Seminars in Fetal & Neonatal Medicine xxx (2013) 1e6
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Necrotizing enterocolitis: The road to zero Jae H. Kim* Divisions of Neonatology & Pediatric Gastroenterology, Hepatology and Nutrition, University of California San Diego, Rady Children’s Hospital of San Diego, 200 West Arbor Dr MPF 1140, San Diego, CA 92103-8774, USA
s u m m a r y Keywords: Necrotizing enterocolitis Neonate Prevention Strategies
Necrotizing enterocolitis (NEC) continues to be the most severe gastrointestinal emergency facing the preterm neonate. The pathogenesis of NEC is still a complex and poorly understood process, but with increasing understanding of the role of enteral feeding, gut immunity and the altered gut microbiota, new opportunities to reduce overall NEC rates are now possible. Prevention strategies continue to lead as the most suitable approaches to reducing NEC, as early diagnosis and rapid effective treatment of NEC are still not optimal. Programmatic changes are equally important as subscribing to individual prevention strategies. The primary focus of this review is to summarize the best strategies we currently have to eliminate NEC within an institution. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction The pathogenesis of NEC has been postulated as the ‘perfect storm’ of several strongly associated factors: immaturity, ischemia, altered gut microflora, and type of enteral feeding [1e6]. The pathologic insult that ensues is a breakdown of the gut barrier and the development of discontinuous to continuous transmural inflammation of small and/or large intestines resulting in severe tissue damage. There is evidence to support that this results from an exaggerated immunologic or inflammatory response in the host [7,8]. The dramatic inflammatory reactions may be escalated by the altered expression of surface receptors such as Toll-like receptor-4 (TLR-4) that is much greater than at later ages [9]. A role for a gestational age window of susceptibility to dysregulated inflammation in the timing of NEC may be present, as NEC occurs after several weeks of age in the smallest preterm infants compared to the first week for older preterm infants [10]. An alternative explanation is that NEC tends to peak when feeds are near maximum and younger gestation infants typically take several weeks to attain that goal. One of the ongoing challenges that still remain is in diagnosing NEC correctly. There are several bowel conditions that have been misclassified as NEC in the past. One of the most important distinctions for clinicians to separate is spontaneous intestinal perforation (SIP) from NEC. These two conditions share some overlap but follow very different pathophysiologies particularly with regards to the degree of inflammation [11,12]. A recent approach has tried to
* Tel.: þ1 619 543 3759; fax: þ1 619 543 3812. E-mail address: [email protected].
reclassify true NEC from NEC-like conditions [13]. The modified Bell’s Staging criteria have helped define many cases of clinical NEC in the past but do not have the resolution to separate these newly defined NEC-like conditions. Some specific variants of NEC are worth noting. Significant progress has been made in defining a newer form of NEC, transfusion-related acute gut injury (TRAGI), which represents a subset of NEC cases that tend to be more serious than the average NEC case [14,15]. Another type of NEC that may fall under different pathophysiologic mechanisms is catastrophic NEC or NEC totalis, a more fulminant form of NEC that almost always leads to death [16,17]. Finally, term infants with NEC often are subject to prolonged periods of hypoperfusion or asphyxia as seen in neonates with cardiac disease, growth restriction, or hypoxiceischemic encephalopathy [18e20].
1.1. Vulnerabilities of being immature The development of NEC is primarily a disease of the very low birth weight preterm infant. The preterm infant has numerous intestinal vulnerabilities that permit opportunities for microbial pathogens to invade and damage tissue and cause severe morbidity and mortality (Box 1). Clinical risk factors for NEC may include prematurity, birth weight, intrapartum antibiotics, maternal age, and indomethacin treatment for patent ductus arteriosus [21]. Mortality of NEC continues to remain high with reports between 15% and 30% [6]. Survivors of NEC can face long-term morbidities including short bowel syndrome and/or intestinal failure, growth impairment and poor neurodevelopmental outcome. The neurodevelopmental impairments are comparable to those seen as
1744-165X/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.siny.2013.10.001
Please cite this article in press as: Kim JH, Necrotizing enterocolitis: The road to zero, Seminars in Fetal & Neonatal Medicine (2013), http:// dx.doi.org/10.1016/j.siny.2013.10.001
2
J.H. Kim / Seminars in Fetal & Neonatal Medicine xxx (2013) 1e6
Box 1 Preterm gut risks for necrotizing enterocolitis.
Dysmotility Abnormal microbiota Decreased mucin barrier Increased gut permeability Reduced immunoglobulins and gut immunity Increased risk to ischemia Slow gastric emptying
sequelae of meningitis [22e24]. Some data suggest that there are no significant differences seen between survivors of NEC or SIP [25]. Surgical NEC compared to medical NEC is associated with greater morbidity [26,27]. Not surprisingly, cytokine levels are found to be high in neonates with NEC and may be one reason for the poor neurodevelopmental outcomes [28]. Neuroimaging correlations with NEC have identified predominant white matter injury to the brain [29]. 1.2. Economic impact of NEC There is now sufficient evidence to make a strong economic argument that all extremely premature infants exclusively receive human milk as their base nutrition. These studies have demonstrated that with current data, and an average NEC rate in the neonatal intensive care unit (NICU), significant cost savings are appreciated by treating all infants
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Necrotizing enterocolitis: The road to zero Jae H. Kim* Divisions of Neonatology & Pediatric Gastroenterology, Hepatology and Nutrition, University of California San Diego, Rady Children’s Hospital of San Diego, 200 West Arbor Dr MPF 1140, San Diego, CA 92103-8774, USA
s u m m a r y Keywords: Necrotizing enterocolitis Neonate Prevention Strategies
Necrotizing enterocolitis (NEC) continues to be the most severe gastrointestinal emergency facing the preterm neonate. The pathogenesis of NEC is still a complex and poorly understood process, but with increasing understanding of the role of enteral feeding, gut immunity and the altered gut microbiota, new opportunities to reduce overall NEC rates are now possible. Prevention strategies continue to lead as the most suitable approaches to reducing NEC, as early diagnosis and rapid effective treatment of NEC are still not optimal. Programmatic changes are equally important as subscribing to individual prevention strategies. The primary focus of this review is to summarize the best strategies we currently have to eliminate NEC within an institution. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction The pathogenesis of NEC has been postulated as the ‘perfect storm’ of several strongly associated factors: immaturity, ischemia, altered gut microflora, and type of enteral feeding [1e6]. The pathologic insult that ensues is a breakdown of the gut barrier and the development of discontinuous to continuous transmural inflammation of small and/or large intestines resulting in severe tissue damage. There is evidence to support that this results from an exaggerated immunologic or inflammatory response in the host [7,8]. The dramatic inflammatory reactions may be escalated by the altered expression of surface receptors such as Toll-like receptor-4 (TLR-4) that is much greater than at later ages [9]. A role for a gestational age window of susceptibility to dysregulated inflammation in the timing of NEC may be present, as NEC occurs after several weeks of age in the smallest preterm infants compared to the first week for older preterm infants [10]. An alternative explanation is that NEC tends to peak when feeds are near maximum and younger gestation infants typically take several weeks to attain that goal. One of the ongoing challenges that still remain is in diagnosing NEC correctly. There are several bowel conditions that have been misclassified as NEC in the past. One of the most important distinctions for clinicians to separate is spontaneous intestinal perforation (SIP) from NEC. These two conditions share some overlap but follow very different pathophysiologies particularly with regards to the degree of inflammation [11,12]. A recent approach has tried to
* Tel.: þ1 619 543 3759; fax: þ1 619 543 3812. E-mail address: [email protected].
reclassify true NEC from NEC-like conditions [13]. The modified Bell’s Staging criteria have helped define many cases of clinical NEC in the past but do not have the resolution to separate these newly defined NEC-like conditions. Some specific variants of NEC are worth noting. Significant progress has been made in defining a newer form of NEC, transfusion-related acute gut injury (TRAGI), which represents a subset of NEC cases that tend to be more serious than the average NEC case [14,15]. Another type of NEC that may fall under different pathophysiologic mechanisms is catastrophic NEC or NEC totalis, a more fulminant form of NEC that almost always leads to death [16,17]. Finally, term infants with NEC often are subject to prolonged periods of hypoperfusion or asphyxia as seen in neonates with cardiac disease, growth restriction, or hypoxiceischemic encephalopathy [18e20].
1.1. Vulnerabilities of being immature The development of NEC is primarily a disease of the very low birth weight preterm infant. The preterm infant has numerous intestinal vulnerabilities that permit opportunities for microbial pathogens to invade and damage tissue and cause severe morbidity and mortality (Box 1). Clinical risk factors for NEC may include prematurity, birth weight, intrapartum antibiotics, maternal age, and indomethacin treatment for patent ductus arteriosus [21]. Mortality of NEC continues to remain high with reports between 15% and 30% [6]. Survivors of NEC can face long-term morbidities including short bowel syndrome and/or intestinal failure, growth impairment and poor neurodevelopmental outcome. The neurodevelopmental impairments are comparable to those seen as
1744-165X/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.siny.2013.10.001
Please cite this article in press as: Kim JH, Necrotizing enterocolitis: The road to zero, Seminars in Fetal & Neonatal Medicine (2013), http:// dx.doi.org/10.1016/j.siny.2013.10.001
2
J.H. Kim / Seminars in Fetal & Neonatal Medicine xxx (2013) 1e6
Box 1 Preterm gut risks for necrotizing enterocolitis.
Dysmotility Abnormal microbiota Decreased mucin barrier Increased gut permeability Reduced immunoglobulins and gut immunity Increased risk to ischemia Slow gastric emptying
sequelae of meningitis [22e24]. Some data suggest that there are no significant differences seen between survivors of NEC or SIP [25]. Surgical NEC compared to medical NEC is associated with greater morbidity [26,27]. Not surprisingly, cytokine levels are found to be high in neonates with NEC and may be one reason for the poor neurodevelopmental outcomes [28]. Neuroimaging correlations with NEC have identified predominant white matter injury to the brain [29]. 1.2. Economic impact of NEC There is now sufficient evidence to make a strong economic argument that all extremely premature infants exclusively receive human milk as their base nutrition. These studies have demonstrated that with current data, and an average NEC rate in the neonatal intensive care unit (NICU), significant cost savings are appreciated by treating all infants
