ARTICLE IN PRESS
PATPHY-799; No. of Pages 7
Pathophysiology xxx (2013) xxx–xxx
Necrotizing enterocolitis is one disease with many origins and potential means of prevention Phillip V. Gordon a,b , Jonathan R. Swanson c,∗ a
c
Pediatrix-Obstetrix Center for Research and Education, Sunrise, FL, United States b Sacred Heart Children’s Hospital, Pensacola, FL, United States Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, United States
Abstract Background: The field of necrotizing enterocolitis (NEC) research has been in existence for over 60 years. During the first five decades little progress in NEC prevention and no definitive progress in treatment was achieved. One of the major determinants of this ineffectiveness may have been a global propensity to lump NEC into a single disease entity rather than a spectrum of diseases with a common outcome. The driver of this philosophy was most likely statistical, in that researchers desired large cohorts to optimize statistical power. Additionally, in the past quarter century, our preterm NEC cohorts were (and in some cases still are) contaminated with spontaneous intestinal perforations (SIP). This completely different acquired neonatal intestinal disease (ANID) markedly alters clinical characteristics and outcomes in NEC cohorts and subsets if not addressed. Unfortunately, cohort size has been proven to be less important than data quality when it comes to NEC over this last decade of research. Emerging progress in NEC prevention has been greatly enhanced as a result of dividing well-defined NEC into subsets of disease origin and investigating these entities individually. Review objectives: The purpose of this review is to offer the bedside clinician a concise, up-to-date review of recent advances in NEC reductionism. The reader should understand the history and basic theory behind NEC subsets, their application to NEC prevention, and comprehend that prevention of NEC requires a comprehensive quality improvement strategy that is likely best realized with a zero tolerance approach. Conclusions: We are entering a new era of NEC prevention. NICUs that embrace and achieve effective NEC prevention strategies will rapidly outpace their contemporaries. Because NEC is still the major driver of morbidity and mortality in most NICUs today, those who reject or fail in this pursuit will likely face increasingly severe consequences due to growing requirements for outcomes transparency. © 2013 Elsevier Ireland Ltd. All rights reserved. Keywords: Necrotizing enterocolitis; Preterm infant; Quality improvement; Prevention
1. Introduction Much of the necrotizing enterocolitis (NEC) literature has been accumulated from the pre-surfactant era. Initial reports in the English literature are from the 1960s [1–4]. Bell’s clinical staging of NEC was published in 1978 and was a major force that facilitated grouping of NEC into patient cohorts rather than as case reports and series [5]. Major advances in neonatal care emerged in this decade (including continuous positive airway pressure (CPAP) and total parental nutrition) and with them a “new NEC” emerged in more premature ∗ Corresponding author at: Department of Pediatrics, University of Virginia, Box 800386, Charlottesville, VA 22908, United States. E-mail address: [email protected] (J.R. Swanson).
infants that survived because of these technologies. It was suggested by some that NEC was not a single disease entity, but rather a disease spectrum, but this concept never gained traction in the literature [6–8]. Some groups also documented NEC increases after surfactant introduction; but NEC in older infants eventually declined, resetting incidence at levels comparable to the pre-surfactant era [9]. In the late 1980s investigators had the following epiphanies: (A) some NEC patients were simply not as sick as the others and (B) combining heterogeneous causes of acquired neonatal intestinal diseases (ANIDs) into datasets obstructed progress in NEC research. Modified Bell’s staging (the exclusion of Bell’s stage I) was a reasonable attempt to address these concerns [10,11]. Unfortunately, in the post-surfactant era, a new ANID emerged [12–14]. It took some years for
0928-4680/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pathophys.2013.11.015
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
PATPHY-799; No. of Pages 7
2
ARTICLE IN PRESS P.V. Gordon, J.R. Swanson / Pathophysiology xxx (2013) xxx–xxx
investigators to determine that there was a robust relationship between early postnatal steroid therapy and spontaneous intestinal perforation (SIP) [15–19]. Subsequent research confirmed SIP to be a distinct disease entity from NEC [20]. This prompted a reformulation of the prevailing NEC definition. SIP most commonly presents as pneumoperitoneum without pneumatosis but was, and in some datasets still is, being misclassified as Bell’s stage IIIb [21]. Because of this, it has been suggested that Bell’s staging be abandoned in favor of a new ANID taxonomy (sometimes called Gordon’s classification) [22]. The goal of such a system, was not to stage the severity of disease (other than surgery and mortality), but to focus on the known differences in SIP and NEC presentation as a means to enrich the quality of NEC data. The removal of SIP from many of the world’s NEC databases has dramatically improved their utility. In recent years, a new approach to NEC data analysis has been NEC reductionism [23]. This research philosophy essentially acknowledges that NEC is a final common endpoint, but reduces NEC into subsets based on disparate etiologies. The advantage of this approach is that it helps to identify variables and risk factors that are both common and distinct between subsets, potentially facilitating quality improvement by allowing it to be tailored to the NEC subset burden that a given NICU may have. Some subsets have been more robustly characterized than others and much work remains to be done, but it has become clear that NEC reductionism offers neonatology new promise. In the short time that it has been employed, it has already moved us well beyond the previous half century of NEC research in our understanding of NEC risk. The remainder of this review will ultimately focus on NEC prevention. We will evaluate how premature infant physiology and biology defines NEC and how this biology leads to specific risk factors. These risk factors, in turn, lead to the need for the development of NEC subgroups and specific preventative strategies for each. Finally, a case is made for individual units to determine their own NEC rates by subgroup to provide the highest quality care. 1.1. Part I: how the biology of prematurity defines NEC One of the most important fundamental advances in our understanding of NEC is an amalgamation of data from both basic and clinical research. Animal models of NEC have shown that the innate immune system and specifically toll-like receptor-4 (TLR4) is crucial component of NEC vulnerability [24–26]. This receptor recognizes lipopolysaccharide and thus is a potent sensor of pathogenic bacteria overgrowth and translocation across the mucous barrier of the mucosa [27,28]. Its surface density increases across the latter half of gestation, increasing the risk of NEC until shortly before term at which time adaptive immunity matures and TLR4 is actively down regulated and actively removed from the cell surface [29]. TLR4 kills bacteria by inducing programmed cell death (apoptosis), thus engulfing and killing
Fig. 1. Summation/consolidation of data about NEC, including time of presentation, percent mortality and incidence of disease stratified by gestational age. Left-sided y-axis equals day of onset indicated by the sphere centers. The sphere diameters indicate the percent of total NEC that presented on that day of life (mean for the gestational age group), and correlate with the x-axis below. The gray columns indicate the percent mortality (right side y-axis). Data for the extrapolations in this figure are based upon summarized data from Refs. [30–33]. In cases where precise data was unavailable in the units needed (for example, if the data were available by birth weight instead of gestational age), the data were extrapolated using the assumption that the population as a whole was appropriate for gestational age and the datasets were representative of a common disease entity. For example, two single center reports were used to overlay the timing of NEC onset onto the national dataset of incidence and mortality.
the invading pathogen. When this happens in utero, the fetus replaces any patches of mucosa that might be compromised by robust apoptosis. Ex utero, if this process gets too potent, it leads to hemorrhagic necrosis and NEC in the preterm infant. The clinical correlate to these events is thought to be the stereotypical onset and timing of preterm NEC, which is more prevalent and more morbid in lower gestation infants, but occurs later in life from the time of birth in these younger infants than in older gestation infants [23,30–34] (Fig. 1). Of equal interest is the observation that the onset becomes uniform as infants approach the developmental window of being “near” term. These findings are precisely what one might predict if TLR4 biology is a major driver of NEC risk. Moreover, looking at such concepts, it becomes clear that TLR4 is likely a contributing cause to most of the NEC in neonatology (since the incidence of NEC at the term end of the figure is relatively small). Thus, the majority of NEC is preterm NEC. There has also been a great deal of work on genetic predisposition and the microbiome that has advanced our understanding of NEC risk and preventative strategies. Twin gestation analyses have supported the belief that NEC risk is familial in origin [35]. Several studies have focused on single nucleotide repeat polymorphisms (SNPs) of the TLR4 gene and its downstream pathway, however these have not been found to be associated with NEC [36]. However, variants of NFKB1, downstream from TLR4, have been associated with NEC as have polymorphisms in the mannose-binding lectin gene [37,38]. Similarly, perturbation of the microbiota of the gastrointestinal tract has been found to play a role in NEC risk.
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
PATPHY-799; No. of Pages 7
ARTICLE IN PRESS P.V. Gordon, J.R. Swanson / Pathophysiology xxx (2013) xxx–xxx
Although no specific change in the gut microbiome has been implicated in NEC, disturbance of the colonization patterns in the developing intestine certainly plays a role [39]. It is thought that bacteria living in the intestine can alter the development of the intestine as well as the infant’s immune system [40]. In order to prevent these changes in colonization, probiotics have been used as a preventative strategy against NEC. Evidence is accumulating that suggests they may protect against NEC [41], however their current role in NEC prevention is controversial due to lack of knowledge of the type of probiotic(s) to use, amount to use, the timing and duration of therapy, and safety profile and they have yet to be used in routine clinical practice [42,43]. 1.2. Part II: concepts in preterm NEC risk Preterm NEC is a multifactorial disease and infants who acquire it do so because they have acquired multiple distinct risk factors that have additive risk (although some risk factors are more severe than others). Understanding this concept is essential to NEC prevention [44]. Although somewhat simplistic, it is useful to think of risk factors as those that are acquired early in life and those that are incurred later (Fig. 2). Early risk factors are generally more global variables that alter commensal biology and favor increased TLR4 signaling and innate immune activation. They are relevant to all preterm infants and should be included as variables to be addressed in
3
any NEC quality improvement initiative. They include failing to feed human milk, failing to initiate early feeds and exposing to prolonged courses of antibiotics [45]. Each of these variables contributes to the same constellation of problems: skewed colonization of the intestine with non-commensal organisms and an atrophic mucosal barrier due to prolonged parental nutrition without feeding [46,47]. Late risk factors are more specific to NEC subsets. Multiple and late transfusions, particularly in infants with severe anemia are associated with one of the most severe forms of NEC (transfusion associated NEC – TANEC) [48–52]. Infants who acquire NEC in temporal clusters, especially in the winter and early summer months, and those who present with high lymphocyte counts represent another subset and the challenge with them is to support them sufficiently to prevent exacerbation of disease and to prevent spread of contagion [53–55]. Infants with cow’s milk intolerance is a mild but emerging NEC subset defined as infants with bloody stool and modest eosinophilia that resolves with discontinuation of all cow’s milk products (this sometimes includes breast milk if the mother has a dairy rich diet) [56,57]. Although it is rare to identify a preterm infant with NEC due to bowel ischemia as the primary risk factor, it is likely that the relative stress of postprandial blood flow exacerbates other risk factors (particularly the infant with anemia who receives transfusions). Late risk factors may be more useful for quality improvement efforts if tailored to the type of NEC subsets found within a given NICU [58].
Fig. 2. Schematic of early versus late risk factors for necrotizing enterocolitis.
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
PATPHY-799; No. of Pages 7
4
ARTICLE IN PRESS P.V. Gordon, J.R. Swanson / Pathophysiology xxx (2013) xxx–xxx
Fig. 3. Schematic depicting predicted subgroup overlap between necrotizing enterocolitis subsets.
1.3. Part III: NEC subgroups have overlap because NEC is a multi-factorial, multi-hit origin disease One concept that many neonatologists and surgeons seem to have difficulty with is the idea that there is overlap between NEC subsets (Fig. 3). The reason for this has more to do with the limitations of our definitions and our datasets than any deficiency with the principles of NEC reductionism. The first thing to realize is that in any patient cohort, disease definitions are defined and patients are categorized according to binary binning (i.e. they either have the disease or variable of interest or they do not). However, only a few databases are sufficiently relational to allow us to determine when individual patients
have two or more related variables in the final analysis. Thus we are unable to quantify how many patients with TANEC also have lymphocytosis, or how many patients with lymphocytosis are in NEC clusters. We have had some success with TANEC and NEC associated with cow’s milk intolerance, but very specific designs must be employed to address such issues [29]. Even though we cannot quantify all of these relationships, it is sometimes useful to try and visualize what we think they look like because some NEC subsets are clearly related. Fig. 3 represents the authors’ opinion of how current NEC subgroups may overlap based on the preterm NEC associated with true bowel ischemia (an entity that does not yet have a good clinical definition) is most commonly associated with TANEC and that NEC in clusters is commonly associated with lymphocytosis, a hallmark of viral infection. Viralinduced NEC is increasing, with published case reports and series of viral pathogens in NEC tripling between 2000 and 2006 [30]. It has been shown that in some centers, rotovirus accounts for as much as 30% of all NEC cases [59]. In contrast, NEC associated with delayed feeding is likely not a true NEC subset (since delayed feeding is an early risk factor), and thus we postulate that this variable has promiscuous overlap similar to that of formula feeding and antibiotic exposure. The more we understand which subgroups are related and which are distinct, the better we will be able to tailor our preventative strategies. 1.4. Part IV: a menu of NEC prevention options We include in this review a compendium of preventative strategies (Table 1). These include the relatively simple preventative strategies for term NEC, the early preventative
Table 1 Recommendations for preventative strategies against NEC. Term NEC Feed breast milk, advance at a rate comparable to breast feeding infant over the first 3 days of life. Avoid gavage if possible.
(B)
Preterm NEC (early risk factor avoidance) Initiate early feedings with mothers or donor milk; advance by protocol at a rate of 15–20 ml/kg/day. (1) (2) Avoid and/or minimize unnecessary antibiotic exposure. Remove central lines as soon as possible. (3) Minimize unnecessary blood draws. (4) (5) Consider fortification with either human milk based fortifiers or elemental formula based fortification. Ensure regular stooling with glycerin when necessary while advancing feeds and fortification. (6)
(B) (B) (B) (D) (A,D) (D)
Preterm NEC (late risk factor avoidance) (1) Avoid elective transfusions, or “topping off,” but also avoid extreme anemia. Hold feeds at least 4 h prior to, during, and 12 h after a late transfusion. (2) (3) When restarting feeds after a transfusion consider continuous and half-volume feeds as transitions. In infants who display rising eosinophilia after O-negative transfusions, consider typed-blood. (4) Prolonged use of traditional nasal CPAP may be a risk factor for NEC. Consider high-flow nasal cannula for respiratory support. (5) (6) Lymphocytosis with ileus should be respected; bacteria may overgrow/translocate (give antibiotics). NEC in clusters or with lymphocytosis should be quarantined to limit spread of contagion. (7) (8) Older preterm infants who have not had a transfusion in the past 48 h with red blood in stools and eosinophilia should be assumed to have cow’s milk intolerance until challenged with an elemental formula (not breast milk). Such infants will not have IgE elevation.
(B,D) (D) (D) (B,D) (B,D) (B,D) (D) (C,D)
Level of research supporting author recommendations: (A) one or more prospective, appropriately powered randomized controlled trials; (B) multiple corroborating retrospective cohort studies; (C) multiple anecdotal or case series reports; (D) author opinion.
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
PATPHY-799; No. of Pages 7
ARTICLE IN PRESS P.V. Gordon, J.R. Swanson / Pathophysiology xxx (2013) xxx–xxx
strategies for global NEC prevention and the more focused NEC subset prevention strategies that should be considered as late strategies. Our feeling is that most early strategies should be seriously considered. Late strategies should be tailored according to the predominant subsets of NEC occurring in the specific NICU and the resources available to successfully facilitate multiple interventions as a group. We admit that the evidence for some of these interventions is not what we would hope for and that we need rigorous studies to help better test their efficacy (for example glycerin). 1.5. Part V: the critical importance of looking at one’s own data One of the things implicit to our approach to NEC is that in order to tailor a quality improvement strategy for NEC, one must know their own data. Not simply the overall incidence of NEC, but the incidence of TANEC, seasonality and cluster data, lymphocytosis associated NEC, and cow’s milk associated NEC. Having annual subset data on NEC allows a NICU to rationally address the effectiveness of their own strategy. People who are not assigning these subset diagnoses to their quality improvement data cannot quantify their success or failure within a given subset. For individuals who do not know where to start, consider TANEC as it is by far the most severe form of preterm NEC in the authors’ opinion. For example, Christensen et al. found that 35% of their surgical NEC cases were associated with late transfusions [49]. In addition, one study found that TANEC cases were more likely to have severe intraventricular hemorrhage than non-TANEC cases (38% vs. 17%, p < 0.001) [60].
2. Discussion Over the course of our careers, we have encountered a number of individuals who have thrown up their hands in frustration at the concept of NEC prevention. Comments have ranged from “It can’t be done” to “I don’t know how, and you don’t either.” Certainly, NEC reductionism does not offer all of the answers today, but individual NICUs can achieve substantial NEC morbidity and mortality reductions for extended periods through comprehensive quality improvement approaches that utilize NEC reductionism. Central line associated blood stream infections (CLABSIs) were once markedly disparate in incidence between NICUs. A national push for a zero tolerance approach and comprehensive quality improvement dramatically leveled the CLABSI incidence across the country. We hope that a similar wave is coming with NEC [44]. What we think is especially important for medical directors to understand is a parallel trend emerging within healthcare reform. Particularly in non-certificate of need states, where greater disparities in NICU outcomes have been documented to exist, insurers are demanding specific institutional outcome data [61]. Perhaps more importantly, state
5
governments (as the largest insurer of the NICU population through Medicaid) are also demanding such data and moving toward its publication as a means to drive quality. Because NEC continues to be the major driver of morbidity and mortality in the NICU nationally, directors who fail or refuse to make meaningful improvements in NEC prevention may face reduction of reimbursement through either capitation or margins that are adjusted for quality. Failure to disclose data will likely be viewed as equivalent to poor outcomes. In this coming age of health care reform and NEC research, neonates may find themselves the beneficiary of confluent trends. NEC reductionism offers new ideas for prevention as well as the menu approach to tailoring a comprehensive strategy. Health care reform will likely make NEC reduction a high priority, helping overcome the frustrations and inertia that have kept many in our field from actively moving forward with such quality improvement efforts. Conflict of interest None declared. References [1] R. Rabl, Necrotizing enterocolitis in premature infants, Beitr. Pathol. Anat. 117 (1957) 266–282. [2] A. Eroess, K. Loerinczi, N. Nemeth, Enterocolitis necroticans in newborn infants, Kinderarztl. Prax. 27 (1959) 403–406. [3] W.E. Berdon, H. Grossman, D.H. Baker, A. Mizrahi, O. Barlow, W.A. Blanc, Necrotizing enterocolitis in the premature infant, Radiology 83 (1964) 879–887. [4] A. Mizrahi, O. Barlow, W. Berdon, W.A. Blanc, W.A. Silverman, Necrotizing enterocolitis in the premature infant, J. Pediatr. 66 (1965) 697–705. [5] M.J. Bell, J.L. Ternberg, R.D. Feigin, J.P. Keating, R. Marshall, L. Barton, T. Brotherton, Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging, Ann. Surg. 187 (1978) 1–7. [6] R.M. Kliegman, A.A. Fanaroff, Neonatal necrotizing enterocolitis in the absence of pneumatosis intestinalis, Am. J. Dis. Child. 136 (1982) 618–620. [7] R.M. Kliegman, A.A. Fanaroff, Neonatal necrotizing enterocolitis: a nine-year experience, Am. J. Dis. Child. 135 (1981) 603–607. [8] J.L. Grosfeld, H. Cheu, M. Schlatter, K.W. West, F.J. Rescorla, Changing trends in necrotizing enterocolitis. Experience with 302 cases in two decades, Ann. Surg. 214 (1991) 300–306. [9] R.C. Holman, B.J. Stoll, M.J. Clarke, R.I. Glass, The epidemiology of necrotizing enterocolitis infant mortality in the United States, Am. J. Public Health 87 (1997) 2026–2031. [10] M. Luig, K. Lui, NSW & ACT NICUS Group, Epidemiology of necrotizing enterocolitis – Part I: changing regional trends in extremely preterm infants over 14 years, J. Paediatr. Child Health 41 (2005) 169–173. [11] J.D. Battaglia, Neonatal surgery: changing patterns 1972–1980, J. Pediatr. Surg. 17 (1982) 666–669. [12] R.M. Kliegman, M. Hack, P. Jones, A.A. Fanaroff, Epidemiologic study of necrotizing enterocolitis among low-birth-weight infants. Absence of identifiable risk factors, J. Pediatr. 100 (1982) 440–444. [13] M.C. Walsh, R.M. Kliegman, Necrotizing enterocolitis: treatment based on staging criteria, Pediatr. Clin. North Am. 33 (1986) 179–201. [14] A. Porter, Spontaneous pneumoperitoneum in the newborn: report of a case, N. Engl. J. Med. 254 (1956) 694–696.
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
PATPHY-799; No. of Pages 7
6
ARTICLE IN PRESS P.V. Gordon, J.R. Swanson / Pathophysiology xxx (2013) xxx–xxx
[15] J.L. Aschner, K.S. Deluga, L.A. Metlay, R.W. Emmens, K.D. Hendricks-Munoz, Spontaneous focal gastrointestinal perforation in very low birth weight infants, J. Pediatr. 113 (1988) 364–367. [16] P. Gordon, J. Rutledge, R. Sawin, S. Thomas, D. Woodrum, Early postnatal dexamethasone increases the risk of focal small bowel perforation in extremely low birth weight infants, J. Perinatol. 19 (1999) 573–577. [17] P.V. Gordon, M.L. Young, D.D. Marshall, Focal small bowel perforation: an adverse effect of early postnatal dexamethasone therapy in extremely low birth weight infants, J. Perinatol. 21 (2001) 156–160. [18] J. Garland, A. Colleen, P. Thomas, V. Whitehead, J. Brand, J. Winston, et al., A three-day course of dexamethasone therapy to prevent chronic lung disease in ventilated neonates: a randomized trial, Pediatrics 104 (1999) 91–99. [19] A.R. Stark, W.A. Carlo, J.E. Tyson, L.-A. Papile, L.L. Wright, S. Shankaran, et al., Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants, N. Engl. J. Med. 344 (2001) 95–101. [20] Vermont Oxford Network Steroid Study Group, Early postnatal dexamethasone therapy for the prevention of chronic lung disease, Pediatrics 108 (2001) 741–748. [21] R. Sinkin, D. Harry, M. Horgan, K. Gallaher, C. Cox, W. Maniscalco, et al., Early dexamethasone – attempting to prevent chronic lung disease, Pediatrics 105 (2000) 542–548. [22] P.V. Gordon, Understanding intestinal vulnerability to perforation in the extremely low birth weight infant, Pediatr. Res. 65 (2009) 138–144. [23] W.H. Yee, A.S. Soraisham, V.S. Shah, K. Aziz, W. Yoon, S.K. Lee, the Canadian Neonatal Network, Incidence and timing of presentation of necrotizing enterocolitis in preterm infants, Pediatrics 129 (2012) e298–e304. [24] T. Jilling, D. Simon, J. Lu, F.J. Meng, D. Li, R. Schy, et al., The roles of bacteria and TLR4 in rat and murine models of necrotizing enterocolitis, J. Immunol. 177 (2006) 3273–3282. [25] C.P. Sodhi, M.D. Neal, R. Siggers, S. Sho, C. Ma, M.F. Branca, et al., Intestinal epithelial Toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice, Gastroenterology 143 (2012) 708–718, http://dx.doi.org/10. 1053/j.gastro.2012.05.053. [26] A. Soliman, K.S. Mechelsen, H. Karahashi, J. Lu, F.J. Meng, X. Qu, et al., Platelet-activating factor induces TLR4 expression in intestinal epithelial cells: implication for the pathogenesis of necrotizing enterocolitis, PLoS One 5 (2010) e15044. [27] S.C. Gribar, C.P. Sodhi, W.M. Richardson, R.J. Anand, G.K. Gittes, M.F. Branca, et al., Reciprocal expression and signaling of TLR4 and TLR9 in the pathogenesis and treatment of necrotizing enterocolitis, J. Immunol. 182 (2009) 636–646. [28] M. Good, C. Sodhi, R. Siggers, T. Prindle, M. Branca, A. Russo, et al., Epithelial Growth Factor Attenuates the Severity of Experimental Necrotizing Enterocolitis and Inhibits Toll-Like Receptor 4 Signaling in Enterocytes, in: E-PAS2011, 2011, p. 2720.3. [29] P. Gordon, R. Christensen, J.H. Weitkamp, A. Maheshwari, Mapping the new world of necrotizing enterocolitis (NEC): review and opinion, e-J. Neonatol. Res. 2 (2012) 145–172. [30] P.V. Gordon, J.R. Swanson, J.T. Attridge, R. Clark, Emerging trends in acquired neonatal intestinal disease: is it time to abandon Bell’s criteria? J. Perinatol. 27 (2007) 661–671. [31] P.V. Gordon, What progress looks like in NEC research, J. Perinatol. 31 (2011) 149. [32] R.H. Clark, P. Gordon, W.M. Walker, M. Laughon, P.B. Smith, A.R. Spitzer, Characteristics of patients who die of necrotizing enterocolitis, J. Perinatol. 32 (2012) 199–204. [33] S.O. Guthrie, P.V. Gordon, V. Thomas, J.A. Thorp, J. Peabody, R.H. Clark, Necrotizing enterocolitis among neonates in the United States, J. Perinatol. 23 (2003) 278–285. [34] R. González-Rivera, R.C. Culverhouse, A. Hamvas, P.I. Tarr, B.B. Warner, The age of necrotizing enterocolitis onset: an application of Sartwell’s incubation period model, J. Perinatol. 31 (2011) 519–523.
[35] V. Bhandari, M.J. Bizzarro, A. Shetty, X. Zhong, G.P. Page, H. Zhang, et al., Familial and genetic susceptibility to major neonatal morbidities in preterm twins, Pediatrics 117 (2006) 1901–1906. [36] C. Young, R. Sharma, M. Handfield, V. Mai, J. Neu, Biomarkers for infants at risk for necrotizing enterocolitis: clues to prevention? Pediatr. Res. 65 (2009) 91R–97R. [37] V. Sampath, M. Le, L. Lane, A.L. Patel, J.D. Cohen, P.M. Simpson, et al., The NFKB1 (g.-24519delATTG) variant is associated with necrotizing enterocolitis (NEC) in premature infants, J. Surg. Res. 169 (2011) e51–e57. [38] G. Prencipe, C. Azzari, M. Moriondo, R. Devito, M. Pezzullo, et al., Association between mannose-binding lectin gene polymorphisms and necrotizing enterocolitis in preterm infants, J. Pediatr. Gastroenterol. Nutr. 55 (2012) 160–165. [39] E.M. Carlisle, M.J. Morowitz, The intestinal microbiome and necrotizing enterocolitis, Curr. Opin. Pediatr. 25 (2013) 382–387. [40] F. Indrio, J. Neu, The intestinal microbiome of infants and the use of probiotics, Curr. Opin. Pediatr. 23 (2011) 145–150. [41] K. Alfaleh, J. Anabrees, D. Bassler, T. Al-Kharfi, Probiotics for the prevention of necrotizing enterocolitis in preterm infants, Cochrane Database Syst. Rev. 3 (2011) CD005496. [42] C.R. Martin, Probiotics for the prevention of necrotizing enterocolitis: not just which ones but also why? J. Pediatr. Gastroenterol. Nutr. 57 (2013) 3. [43] R.M. Patel, P.W. Denning, Therapeutic use of prebiotics, probiotics, and postbiotics to prevent necrotizing enterocolitis: what is the current evidence, Clin. Pernatol. 40 (2013) 11–25. [44] J.R. Swanson, Necrotizing enterocolitis: is it time for zero tolerance? J. Perinatol. 33 (2013) 1–2. [45] S.M. Gephart, J.M. McGrath, J.A. Effken, M.D. Halpern, Necrotizing enterocolitis risk: state of the science, Adv. Neonatal Care 12 (2012) 77–87. [46] R.M. Torrazza, J. Neu, The altered gut microbiome and necrotizing enterocolitis, Clin. Perinatol. 40 (2013) 93–108. [47] J. Neu, W.A. Walker, Necrotizing enterocolitis, N. Engl. J. Med. 364 (2011) 255–264. [48] R. Singh, P.F. Visintainer, I.D. Frantz, B.L. Shah, K.M. Meyer, S.A. Favila, et al., Association of necrotizing enterocolitis with anemia and packed red blood cell transfusions in preterm infants, J. Perinatol. 31 (2011) 176–182. [49] R.D. Christensen, D.K. Lambert, E. Henry, S.E. Wiedmeier, G.L. Snow, V.L. Baer, et al., Is ‘transfusion-associated necrotizing enterocolitis’ an authentic pathogenic entity? Transfusion (Paris) 50 (2010) 1106–1112. [50] R.D. Christensen, Associations between “early” red blood cell transfusion and severe intraventricular hemorrhage, and between “late” red blood cell transfusion and necrotizing enterocolitis, Semin. Perinatol. 36 (2012) 283–289. [51] E.F. La Gamma, J. Blau, Transfusion-related acute gut injury: feeding, flora, flow, and barrier defense, Semin. Perinatol. 36 (2012) 294–305. [52] S.C. Amin, J.L. Remon, G.C. Subbarao, A. Maheshwari, Association between red cell transfusions and necrotizing enterocolitis, J. Matern. Fetal Neonatal Med. 25 (2012) 85–89. [53] A.B. Hair, J.R. Swanson, J.T. Attridge, Lymphocytosis at necrotizing enterocolitis presentation is associated with higher mortality, increased feeding volumes and more formula exposure in an 11 year, single center retrospective study, e-J. Neonatal Res. 2 (2011) 37–43. [54] P.V. Gordon, S. Thibeau, C. Pennier, H. Ginsberg, V. Lunyong, M. Cortez, et al., Is lymphocytosis an adjunct predictor of NEC mortality in low gestation infants? e-J. Neonatal Res. 2 (2012) 29–36. [55] J. Meinzen-Derr, A.L. Morrow, R.W. Hornung, E.F. Donovan, K.N. Dietrich, P.A. Succop, Epidemiology of necrotizing enterocolitis temporal clustering in two neonatology practices, J. Pediatr. 154 (2009) 656–661. [56] R.D. Christensen, D.K. Lambert, P.V. Gordon, V.L. Baer, E. Gerday, E. Henry, Neonates presenting with bloody stools and eosinophilia can progress to two different types of necrotizing enterocolitis, J. Perinatol. 32 (2012) 874–879.
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
PATPHY-799; No. of Pages 7
ARTICLE IN PRESS P.V. Gordon, J.R. Swanson / Pathophysiology xxx (2013) xxx–xxx
[57] P. Srinivasan, M. Brandler, A. D’Souza, P. Millman, H. Moreau, Allergic enterocolitis presenting as recurrent necrotizing enterocolitis in preterm neonates, J. Perinatol. 30 (2010) 431–433. [58] J. Benjamin, E. Chong, J. Reynolds, P.V. Gordon, Detailed analysis of NEC risks across a decade in a low incidence NICU: can we drive the incidence of NEC toward zero? e-J. Neonatol. Res. 2 (2012) 181–189. [59] R. Sharma, R.D. Garrison, D. Tepas, D.L. Mollitt, P. Pieper, M.L. Hudak, et al., Rotavirus-associated necrotizing enterocolitis: an insight
7
into a potentially preventable disease? J. Pediatr. Surg. 39 (2004) 453–457. [60] A.I. Stritzke, J. Smyth, A. Synnes, S.K. Lee, P.S. Shah, Transfusionassociated necrotizing enterocolitis in neonates, Arch. Dis. Child. Fetal Neonatal Ed. 98 (2013) F10–F14. [61] S.A. Lorch, P. Maheshwari, O. Even-Shoshan, The impact of certificate of need programs on neonatal intensive care units, J. Perinatol. 32 (2012) 39–44.
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
PATPHY-799; No. of Pages 7
Pathophysiology xxx (2013) xxx–xxx
Necrotizing enterocolitis is one disease with many origins and potential means of prevention Phillip V. Gordon a,b , Jonathan R. Swanson c,∗ a
c
Pediatrix-Obstetrix Center for Research and Education, Sunrise, FL, United States b Sacred Heart Children’s Hospital, Pensacola, FL, United States Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, United States
Abstract Background: The field of necrotizing enterocolitis (NEC) research has been in existence for over 60 years. During the first five decades little progress in NEC prevention and no definitive progress in treatment was achieved. One of the major determinants of this ineffectiveness may have been a global propensity to lump NEC into a single disease entity rather than a spectrum of diseases with a common outcome. The driver of this philosophy was most likely statistical, in that researchers desired large cohorts to optimize statistical power. Additionally, in the past quarter century, our preterm NEC cohorts were (and in some cases still are) contaminated with spontaneous intestinal perforations (SIP). This completely different acquired neonatal intestinal disease (ANID) markedly alters clinical characteristics and outcomes in NEC cohorts and subsets if not addressed. Unfortunately, cohort size has been proven to be less important than data quality when it comes to NEC over this last decade of research. Emerging progress in NEC prevention has been greatly enhanced as a result of dividing well-defined NEC into subsets of disease origin and investigating these entities individually. Review objectives: The purpose of this review is to offer the bedside clinician a concise, up-to-date review of recent advances in NEC reductionism. The reader should understand the history and basic theory behind NEC subsets, their application to NEC prevention, and comprehend that prevention of NEC requires a comprehensive quality improvement strategy that is likely best realized with a zero tolerance approach. Conclusions: We are entering a new era of NEC prevention. NICUs that embrace and achieve effective NEC prevention strategies will rapidly outpace their contemporaries. Because NEC is still the major driver of morbidity and mortality in most NICUs today, those who reject or fail in this pursuit will likely face increasingly severe consequences due to growing requirements for outcomes transparency. © 2013 Elsevier Ireland Ltd. All rights reserved. Keywords: Necrotizing enterocolitis; Preterm infant; Quality improvement; Prevention
1. Introduction Much of the necrotizing enterocolitis (NEC) literature has been accumulated from the pre-surfactant era. Initial reports in the English literature are from the 1960s [1–4]. Bell’s clinical staging of NEC was published in 1978 and was a major force that facilitated grouping of NEC into patient cohorts rather than as case reports and series [5]. Major advances in neonatal care emerged in this decade (including continuous positive airway pressure (CPAP) and total parental nutrition) and with them a “new NEC” emerged in more premature ∗ Corresponding author at: Department of Pediatrics, University of Virginia, Box 800386, Charlottesville, VA 22908, United States. E-mail address: [email protected] (J.R. Swanson).
infants that survived because of these technologies. It was suggested by some that NEC was not a single disease entity, but rather a disease spectrum, but this concept never gained traction in the literature [6–8]. Some groups also documented NEC increases after surfactant introduction; but NEC in older infants eventually declined, resetting incidence at levels comparable to the pre-surfactant era [9]. In the late 1980s investigators had the following epiphanies: (A) some NEC patients were simply not as sick as the others and (B) combining heterogeneous causes of acquired neonatal intestinal diseases (ANIDs) into datasets obstructed progress in NEC research. Modified Bell’s staging (the exclusion of Bell’s stage I) was a reasonable attempt to address these concerns [10,11]. Unfortunately, in the post-surfactant era, a new ANID emerged [12–14]. It took some years for
0928-4680/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pathophys.2013.11.015
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
PATPHY-799; No. of Pages 7
2
ARTICLE IN PRESS P.V. Gordon, J.R. Swanson / Pathophysiology xxx (2013) xxx–xxx
investigators to determine that there was a robust relationship between early postnatal steroid therapy and spontaneous intestinal perforation (SIP) [15–19]. Subsequent research confirmed SIP to be a distinct disease entity from NEC [20]. This prompted a reformulation of the prevailing NEC definition. SIP most commonly presents as pneumoperitoneum without pneumatosis but was, and in some datasets still is, being misclassified as Bell’s stage IIIb [21]. Because of this, it has been suggested that Bell’s staging be abandoned in favor of a new ANID taxonomy (sometimes called Gordon’s classification) [22]. The goal of such a system, was not to stage the severity of disease (other than surgery and mortality), but to focus on the known differences in SIP and NEC presentation as a means to enrich the quality of NEC data. The removal of SIP from many of the world’s NEC databases has dramatically improved their utility. In recent years, a new approach to NEC data analysis has been NEC reductionism [23]. This research philosophy essentially acknowledges that NEC is a final common endpoint, but reduces NEC into subsets based on disparate etiologies. The advantage of this approach is that it helps to identify variables and risk factors that are both common and distinct between subsets, potentially facilitating quality improvement by allowing it to be tailored to the NEC subset burden that a given NICU may have. Some subsets have been more robustly characterized than others and much work remains to be done, but it has become clear that NEC reductionism offers neonatology new promise. In the short time that it has been employed, it has already moved us well beyond the previous half century of NEC research in our understanding of NEC risk. The remainder of this review will ultimately focus on NEC prevention. We will evaluate how premature infant physiology and biology defines NEC and how this biology leads to specific risk factors. These risk factors, in turn, lead to the need for the development of NEC subgroups and specific preventative strategies for each. Finally, a case is made for individual units to determine their own NEC rates by subgroup to provide the highest quality care. 1.1. Part I: how the biology of prematurity defines NEC One of the most important fundamental advances in our understanding of NEC is an amalgamation of data from both basic and clinical research. Animal models of NEC have shown that the innate immune system and specifically toll-like receptor-4 (TLR4) is crucial component of NEC vulnerability [24–26]. This receptor recognizes lipopolysaccharide and thus is a potent sensor of pathogenic bacteria overgrowth and translocation across the mucous barrier of the mucosa [27,28]. Its surface density increases across the latter half of gestation, increasing the risk of NEC until shortly before term at which time adaptive immunity matures and TLR4 is actively down regulated and actively removed from the cell surface [29]. TLR4 kills bacteria by inducing programmed cell death (apoptosis), thus engulfing and killing
Fig. 1. Summation/consolidation of data about NEC, including time of presentation, percent mortality and incidence of disease stratified by gestational age. Left-sided y-axis equals day of onset indicated by the sphere centers. The sphere diameters indicate the percent of total NEC that presented on that day of life (mean for the gestational age group), and correlate with the x-axis below. The gray columns indicate the percent mortality (right side y-axis). Data for the extrapolations in this figure are based upon summarized data from Refs. [30–33]. In cases where precise data was unavailable in the units needed (for example, if the data were available by birth weight instead of gestational age), the data were extrapolated using the assumption that the population as a whole was appropriate for gestational age and the datasets were representative of a common disease entity. For example, two single center reports were used to overlay the timing of NEC onset onto the national dataset of incidence and mortality.
the invading pathogen. When this happens in utero, the fetus replaces any patches of mucosa that might be compromised by robust apoptosis. Ex utero, if this process gets too potent, it leads to hemorrhagic necrosis and NEC in the preterm infant. The clinical correlate to these events is thought to be the stereotypical onset and timing of preterm NEC, which is more prevalent and more morbid in lower gestation infants, but occurs later in life from the time of birth in these younger infants than in older gestation infants [23,30–34] (Fig. 1). Of equal interest is the observation that the onset becomes uniform as infants approach the developmental window of being “near” term. These findings are precisely what one might predict if TLR4 biology is a major driver of NEC risk. Moreover, looking at such concepts, it becomes clear that TLR4 is likely a contributing cause to most of the NEC in neonatology (since the incidence of NEC at the term end of the figure is relatively small). Thus, the majority of NEC is preterm NEC. There has also been a great deal of work on genetic predisposition and the microbiome that has advanced our understanding of NEC risk and preventative strategies. Twin gestation analyses have supported the belief that NEC risk is familial in origin [35]. Several studies have focused on single nucleotide repeat polymorphisms (SNPs) of the TLR4 gene and its downstream pathway, however these have not been found to be associated with NEC [36]. However, variants of NFKB1, downstream from TLR4, have been associated with NEC as have polymorphisms in the mannose-binding lectin gene [37,38]. Similarly, perturbation of the microbiota of the gastrointestinal tract has been found to play a role in NEC risk.
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
PATPHY-799; No. of Pages 7
ARTICLE IN PRESS P.V. Gordon, J.R. Swanson / Pathophysiology xxx (2013) xxx–xxx
Although no specific change in the gut microbiome has been implicated in NEC, disturbance of the colonization patterns in the developing intestine certainly plays a role [39]. It is thought that bacteria living in the intestine can alter the development of the intestine as well as the infant’s immune system [40]. In order to prevent these changes in colonization, probiotics have been used as a preventative strategy against NEC. Evidence is accumulating that suggests they may protect against NEC [41], however their current role in NEC prevention is controversial due to lack of knowledge of the type of probiotic(s) to use, amount to use, the timing and duration of therapy, and safety profile and they have yet to be used in routine clinical practice [42,43]. 1.2. Part II: concepts in preterm NEC risk Preterm NEC is a multifactorial disease and infants who acquire it do so because they have acquired multiple distinct risk factors that have additive risk (although some risk factors are more severe than others). Understanding this concept is essential to NEC prevention [44]. Although somewhat simplistic, it is useful to think of risk factors as those that are acquired early in life and those that are incurred later (Fig. 2). Early risk factors are generally more global variables that alter commensal biology and favor increased TLR4 signaling and innate immune activation. They are relevant to all preterm infants and should be included as variables to be addressed in
3
any NEC quality improvement initiative. They include failing to feed human milk, failing to initiate early feeds and exposing to prolonged courses of antibiotics [45]. Each of these variables contributes to the same constellation of problems: skewed colonization of the intestine with non-commensal organisms and an atrophic mucosal barrier due to prolonged parental nutrition without feeding [46,47]. Late risk factors are more specific to NEC subsets. Multiple and late transfusions, particularly in infants with severe anemia are associated with one of the most severe forms of NEC (transfusion associated NEC – TANEC) [48–52]. Infants who acquire NEC in temporal clusters, especially in the winter and early summer months, and those who present with high lymphocyte counts represent another subset and the challenge with them is to support them sufficiently to prevent exacerbation of disease and to prevent spread of contagion [53–55]. Infants with cow’s milk intolerance is a mild but emerging NEC subset defined as infants with bloody stool and modest eosinophilia that resolves with discontinuation of all cow’s milk products (this sometimes includes breast milk if the mother has a dairy rich diet) [56,57]. Although it is rare to identify a preterm infant with NEC due to bowel ischemia as the primary risk factor, it is likely that the relative stress of postprandial blood flow exacerbates other risk factors (particularly the infant with anemia who receives transfusions). Late risk factors may be more useful for quality improvement efforts if tailored to the type of NEC subsets found within a given NICU [58].
Fig. 2. Schematic of early versus late risk factors for necrotizing enterocolitis.
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
PATPHY-799; No. of Pages 7
4
ARTICLE IN PRESS P.V. Gordon, J.R. Swanson / Pathophysiology xxx (2013) xxx–xxx
Fig. 3. Schematic depicting predicted subgroup overlap between necrotizing enterocolitis subsets.
1.3. Part III: NEC subgroups have overlap because NEC is a multi-factorial, multi-hit origin disease One concept that many neonatologists and surgeons seem to have difficulty with is the idea that there is overlap between NEC subsets (Fig. 3). The reason for this has more to do with the limitations of our definitions and our datasets than any deficiency with the principles of NEC reductionism. The first thing to realize is that in any patient cohort, disease definitions are defined and patients are categorized according to binary binning (i.e. they either have the disease or variable of interest or they do not). However, only a few databases are sufficiently relational to allow us to determine when individual patients
have two or more related variables in the final analysis. Thus we are unable to quantify how many patients with TANEC also have lymphocytosis, or how many patients with lymphocytosis are in NEC clusters. We have had some success with TANEC and NEC associated with cow’s milk intolerance, but very specific designs must be employed to address such issues [29]. Even though we cannot quantify all of these relationships, it is sometimes useful to try and visualize what we think they look like because some NEC subsets are clearly related. Fig. 3 represents the authors’ opinion of how current NEC subgroups may overlap based on the preterm NEC associated with true bowel ischemia (an entity that does not yet have a good clinical definition) is most commonly associated with TANEC and that NEC in clusters is commonly associated with lymphocytosis, a hallmark of viral infection. Viralinduced NEC is increasing, with published case reports and series of viral pathogens in NEC tripling between 2000 and 2006 [30]. It has been shown that in some centers, rotovirus accounts for as much as 30% of all NEC cases [59]. In contrast, NEC associated with delayed feeding is likely not a true NEC subset (since delayed feeding is an early risk factor), and thus we postulate that this variable has promiscuous overlap similar to that of formula feeding and antibiotic exposure. The more we understand which subgroups are related and which are distinct, the better we will be able to tailor our preventative strategies. 1.4. Part IV: a menu of NEC prevention options We include in this review a compendium of preventative strategies (Table 1). These include the relatively simple preventative strategies for term NEC, the early preventative
Table 1 Recommendations for preventative strategies against NEC. Term NEC Feed breast milk, advance at a rate comparable to breast feeding infant over the first 3 days of life. Avoid gavage if possible.
(B)
Preterm NEC (early risk factor avoidance) Initiate early feedings with mothers or donor milk; advance by protocol at a rate of 15–20 ml/kg/day. (1) (2) Avoid and/or minimize unnecessary antibiotic exposure. Remove central lines as soon as possible. (3) Minimize unnecessary blood draws. (4) (5) Consider fortification with either human milk based fortifiers or elemental formula based fortification. Ensure regular stooling with glycerin when necessary while advancing feeds and fortification. (6)
(B) (B) (B) (D) (A,D) (D)
Preterm NEC (late risk factor avoidance) (1) Avoid elective transfusions, or “topping off,” but also avoid extreme anemia. Hold feeds at least 4 h prior to, during, and 12 h after a late transfusion. (2) (3) When restarting feeds after a transfusion consider continuous and half-volume feeds as transitions. In infants who display rising eosinophilia after O-negative transfusions, consider typed-blood. (4) Prolonged use of traditional nasal CPAP may be a risk factor for NEC. Consider high-flow nasal cannula for respiratory support. (5) (6) Lymphocytosis with ileus should be respected; bacteria may overgrow/translocate (give antibiotics). NEC in clusters or with lymphocytosis should be quarantined to limit spread of contagion. (7) (8) Older preterm infants who have not had a transfusion in the past 48 h with red blood in stools and eosinophilia should be assumed to have cow’s milk intolerance until challenged with an elemental formula (not breast milk). Such infants will not have IgE elevation.
(B,D) (D) (D) (B,D) (B,D) (B,D) (D) (C,D)
Level of research supporting author recommendations: (A) one or more prospective, appropriately powered randomized controlled trials; (B) multiple corroborating retrospective cohort studies; (C) multiple anecdotal or case series reports; (D) author opinion.
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
PATPHY-799; No. of Pages 7
ARTICLE IN PRESS P.V. Gordon, J.R. Swanson / Pathophysiology xxx (2013) xxx–xxx
strategies for global NEC prevention and the more focused NEC subset prevention strategies that should be considered as late strategies. Our feeling is that most early strategies should be seriously considered. Late strategies should be tailored according to the predominant subsets of NEC occurring in the specific NICU and the resources available to successfully facilitate multiple interventions as a group. We admit that the evidence for some of these interventions is not what we would hope for and that we need rigorous studies to help better test their efficacy (for example glycerin). 1.5. Part V: the critical importance of looking at one’s own data One of the things implicit to our approach to NEC is that in order to tailor a quality improvement strategy for NEC, one must know their own data. Not simply the overall incidence of NEC, but the incidence of TANEC, seasonality and cluster data, lymphocytosis associated NEC, and cow’s milk associated NEC. Having annual subset data on NEC allows a NICU to rationally address the effectiveness of their own strategy. People who are not assigning these subset diagnoses to their quality improvement data cannot quantify their success or failure within a given subset. For individuals who do not know where to start, consider TANEC as it is by far the most severe form of preterm NEC in the authors’ opinion. For example, Christensen et al. found that 35% of their surgical NEC cases were associated with late transfusions [49]. In addition, one study found that TANEC cases were more likely to have severe intraventricular hemorrhage than non-TANEC cases (38% vs. 17%, p < 0.001) [60].
2. Discussion Over the course of our careers, we have encountered a number of individuals who have thrown up their hands in frustration at the concept of NEC prevention. Comments have ranged from “It can’t be done” to “I don’t know how, and you don’t either.” Certainly, NEC reductionism does not offer all of the answers today, but individual NICUs can achieve substantial NEC morbidity and mortality reductions for extended periods through comprehensive quality improvement approaches that utilize NEC reductionism. Central line associated blood stream infections (CLABSIs) were once markedly disparate in incidence between NICUs. A national push for a zero tolerance approach and comprehensive quality improvement dramatically leveled the CLABSI incidence across the country. We hope that a similar wave is coming with NEC [44]. What we think is especially important for medical directors to understand is a parallel trend emerging within healthcare reform. Particularly in non-certificate of need states, where greater disparities in NICU outcomes have been documented to exist, insurers are demanding specific institutional outcome data [61]. Perhaps more importantly, state
5
governments (as the largest insurer of the NICU population through Medicaid) are also demanding such data and moving toward its publication as a means to drive quality. Because NEC continues to be the major driver of morbidity and mortality in the NICU nationally, directors who fail or refuse to make meaningful improvements in NEC prevention may face reduction of reimbursement through either capitation or margins that are adjusted for quality. Failure to disclose data will likely be viewed as equivalent to poor outcomes. In this coming age of health care reform and NEC research, neonates may find themselves the beneficiary of confluent trends. NEC reductionism offers new ideas for prevention as well as the menu approach to tailoring a comprehensive strategy. Health care reform will likely make NEC reduction a high priority, helping overcome the frustrations and inertia that have kept many in our field from actively moving forward with such quality improvement efforts. Conflict of interest None declared. References [1] R. Rabl, Necrotizing enterocolitis in premature infants, Beitr. Pathol. Anat. 117 (1957) 266–282. [2] A. Eroess, K. Loerinczi, N. Nemeth, Enterocolitis necroticans in newborn infants, Kinderarztl. Prax. 27 (1959) 403–406. [3] W.E. Berdon, H. Grossman, D.H. Baker, A. Mizrahi, O. Barlow, W.A. Blanc, Necrotizing enterocolitis in the premature infant, Radiology 83 (1964) 879–887. [4] A. Mizrahi, O. Barlow, W. Berdon, W.A. Blanc, W.A. Silverman, Necrotizing enterocolitis in the premature infant, J. Pediatr. 66 (1965) 697–705. [5] M.J. Bell, J.L. Ternberg, R.D. Feigin, J.P. Keating, R. Marshall, L. Barton, T. Brotherton, Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging, Ann. Surg. 187 (1978) 1–7. [6] R.M. Kliegman, A.A. Fanaroff, Neonatal necrotizing enterocolitis in the absence of pneumatosis intestinalis, Am. J. Dis. Child. 136 (1982) 618–620. [7] R.M. Kliegman, A.A. Fanaroff, Neonatal necrotizing enterocolitis: a nine-year experience, Am. J. Dis. Child. 135 (1981) 603–607. [8] J.L. Grosfeld, H. Cheu, M. Schlatter, K.W. West, F.J. Rescorla, Changing trends in necrotizing enterocolitis. Experience with 302 cases in two decades, Ann. Surg. 214 (1991) 300–306. [9] R.C. Holman, B.J. Stoll, M.J. Clarke, R.I. Glass, The epidemiology of necrotizing enterocolitis infant mortality in the United States, Am. J. Public Health 87 (1997) 2026–2031. [10] M. Luig, K. Lui, NSW & ACT NICUS Group, Epidemiology of necrotizing enterocolitis – Part I: changing regional trends in extremely preterm infants over 14 years, J. Paediatr. Child Health 41 (2005) 169–173. [11] J.D. Battaglia, Neonatal surgery: changing patterns 1972–1980, J. Pediatr. Surg. 17 (1982) 666–669. [12] R.M. Kliegman, M. Hack, P. Jones, A.A. Fanaroff, Epidemiologic study of necrotizing enterocolitis among low-birth-weight infants. Absence of identifiable risk factors, J. Pediatr. 100 (1982) 440–444. [13] M.C. Walsh, R.M. Kliegman, Necrotizing enterocolitis: treatment based on staging criteria, Pediatr. Clin. North Am. 33 (1986) 179–201. [14] A. Porter, Spontaneous pneumoperitoneum in the newborn: report of a case, N. Engl. J. Med. 254 (1956) 694–696.
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
PATPHY-799; No. of Pages 7
6
ARTICLE IN PRESS P.V. Gordon, J.R. Swanson / Pathophysiology xxx (2013) xxx–xxx
[15] J.L. Aschner, K.S. Deluga, L.A. Metlay, R.W. Emmens, K.D. Hendricks-Munoz, Spontaneous focal gastrointestinal perforation in very low birth weight infants, J. Pediatr. 113 (1988) 364–367. [16] P. Gordon, J. Rutledge, R. Sawin, S. Thomas, D. Woodrum, Early postnatal dexamethasone increases the risk of focal small bowel perforation in extremely low birth weight infants, J. Perinatol. 19 (1999) 573–577. [17] P.V. Gordon, M.L. Young, D.D. Marshall, Focal small bowel perforation: an adverse effect of early postnatal dexamethasone therapy in extremely low birth weight infants, J. Perinatol. 21 (2001) 156–160. [18] J. Garland, A. Colleen, P. Thomas, V. Whitehead, J. Brand, J. Winston, et al., A three-day course of dexamethasone therapy to prevent chronic lung disease in ventilated neonates: a randomized trial, Pediatrics 104 (1999) 91–99. [19] A.R. Stark, W.A. Carlo, J.E. Tyson, L.-A. Papile, L.L. Wright, S. Shankaran, et al., Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants, N. Engl. J. Med. 344 (2001) 95–101. [20] Vermont Oxford Network Steroid Study Group, Early postnatal dexamethasone therapy for the prevention of chronic lung disease, Pediatrics 108 (2001) 741–748. [21] R. Sinkin, D. Harry, M. Horgan, K. Gallaher, C. Cox, W. Maniscalco, et al., Early dexamethasone – attempting to prevent chronic lung disease, Pediatrics 105 (2000) 542–548. [22] P.V. Gordon, Understanding intestinal vulnerability to perforation in the extremely low birth weight infant, Pediatr. Res. 65 (2009) 138–144. [23] W.H. Yee, A.S. Soraisham, V.S. Shah, K. Aziz, W. Yoon, S.K. Lee, the Canadian Neonatal Network, Incidence and timing of presentation of necrotizing enterocolitis in preterm infants, Pediatrics 129 (2012) e298–e304. [24] T. Jilling, D. Simon, J. Lu, F.J. Meng, D. Li, R. Schy, et al., The roles of bacteria and TLR4 in rat and murine models of necrotizing enterocolitis, J. Immunol. 177 (2006) 3273–3282. [25] C.P. Sodhi, M.D. Neal, R. Siggers, S. Sho, C. Ma, M.F. Branca, et al., Intestinal epithelial Toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice, Gastroenterology 143 (2012) 708–718, http://dx.doi.org/10. 1053/j.gastro.2012.05.053. [26] A. Soliman, K.S. Mechelsen, H. Karahashi, J. Lu, F.J. Meng, X. Qu, et al., Platelet-activating factor induces TLR4 expression in intestinal epithelial cells: implication for the pathogenesis of necrotizing enterocolitis, PLoS One 5 (2010) e15044. [27] S.C. Gribar, C.P. Sodhi, W.M. Richardson, R.J. Anand, G.K. Gittes, M.F. Branca, et al., Reciprocal expression and signaling of TLR4 and TLR9 in the pathogenesis and treatment of necrotizing enterocolitis, J. Immunol. 182 (2009) 636–646. [28] M. Good, C. Sodhi, R. Siggers, T. Prindle, M. Branca, A. Russo, et al., Epithelial Growth Factor Attenuates the Severity of Experimental Necrotizing Enterocolitis and Inhibits Toll-Like Receptor 4 Signaling in Enterocytes, in: E-PAS2011, 2011, p. 2720.3. [29] P. Gordon, R. Christensen, J.H. Weitkamp, A. Maheshwari, Mapping the new world of necrotizing enterocolitis (NEC): review and opinion, e-J. Neonatol. Res. 2 (2012) 145–172. [30] P.V. Gordon, J.R. Swanson, J.T. Attridge, R. Clark, Emerging trends in acquired neonatal intestinal disease: is it time to abandon Bell’s criteria? J. Perinatol. 27 (2007) 661–671. [31] P.V. Gordon, What progress looks like in NEC research, J. Perinatol. 31 (2011) 149. [32] R.H. Clark, P. Gordon, W.M. Walker, M. Laughon, P.B. Smith, A.R. Spitzer, Characteristics of patients who die of necrotizing enterocolitis, J. Perinatol. 32 (2012) 199–204. [33] S.O. Guthrie, P.V. Gordon, V. Thomas, J.A. Thorp, J. Peabody, R.H. Clark, Necrotizing enterocolitis among neonates in the United States, J. Perinatol. 23 (2003) 278–285. [34] R. González-Rivera, R.C. Culverhouse, A. Hamvas, P.I. Tarr, B.B. Warner, The age of necrotizing enterocolitis onset: an application of Sartwell’s incubation period model, J. Perinatol. 31 (2011) 519–523.
[35] V. Bhandari, M.J. Bizzarro, A. Shetty, X. Zhong, G.P. Page, H. Zhang, et al., Familial and genetic susceptibility to major neonatal morbidities in preterm twins, Pediatrics 117 (2006) 1901–1906. [36] C. Young, R. Sharma, M. Handfield, V. Mai, J. Neu, Biomarkers for infants at risk for necrotizing enterocolitis: clues to prevention? Pediatr. Res. 65 (2009) 91R–97R. [37] V. Sampath, M. Le, L. Lane, A.L. Patel, J.D. Cohen, P.M. Simpson, et al., The NFKB1 (g.-24519delATTG) variant is associated with necrotizing enterocolitis (NEC) in premature infants, J. Surg. Res. 169 (2011) e51–e57. [38] G. Prencipe, C. Azzari, M. Moriondo, R. Devito, M. Pezzullo, et al., Association between mannose-binding lectin gene polymorphisms and necrotizing enterocolitis in preterm infants, J. Pediatr. Gastroenterol. Nutr. 55 (2012) 160–165. [39] E.M. Carlisle, M.J. Morowitz, The intestinal microbiome and necrotizing enterocolitis, Curr. Opin. Pediatr. 25 (2013) 382–387. [40] F. Indrio, J. Neu, The intestinal microbiome of infants and the use of probiotics, Curr. Opin. Pediatr. 23 (2011) 145–150. [41] K. Alfaleh, J. Anabrees, D. Bassler, T. Al-Kharfi, Probiotics for the prevention of necrotizing enterocolitis in preterm infants, Cochrane Database Syst. Rev. 3 (2011) CD005496. [42] C.R. Martin, Probiotics for the prevention of necrotizing enterocolitis: not just which ones but also why? J. Pediatr. Gastroenterol. Nutr. 57 (2013) 3. [43] R.M. Patel, P.W. Denning, Therapeutic use of prebiotics, probiotics, and postbiotics to prevent necrotizing enterocolitis: what is the current evidence, Clin. Pernatol. 40 (2013) 11–25. [44] J.R. Swanson, Necrotizing enterocolitis: is it time for zero tolerance? J. Perinatol. 33 (2013) 1–2. [45] S.M. Gephart, J.M. McGrath, J.A. Effken, M.D. Halpern, Necrotizing enterocolitis risk: state of the science, Adv. Neonatal Care 12 (2012) 77–87. [46] R.M. Torrazza, J. Neu, The altered gut microbiome and necrotizing enterocolitis, Clin. Perinatol. 40 (2013) 93–108. [47] J. Neu, W.A. Walker, Necrotizing enterocolitis, N. Engl. J. Med. 364 (2011) 255–264. [48] R. Singh, P.F. Visintainer, I.D. Frantz, B.L. Shah, K.M. Meyer, S.A. Favila, et al., Association of necrotizing enterocolitis with anemia and packed red blood cell transfusions in preterm infants, J. Perinatol. 31 (2011) 176–182. [49] R.D. Christensen, D.K. Lambert, E. Henry, S.E. Wiedmeier, G.L. Snow, V.L. Baer, et al., Is ‘transfusion-associated necrotizing enterocolitis’ an authentic pathogenic entity? Transfusion (Paris) 50 (2010) 1106–1112. [50] R.D. Christensen, Associations between “early” red blood cell transfusion and severe intraventricular hemorrhage, and between “late” red blood cell transfusion and necrotizing enterocolitis, Semin. Perinatol. 36 (2012) 283–289. [51] E.F. La Gamma, J. Blau, Transfusion-related acute gut injury: feeding, flora, flow, and barrier defense, Semin. Perinatol. 36 (2012) 294–305. [52] S.C. Amin, J.L. Remon, G.C. Subbarao, A. Maheshwari, Association between red cell transfusions and necrotizing enterocolitis, J. Matern. Fetal Neonatal Med. 25 (2012) 85–89. [53] A.B. Hair, J.R. Swanson, J.T. Attridge, Lymphocytosis at necrotizing enterocolitis presentation is associated with higher mortality, increased feeding volumes and more formula exposure in an 11 year, single center retrospective study, e-J. Neonatal Res. 2 (2011) 37–43. [54] P.V. Gordon, S. Thibeau, C. Pennier, H. Ginsberg, V. Lunyong, M. Cortez, et al., Is lymphocytosis an adjunct predictor of NEC mortality in low gestation infants? e-J. Neonatal Res. 2 (2012) 29–36. [55] J. Meinzen-Derr, A.L. Morrow, R.W. Hornung, E.F. Donovan, K.N. Dietrich, P.A. Succop, Epidemiology of necrotizing enterocolitis temporal clustering in two neonatology practices, J. Pediatr. 154 (2009) 656–661. [56] R.D. Christensen, D.K. Lambert, P.V. Gordon, V.L. Baer, E. Gerday, E. Henry, Neonates presenting with bloody stools and eosinophilia can progress to two different types of necrotizing enterocolitis, J. Perinatol. 32 (2012) 874–879.
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
PATPHY-799; No. of Pages 7
ARTICLE IN PRESS P.V. Gordon, J.R. Swanson / Pathophysiology xxx (2013) xxx–xxx
[57] P. Srinivasan, M. Brandler, A. D’Souza, P. Millman, H. Moreau, Allergic enterocolitis presenting as recurrent necrotizing enterocolitis in preterm neonates, J. Perinatol. 30 (2010) 431–433. [58] J. Benjamin, E. Chong, J. Reynolds, P.V. Gordon, Detailed analysis of NEC risks across a decade in a low incidence NICU: can we drive the incidence of NEC toward zero? e-J. Neonatol. Res. 2 (2012) 181–189. [59] R. Sharma, R.D. Garrison, D. Tepas, D.L. Mollitt, P. Pieper, M.L. Hudak, et al., Rotavirus-associated necrotizing enterocolitis: an insight
7
into a potentially preventable disease? J. Pediatr. Surg. 39 (2004) 453–457. [60] A.I. Stritzke, J. Smyth, A. Synnes, S.K. Lee, P.S. Shah, Transfusionassociated necrotizing enterocolitis in neonates, Arch. Dis. Child. Fetal Neonatal Ed. 98 (2013) F10–F14. [61] S.A. Lorch, P. Maheshwari, O. Even-Shoshan, The impact of certificate of need programs on neonatal intensive care units, J. Perinatol. 32 (2012) 39–44.
Please cite this article in press as: P.V. Gordon, J.R. Swanson, Necrotizing enterocolitis is one disease with many origins and potential means of prevention, Pathophysiology (2013), http://dx.doi.org/10.1016/j.pathophys.2013.11.015
