the data. In an evaluation of 300 retrospective case-series studies from the pediatric surgery literature, only 39% of studies reported more than half of 16 essential details, outlined in Table 2.54 Without this information, it is difficult, if not impossible, for the reader to judge the validity of the results from an observational study. In 1996 the CONSORT (Consolidated Standards of Reporting Trials) statement was implemented which has led to an improvement in clinical trials reporting.55 The Journal of Pediatric Surgery became the second English-language surgical journal to adopt these reporting guidelines in December 2001.56 However, analogous standardized reporting guidelines are also necessary for observational data reporting. Prospective authors should be given a checklist of essential reporting elements. These guidelines could streamline peer review, remove subjectivity from the assessment of methodologic rigor, and improve the quality of reports in the literature.57 Necessary improvements in the state of evidence regarding the surgical care of NEC are reflective of improvements that need to occur in all areas of pediatric surgical care.

tion. This study focused on the differences between isolated perforation and more advanced NEC. Results will be published contemporaneously with this paper.58 A multi-center database for neonatal surgical anomalies has received funding through the Glaser Pediatric Research Network and has started accumulating prospective data on children with NEC.59 The primary aim of this effort is to determine the risk factors for babies with NEC to develop progression to severe NEC. Donovan and coworkers have begun an effort to develop a mathematical model defining risk factors for the development of NEC. These investigators hope to identify “at risk” groups who can become the focus for trials of novel approaches to prevention of NEC.60 The clinical trials evaluating peritoneal drainage versus laparotomy were previously mentioned and will soon be providing valuable results. NEC remains a challenging disease for pediatric surgeons. The critical questions regarding surgical care remain unanswered after over 30 years of research. These include: what is the optimal time for operative intervention; the optimal strategy for intervention; and the specific techTable 2 Number 1 2 3 4 5

6 7 8

9 10 11

Current and future directions

12

Numerous research efforts at various stages of development are already beginning to change the paradigm of surgical research on NEC. Investigators are no longer willing to accept anecdotal and uncontrolled case-series reports and are initiating studies that will provide a higher level of clinical evidence. Blakely and coworkers have led 15 centers of the NICHD Neonatal Network in a prospective observational study of patients with NEC requiring opera-

13 14 15 16

Essential reporting criteria for all clinical studies Criteria Description of participating surgeons/institutions Can the number of participating centers be determined? Can the practice type of participating centers be determined? Can the number of surgeons who actually operated in the study be determined? Can the reader determine the authors’ prior experience with the reported procedure? Is the timeline when all cases were performed clearly documented? Description and definition of cases Was the patient population which the cases were selected from described? Are the diagnostic criteria used to identify cases clearly documented? Are selection and/or exclusion criteria for cases clearly documented? Description of the intervention Is the surgical technique adequately described? Do the authors mention any attempt to standardize operative technique? Do the authors mention any attempt to standardize perioperative care? Analysis of outcome data Is the mean and range of relevant demographic variables reported? Are outcome variables presented with appropriate measures of variability? Are diagnostic methods for assessing outcome(s) of interest clearly described? Do the authors address whether there is any missing data? Is the number and nature of complications addressed?

Henry and Moss

Surgical Therapy for NEC

niques that are appropriate during that intervention? To answer these questions, traditional research techniques such as single-institution retrospective case series must be replaced by properly designed prospective multi-institutional studies. With a cooperative and scientifically rigorous approach, pediatric surgeons and neonatologists can look forward to improved outcomes for babies afflicted with NEC.

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