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nutrients
Review
Nutrition in Necrotizing Enterocolitis and Following
Intestinal Resection
Jocelyn Ou 1, †, Cathleen M. Courtney 2, †, Allie E. Steinberger 2, Maria E. Tecos 2
and Brad W. Warner 2, *
1Department of Pediatrics, Division of Newborn Medicine, Washington University School of Medicine,
St. Louis, MO 63110, USA; jocelyn.ou@wustl.edu
2Department of Surgery, Division of Pediatric Surgery, Washington University School of Medicine,
St. Louis, MO 63110, USA; c.courtney@wustl.edu (C.M.C.); allie.steinberger@wustl.edu (A.E.S.);
metecos@wustl.edu (M.E.T.)
*Correspondence: brad.warner@wustl.edu; Tel.: 314-454-6022
†These authors contributed equally to this work.
Received: 16 January 2020; Accepted: 14 February 2020; Published: 18 February 2020
Abstract:
This review aims to discuss the role of nutrition and feeding practices in necrotizing
enterocolitis (NEC), NEC prevention, and its complications, including surgical treatment. A thorough
PubMed search was performed with a focus on meta-analyses and randomized controlled trials
when available. There are several variables in nutrition and the feeding of preterm infants with
the intention of preventing necrotizing enterocolitis (NEC). Starting feeds later rather than earlier,
advancing feeds slowly and continuous feeds have not been shown to prevent NEC and breast milk
remains the only effective prevention strategy. The lack of medical treatment options for NEC often
leads to disease progression requiring surgical resection. Following resection, intestinal adaptation
occurs, during which villi lengthen and crypts deepen to increase the functional capacity of remaining
bowel. The effect of macronutrients on intestinal adaptation has been extensively studied in animal
models. Clinically, the length and portion of intestine that is resected may lead to patients requiring
parenteral nutrition, which is also reviewed here. There remain significant gaps in knowledge
surrounding many of the nutritional aspects of NEC and more research is needed to determine
optimal feeding approaches to prevent NEC, particularly in infants younger than 28 weeks and
<1000 grams. Additional research is also needed to identify biomarkers reflecting intestinal recovery
following NEC diagnosis individualize when feedings should be safely resumed for each patient.
Keywords:
necrotizing enterocolitis; prematurity; intestinal resection; short bowel syndrome;
intestinal adaptation; microbiome; parenteral nutrition; hormones; breast milk
1. Introduction
Necrotizing enterocolitis (NEC) remains one of the most devastating diagnoses in premature
neonates. Although its incidence varies amongst different neonatal intensive care units, the mean
prevalence of NEC is 7% in infants between 500–1500 grams and the disease has a high morbidity and
mortality [
1
]. The exact pathophysiology of NEC is unknown, but the immature intestinal barrier and
intestinal dysbiosis are two important factors that likely contribute to intestinal inflammation and injury
seen in the disease [
1
,
2
]. Because of its nonspecific symptoms, NEC is difficult to diagnose. Currently,
Bell’s staging, first introduced in 1978 by Bell et al. and modified by Kligeman and Walsh in 1986,
is widely used to stratify disease severity and guide treatment (Figure 1). For Bell’s stage 1 (suspected,
but not confirmed NEC) and Bell’s stage 2 (confirmed pneumatosis intestinalis with or without portal
venous gas) [
2
], parenteral nutrition (PN) and broad-spectrum antibiotics are initiated, and enteral
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Nutrients 2020,12, 520 2 of 16
feeds are held for 7–14 days. Because the management of disease in these stages is non-operative,
Bell’s stage 1 and Bell’s stage 2 are also known as “medical NEC.” If disease progresses despite
holding feeds and starting antibiotics, surgery is required in Bell’s stage 3, which is characterized
by hemodynamic instability in addition to severe thrombocytopenia, disseminated intravascular
coagulopathy, and peritonitis (IIA) or pneumoperitoneum (IIB) [
2
,
3
]. Surgical NEC increases disease
mortality from 3% to 30% [
4
]. Not infrequently, the length of bowel needed to be removed can be
significant, resulting in short bowel syndrome.
On a cellular level, intestinal adaptation occurs after massive bowel resection as a compensatory
response by the remnant bowel wherein villi elongate, crypts deepen, and enterocyte proliferation
is enhanced. Together, these changes function to increase the functional absorptive capacity per
unit length of the remnant bowel [
5
]. This review aims to summarize the role of nutrition in NEC,
including its prevention, complications, and sequelae of surgical treatment. A thorough PubMed search
was performed using search terms that included “preterm enteral feeding”, “early enteral feeding”,
“feeding necrotizing enterocolitis”, “intestinal adaptation”, “intestinal adaptation macronutrients”
and “parenteral nutrition necrotizing enterocolitis.” Meta-analyses and randomized controlled trials
were reviewed on these topics when available; otherwise, pre-clinical animal trials were reviewed.
We included studies pertaining to nutrition in NEC, specifically those examining feeding comparisons
in which NEC was a primary or secondary outcome. Reports not focused on NEC as a primary or
secondary outcome or those discussing NEC without a clear definition were excluded.
2. NEC Prevention
2.1. Delivery of Feeds
2.1.1. Initiation of Feeds
Historically, it was thought that delaying enteral feeds would decrease the incidence of NEC.
However, a 2013 Cochrane review found that there was no increased incidence of NEC when beginning
trophic feeds early (within 96 hours of birth) and continuing them for a week compared to fasting
and starting feeds at 7 or more days of life in very preterm (<32 weeks) or very low birthweight
(<1500 grams) infants [
6
]. Starting enteral nutrition early also was not protective against NEC in this
population. Initiating enteral feeds early appears to be safe for preterm and very low birthweight infants
and beginning feeds at a higher volume may also be beneficial. A 2019 meta-analysis conducted by
Alshaikh, et al. compared the safety of starting total enteral feeds at 80 ml/kg/d to starting enteral feeds
at the conventional volume of 20 ml/kg/d. There was no difference in the incidence of NEC or feeding
intolerance when starting early total enteral feeds, with the added benefit of decreased late-onset sepsis
and decreased length of hospital stay by 1.3 days [
7
]. However, the conclusions that can be drawn
from this meta-analysis for infants <1000 g and <28 weeks are limited, as the studies included in the
analysis included infants between 28–36 weeks’ gestational age and between
1000–1500 g.
In a 2019
randomized controlled trial, Nangia, et al. compared starting very low birthweight infants between
28–34 weeks’ gestational age on total enteral feeds (80 ml/kg/day) on the first day of life to starting
infants at the conventional enteral feeding volume (20 ml/kg/day) supplemented with intravenous
fluids. The study found no difference in the incidence of NEC between the two groups, with 1.1%
in the early total enteral feeding group compared to 5.8% in the conventional enteral feeding group
(p=0.12). However, infants in the early total enteral feeding group reached goal feeds on average
of 3.6 days sooner. This group also had fewer complications such as sepsis or feeding intolerance,
and ultimately had shorter lengths of stay [8].
Nutrients 2020,12, 520 3 of 16
Figure 1.
Summary of the Pathophysiology, Treatment Strategies, and Unknowns of Necrotizing
Enterocolitis. The pathophysiology of NEC is multi-faceted, involving intestinal barrier dysfunction,
decreased IgA, and altered microbiota. Current treatment strategies include stopping feeds and starting
antibiotics based on disease severity, as classified by Bell’s staging. Much remains unknown about
disease prevention, diagnosis, and treatment. Figure created with Biorender.com. Abbreviations:
Immunoglobulin A (IgA), NEC (Necrotizing enterocolitis), NPO (nil per os).
2.1.2. Feeding Advancement
Once feeds are successfully initiated and tolerated, the next consideration is the rate of feed
advancement. Although there is significant variation in advancement protocols amongst different
neonatal intensive care units, feeds are typically increased by 15–35 ml/kg each day, depending on
infant size. Dorling, et al. conducted a randomized controlled trial comparing slow (18 ml/kg/day)
and rapid (30 ml/kg/day) feed advancement that showed no significant difference in survival without
moderate or severe neurologic deficits at 24 months in very preterm (<32 weeks) and very low birth
weight infants [
9
]. Rapid advancement of feeds also did not increase the incidence of NEC when
compared to slow advancement. Advancing feeds more rapidly and thus allowing infants to reach full
feeds sooner may lead to increased caloric intake and better growth, as well as decreased duration of
parenteral nutrition.
2.1.3. Bolus and Continuous Feeding
Bolus feeding has the advantage of gut stimulation, which promotes normal functioning and tissue
maturation. Conversely, continuous feeding provides an opportunity for slow and steady nutrient
introduction, which may allow for better tolerance and absorption in the setting of less distension and
diarrhea [
10
,
11
]. In a recent meta-analysis, Wang, et al. found that although there was no difference
in growth parameters or length of hospitalization, bolus-fed preterm (<37 weeks’ gestational age),
low birthweight (<2500 grams) infants reached feeds sooner (mean difference 0.98 days) with a similar
incidence of NEC compared to infants receiving continuous feeds [
12
]. This meta-analysis includes
infants up to 2500 grams, but found no differences in subgroup analysis of infants with birthweight
<1000 grams and >1000 grams.
Randomized controlled trials have disproven previous observational data that delaying the
initiation of feeds, starting at a smaller volume, and advancing feeds slowly may decrease the incidence
of NEC. Evidence remains limited in extremely preterm and extremely low birthweight infants;
Nutrients 2020,12, 520 4 of 16
a feasible approach to feeding preterm infants may be initiating feeds as soon as an infant is clinically
stable and advancing by 30 ml/kg/day as tolerated. For very low birthweight infants, starting feeds
within 96 hours of birth and advancing at 30 ml/kg/day have both been shown to be safe and allow
infants to reach full feeds sooner. However, despite decreasing the number of days infants require
parenteral nutrition, advancing feeds faster does not decrease the incidence of late-onset sepsis and in
general, the benefit of reaching full feeds faster may be limited. The most beneficial approach may
be for each neonatal intensive care unit to standardize their feeding protocols and ensure that are
consistently followed.
2.2. Composition of Feeds
2.2.1. Osmolality
Human breast milk has an osmolality of around 300 mOsm/l, whereas commercially available
enteral formulas have osmolalities of less than 450 mOsm/l [
13
]. In order to meet a preterm infant’s
nutritional and growth requirements, both breast milk and infant formulas require caloric fortification
and supplements, thereby increasing osmolarity. Multi-nutrient fortification adds protein, vitamins,
and other minerals and increases the osmolality of breast milk to 400 mOsm/l [
13
]. Historically,
administration of hyperosmolar formula was thought to be associated with an increased risk for the
development of necrotizing enterocolitis (NEC). This was based on a handful of small-scale studies in
the 1970s, all of which failed to provide a durable mechanism of mucosal injury [
14
,
15
]. More recently,
Miyake, et al. looked at hyperosmolar enteral formula compared to diluted formula in a mouse model
of NEC. They found that the inflammatory response, mucosal injury, and incidence of NEC was the
same in both experimental groups [
16
]. In other animal studies, the only reported adverse outcome
associated with hyperosmolar feeds was delayed gastric emptying [
13
]. Lastly, in humans, a 2016
Cochrane review concluded that there is weak evidence showing that nutrient fortification does not
increase the incidence of NEC in preterm infants. It does increase in-hospital growth rate (weight
1.81 g/kg/day, length 0.12 cm/week, head circumference 0.08 cm/week), but does not seem to improve
long-term growth and development [
17
]. Because in-hospital growth rates are improved and the
incidence of NEC is not increased with hyperosmolar feeds, the benefit of additional nutrients and
other supplements warrants fortification of human breast milk. The data on the effect of fortification
on neurodevelopment and growth beyond infancy is very limited and needs to be studied further.
2.2.2. Breast Milk
Human milk is the only modifiable risk factor that has been consistently shown to protect against
the development of NEC [
18
,
19
]. Since the 1990s, the incidence of NEC has been described as 6–10 times
higher in exclusively formula-fed infants compared to exclusively breastfed infants [20]. The specific
mechanisms by which breast milk is protective continue to be studied. However, several non-nutrient
components have been found to contribute to the immune functions of the gastrointestinal tract and
augment mucosal integrity [
21
,
22
]. These include secretory IgA, growth hormones (epidermal growth
factor, insulin, and insulin-like growth factor), polyunsaturated fatty acids, and oligosaccharides.
A 2019 study found that not only is an infant’s IgA largely derived from maternal milk in the first
month of life, but also that infants with NEC have larger proportions of IgA-unbound bacteria
compared to age-matched controls. In the same study, Gopalakrishna, et al. used a murine model
and concluded that pups reared by IgA-deficient mothers were not protected from NEC [
23
]. It
has also been hypothesized that the beneficial effects of human milk relate to how diet affects gut
microbiota and the developing immune system. Human breast milk contains oligosaccharides known
to stimulate “healthy” bacteria and in a murine model, has been shown to downregulate bacterial
related inflammatory signaling pathways [24].
Nutrients 2020,12, 520 5 of 16
2.2.3. Donor Breast Milk
Although mother’s own milk is preferred for preterm and low birth weight infants, infants often
need to be supplemented with donor breast milk or formula when maternal supply is inadequate.
Donor milk has also been shown to have a protective effect on NEC incidence when compared to
cow’s milk and other formulas, with a 79% reduced risk [
25
–
28
]. A 2019 Cochrane Database review of
12 trials found that although formula-fed or supplemented preterm and low birth weight infants did
have increased growth compared to those fed with donor breast milk, they also exhibited a higher risk
of NEC (typical risk ratio 1.87) [29].
2.2.4. Cow’s Milk Formula
Prior literature has established a higher incidence of NEC when cow’s milk formula is used
instead of mother’s own milk [
25
,
30
]. In addition to the protective factors that breast milk contains,
it’s been hypothesized that the intestinal reaction to cow’s milk proteins could also contribute to disease
pathogenesis. In small cohorts of infants with NEC, a group has found an increase in cytokine response
(interferon-
γ
, IL-4, and IL-5) to cow’s milk proteins beta-lactoglobulin and casein [
31
]. Interestingly,
bovine milk-derived exosomes have been shown to combat experimentally induced NEC by stimulating
goblet cells and mitigating decreases in mucin 2 (MUC2) and glucose regulated protein 94 (GRP94).
Isolation and administration of such exosomes could be useful for infants at high risk for NEC for
whom breast milk cannot be obtained [32].
3. Medical NEC
Symptoms seen in the early stages of NEC may mimic feeding intolerance or other abdominal
pathologies. The modified Bell’s staging criteria include neutropenia, thrombocytopenia, coagulation
factors, and metabolic acidosis as laboratory markers that can aid clinicians in diagnosing more
advanced NEC [
3
]. However, these laboratory values are non-specific and are less likely to be
reliable markers for disease in early stages or to predict intestinal recovery and safety to restart feeds.
In addition to antibiotics, current nutritional management for NEC includes stopping feeds and starting
parenteral nutrition.
3.1. NPO Duration
Patients’ nil per os (NPO) status is largely driven by clinical assessment. Decreased apneic
and bradycardic events in conjunction with laboratory values including blood gas, white count,
and thrombocytopenia, as well as abdominal imaging without the appearance of portal venous
gas or pneumatosis intestinalis are indications of improving clinical status [
33
]. Despite apparent
improvement in clinical status, clinicians may hesitate to restart feeds after an NPO period, as objective
evidence reflecting the optimal time to begin feeding is lacking. A meta-analysis conducted by Hock,
et al. found no significant difference in adverse outcomes in patients given early (within 5 days of NEC
diagnosis) and late (>5 days after NEC diagnosis) feeds [
34
]. Bonhorst, et al. utilized ultrasonography
and compared outcomes following restarting feeding after 3 consecutive days without portal venous
gas to restarting feeding after 10 days without portal venous gas. Earlier feeds were associated with
fewer complications, shorter antibiotic courses, quicker progression to goal feeds, and shorter length
of stay [35].
In addition to using imaging as an objective measure for readiness and safety to restart feeds,
specific laboratory values and biomarkers would be useful. In a 2019 prospective observational
cohort study, Kuik, et al. measured the regional intestinal oxygen saturation (r
int
SO
2
) by near-infrared
spectroscopy (NIRS) and intestinal fatty acid binding protein (I-FABP
u
) in the urine of 27 preterm
infants. The study found that when measured after the first re-feed, these markers were predictive of
post-NEC stricture, though not of recurrent NEC [
36
]. Additionally, a recent study on infants between
24–40 weeks postmenstrual age found high intestinal alkaline phosphatase (IAP) in stool and low
Nutrients 2020,12, 520 6 of 16
IAP enzyme activity in patients with NEC compared to those without disease; IAP also was a useful
biomarker for disease severity [
37
]. Clinicians should attempt to minimize NPO time and begin
refeeding patients as soon as clinical improvement is determined by vital sign stability and abdominal
examination, as well as resolving thrombocytopenia and abdominal radiography or ultrasonography.
Identifying biomarkers such as IAP that reflect a patient’s disease severity and intestinal recovery
could be useful in individualizing NPO duration to minimize complications associated with prolonged
NPO status.
3.2. Parenteral Nutrition
PN is initiated in patients who are made NPO following NEC diagnosis. It is comprised of
carbohydrates, amino acids, lipids, electrolytes, minerals, and vitamins administered intravenously to
allow for bowel rest. PN should be started early with adequate protein (3.5–4 g/kg/day) to maintain
a positive nitrogen balance, improve weight gain, and to allow repair of injured tissue [
1
,
38
–
40
].
However, it has been shown that supplemental PN at NEC onset does not appear to significantly
improve outcomes, with no decrease in the rate of surgical intervention or in-hospital mortality [
41
].
PN is discontinued once enteral feedings approach goal volumes [42].
4. Surgical NEC
In cases of NEC refractory to medical management or NEC leading to intestinal perforation,
surgery is indicated (i.e., “surgical NEC”). A complication of NEC following extensive intestinal
resection is short bowel syndrome (SBS) and subsequent intestinal failure (IF) wherein the small
bowel is unable to adequately absorb fluids, electrolytes, and nutrients required to support growth
and development [
43
]. Nutrition therefore must be provided through parenteral nutrition. The key
compensatory process involved in reaching enteral autonomy is intestinal adaptation. Adaptation is
characterized by structural and functional changes that compensate for the loss of intestinal mucosal
surface area [
44
] and involves an increase in villus height and crypt depth, myocyte and enterocyte
proliferation, a decrease in enterocyte apoptosis, and elongation and dilatation of the remnant small
bowel [
45
]. Therefore, post-operative nutrition strategies focused on enhancing the intestinal adaptive
response remain a cornerstone of treatment. Factors known to play important roles in adaptation
and enteral autonomy include length of remnant bowel, specific macronutrients, and the composition
of PN.
4.1. Enteral Feeding
While the optimal enteral formulation for pediatric SBS is still unknown, the data consistently
supports the benefit of breast milk in intestinal adaptation [
46
]. In addition to growth factors and
immunoglobulins, breast milk contains key oligosaccharides that act in a prebiotic manner to stimulate
enterocyte proliferation and positively regulate the intestinal microbiome [
47
]. The most abundant
of these is 2’-fucosyllactose (2’-FL). A few preclinical studies have investigated the effects of 2’-FL
enteral supplementation on various intestinal inflammatory diseases. Mezoff, et al. demonstrated
that 2’-FL augments intestinal adaptation after ileocecal resection by optimizing energy processing
by the gut microbiome [
48
]. Another group showed that 2’-FL significantly decreased the severity of
colitis in interleukin-10 null mice through enhanced epithelial integrity and expansion of a positive gut
microbial environment [47].
4.2. Anatomical Considerations
4.2.1. Intestinal Length
Following surgical NEC, remnant length and anatomy become major determinants of disease
severity [
49
]. It is well demonstrated that residual intestinal length is inversely proportional both to
duration of PN and mortality [
50
–
52
]. While there is no definitive threshold, data suggests that greater
Nutrients 2020,12, 520 7 of 16
than 40 cm of remnant small bowel length (SBL) in the presence or absence of an ileocecal valve (ICV)
is associated with improved outcomes [
50
]. The effect of an intact ICV is somewhat controversial and
likely a surrogate for the presence of colonic mucosa. This may be more important in patients with less
than 15 cm [
53
]. Quiros-Tejeira, et al. showed that both survival and enteral adaptation were increased
when more than 38 cm of small bowel length remained [
50
]. Lastly, Goulet, et al. analyzed 87 SBS
children based on PN weaning and reported that all patients in the PN-dependent group had less than
40 cm of SBL and/or absent ICV. Conversely, patients with persistent enteral independence had SBL of
57 +/
−
19 cm [
51
]. Given the rapid intestinal elongation that normally occurs in late gestation, studies
have recommended using the percentage of expected length as opposed to absolute remnant length
in neonates. By this metric, Spencer, et al. found that greater than 10% age-adjusted remnant bowel
length was highly predictive of both survival and enteral autonomy [52].
4.2.2. Segment Functionality
Given the segmental functionality of the gastrointestinal tract, the site of bowel resection has
a substantial impact on the need for long-term nutritional support [
54
]. The three most common
resection patterns in SBS are jejunoileal anastomosis, jejunocolic anastomosis, and jejunostomy.
These anatomical permutations are associated with a predictable range of outcomes based on digestive
and absorptive capacity.
Patients with jejunoileal anastomoses (mostly jejenum removed) have the highest likelihood of
achieving enteral autonomy. This proximal resection spares the ileum, which has the greatest capacity
for structural and functional adaptation [
55
]. In addition, the presence of the ileocecal valve and colonic
continuity may mitigate intestinal transit time and excessive fluid losses [
54
]. Despite the intestinal
adaptive capacity of patients with jejunoileal anastamoses, this population still experiences gastric
hypersecretion secondary to loss of regulatory humoral action (cholecystokinin, secretin, vasoactive
intestinal peptide, and serotonin) in the jejunum. This can transiently affect intestinal motility and
increase gastric emptying and acid output. Administration of H
2
antagonists and proton pump
inhibitors may be helpful [56].
Patients with jejunocolic anastomoses (mostly ileum removed) are often more difficult to manage,
as the jejunum lacks the robust adaptive capacity of the distal small bowel [
56
]. Decreased water
absorption along the proximal remnant length overwhelms the compensatory abilities of the colon,
leading to fluid and electrolyte losses through diarrhea [
54
]. Furthermore, the ileum is the primary
site of vitamin B12 and bile salt absorption. Consequent disruptions of the enterohepatic circulation
result in fat malabsorption, steatorrhea, marked vitamin deficiencies, and renal oxalate stones [
56
].
Lastly, ileal resection can impact local hormonal control of gut motility through dysregulation of
enteroglucagon and peptide YY [
54
]. As discussed above, loss of the ICV may be a negative predictor of
long-term enteral autonomy. The ICV may play a role in the prevention of colonic bacterial migration
into a small bowel environment that is vulnerable to bacterial overgrowth [
57
]. Ileocolic resections will
result in variable PN dependence, which is higher when less than 60 cm of proximal SBL remains [
54
].
End jejunostomy patients have the most severe malabsorptive phenotype and the highest likelihood
of requiring long-term parenteral support [
55
]. In addition to the specific issues encountered with
ileal resections, this population also lacks any of the absorptive, digestive and energy-salvaging
compensation afforded by colonic continuity [
54
]. Accelerated rates of gastric emptying and intestinal
transit due to changes in the intestinal hormonal milieu further minimize nutrient interaction with jejunal
luminal mucosa. Net losses of fluid and electrolytes from high enterostomy output often exceed patient
intake, necessitating supplementation with PN and intravenous fluid administration [
56
]. These patients
must be carefully monitored for dehydration, metabolic disturbances and nutrient deficiencies.
4.3. Ostomy Replacement
Fluid and electrolyte losses are significant problems in the pediatric SBS population and require
diligent monitoring and repletion. This is especially true for children with small bowel ostomies.
Nutrients 2020,12, 520 8 of 16
The degree of malabsorption, dehydration and metabolic disturbances are commensurate to the length
of small intestine remaining and the site of resection [
58
]. While an adaptive compensatory response is
seen in patients with ileostomies, there is little evidence of structural or functional adaptation in those
with jejunostomies. Despite optimized nutritional management and fluid balance, these patients are
likely to require prolonged PN [
58
]. Furthermore, if less than 75 cm of small bowel remains in the
presence of a jejunostomy, the ability to wean from parenteral nutritional or saline support is significantly
impaired [
58
]. Patients with SBS and enterostomies tend to lose considerable amounts of sodium
in stool causing secondary hyperaldosteronemia and significant potassium losses in the urine [
59
].
This often requires separate parenteral saline repletion in addition to the sodium provided from PN in
amounts up to 8–10 mEq/kg/day [
59
]. Ostomy output and electrolytes should be closely observed to
maintain hydration with urine output of at least 1–2 ml/kg/day and urine sodium >30 mEq/L [59].
High ostomy output is generally defined as greater than 40 ml/kg per 24 hours, with the severity
of losses highly dependent on the length and site of remaining bowel. Provision of adequate fluids
to prevent and treat dehydration is tantamount in this population, as the risk of hypotension and
pre-renal failure are high [
58
]. Fluid needs are typically delivered through a combination of PN and
EN, but may require supplemental intravenous fluids in cases of excessive loss [49].
4.4. Macronutrients
4.4.1. Fat
Several preclinical studies have shown that lipids in particular are associated with an enhanced
adaptation response. Rats fed high fat diets (HFD) had significantly increased bowel weight and villus
height post-resection when compared to those fed standard chow [
60
]. Choi, et al. randomized mice to
low (12% kcal fat), medium (44% kcal fat) and high (71% kcal fat) fat diets after 50% proximal small
bowel resection (SBR) and demonstrated that increased enteral fat concentration (HFD) optimally
prevented postoperative catabolic responses and increased lean mass after SBR [
61
]. Conversely,
in another rat model, low fat diets, despite comparable caloric intake, negatively impacted adaptation
as evidenced by decreased body weight, reduced expression of fat transporters and attenuated villus
height and enterocyte proliferation [62].
Moreover, the specific kind of enteral fat appears to play an important role in intestinal adaptation.
In rats, long-chain fatty acids (LCFA) are superior to medium-chain fatty acids (MCFA) in augmenting
both the structural and functional intestinal response following SBR [
63
]. While most studies have
focused on polyunsaturated LCFA (LCPUFAs) such as menhaden oil, the relative benefit compared
to saturated FAs is still debated. Menhaden oil is an excellent source of the omega-3 fatty acids
eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) [
64
]. EPA and DHA are not only
precursors of anti-inflammatory prostaglandins and associated with improved cardiovascular profiles,
but they have also been shown to enhance intestinal adaptation after massive small bowel resection.
Kollman, et al. demonstrated that resected rats fed LCPUFA-enhanced diets demonstrated significantly
increased intestinal mucosal mass in a dose-dependent manner [
65
]. Another study found that in
a mouse model, menhaden oil (versus saturated and monounsaturated fats) resulted in the highest
percent of lean mass and greatest weight retention after SBR, though adaptation was indistinguishable
across diets [
66
]. The benefit of LCFAs is attributed to its anti-inflammatory metabolite (prostaglandins),
as inhibition with aspirin, a cyclo-oxygenase inhibitor, reduces the predicted intestinal adaptive
response [
67
]. Although LCFAs have the greatest trophic yield, their absorption can be suboptimal in
patients with extensive distal resections due to compromised enterohepatic circulation. While MCFAs
are more water soluble, they have not been shown to have a robust effect on adaptation in mice and
have significant osmotic sequelae which can exacerbate diarrhea and fluid losses [
68
]. Most of what
is known about the effect of fats on adaptation is from preclinical animal models, but a high fat diet,
specifically with LCFA, have been shown to support adaptation in these models and could potentially
increase intestinal adaptation in patients following resection as well.
Nutrients 2020,12, 520 9 of 16
4.4.2. Protein
Most of the literature surrounding the protein composition of enteral nutrition is focused on
absorption rather than adaptation. Elemental (fully digested) or semi-elemental (partially digested)
enteral formulas have historically been preferred in infants with SBS in an effort to maximize absorption
in the remnant bowel. For a subset of patients, losses can occur both in the bowel effluent and through
loss of protein exudate. This double hit is akin to a protein-losing enteropathy, necessitating increased
protein requirements for adequate growth. The extent to which children with persistent malabsorption
and intolerance may benefit from a hydrolyzed formula is not known. A small study of four children
with SBS found that after initiating a hydrolyzed formula, subjects that previously had persistent
feeding intolerance were able to be weaned offparenteral nutrition within 15 months [
69
]. A possible
explanation for improved tolerance on hydrolyzed formula could be non-IgE mediated cow’s milk
protein sensitization seen in infants with NEC [
31
]. However, it is difficult to draw conclusions from the
small population that was observed. Additionally, it has been shown that 70–90% of protein absorption
ability is retained after massive intestinal resection in human neonates [
70
]. It was previously theorized
that the lack of MCTs and lactose in extensively hydrolyzed formulas may lead to easier digestion in
patients with SBS. However, in a randomized crossover trial comparing protein hydrosylate formula to
standard formulas in children with SBS, Ksiazyk et al. found no differences in intestinal permeability,
energy expenditure, or nitrogen balance [46].
Providing adequate amino acids after intestinal resection is important. Glutamine serves as the
primary fuel substrate for intestinal cells, promoting enterocyte proliferation and protein synthesis [
71
].
In preclinical rat models, there is a marked increase in glutamine and total amino acid uptake in the
early adaptive phases following SBR. Unfortunately, supplementing enteral nutrition with glutamine
or arginine after massive intestinal loss in humans has failed to improve adaptive responses and
thus remains controversial [
71
,
72
]. Additionally, recent data suggests that complex nutrients promote
greater intestinal adaptation. In this “functional workload” hypothesis, the remnant bowel meets the
digestive demand of the nutrients encountered and there is thus a more robust compensatory response
when infants are fed a non-hydrolyzed formula [57].
Ultimately, optimal protein intake from enteral nutrition should take into consideration remnant
bowel length, absorptive capacity, and feeding tolerance. The goal is to achieve a positive nitrogen
balance through improved nitrogen absorption. The data on the impact of formula protein content and
composition on intestinal adaptation is sparse and the variation amongst formulas makes comparison
of studies difficult. Although there is no robust evidence that elemental formula is superior to
non-hydrolyzed formula, there is data showing that patients with SBS may tolerate it better and it is
commonly used in the pediatric SBS population.
4.4.3. Oligosaccharides
After intestinal resection, the bowel undergoes significant functional adaptation as evidenced in
a rat model by increased densities of both key digestive enzymes and glucose transporters [
64
]. Excessive
administration of simple carbohydrates should be avoided given their considerable osmotic effects.
Energy can be derived from complex carbohydrates and soluble fibers processed in the colon.
These undigested macromolecules are metabolized by colonic bacteria to produce short chain fatty
acids (SCFAs) such as butyrate [
67
]. Butyrate is the primary fuel substrate for colonocytes and has been
shown to play an important role in intestinal adaptation in both rats [
73
] and piglets [
48
]. In neonatal
piglets that underwent 80% distal SBR, butyrate supplementation markedly increased the structural
and functional indices of intestinal adaptation in both the acute and chronic phases [
48
]. Similar
findings were recapitulated using a rodent SBS model. DNA, RNA and protein content per unit
mucosal weight all increased post-resection in fiber- and butyrate-supplemented diet compared to
controls [
73
]. In humans, these benefits are mitigated by the length of residual colon and colonic
continuity. Furthermore, simple carbohydrates in excess also have significant osmotic influence that
Nutrients 2020,12, 520 10 of 16
may exacerbate diarrhea and extraneous losses [
57
]. Preferably, carbohydrates should comprise no
more than 40% of the total caloric provision [57].
4.5. Parenteral Nutrition
Surgical NEC typically delays the time until enteral autonomy and prolonged PN use (>21 days)
may be required. Allin, et al. demonstrated that the need for PN support at 28 days post-decision to
intervene surgically is associated with increased one-year mortality [
74
]. In clinical practice, intestinal
insufficiency may be indirectly measured by the level of PN required for normal or catch up growth [
75
].
Patients with less remaining bowel require more PN and a residual length of 15–40 cm is associated
with PN weaning [
50
,
51
,
76
–
78
]. The primary metabolic complication associated with PN is intestinal
failure associated liver disease (IFALD), which is characterized by direct hyperbilirubinemia, elevated
transaminases, and liver synthetic dysfunction [
53
]. Some modifications to PN can be made to reduce
the risk for liver injury, such as not overfeeding and cycling infusions [
42
]. Improvement of cholestasis
also depends on maintaining an appropriate protein-to-energy ratio in PN [
79
]. However, the most
heavily studied factor implicated in PN-associated liver disease is intravenous lipid emulsions (ILE).
PN Lipid Source
ILEs are a crucial component of PN, as they are a source of essential fatty acids and non-protein
calories. Several factors should be taken into consideration when choosing an ILE for parenteral use:
the content of essential fatty acids (FAs), the ratio of polyunsaturated fatty acids omega-6 to omega-3,
the quantity of
α
-tocopherol, and phytosterols. Monitoring FA profiles of children with IF is critical to
their nutrition management.
Soybean-based (SO) lipid emulsions were previously considered the standard of care for providing
fatty acids to children with intestinal failure. However, SO contains a 7:1 ratio of omega-6: omega-3,
whereas the optimal ratio is 4:1 to minimize the production of inflammatory mediators [
80
,
81
]. It also
has a high concentration of phytosterols, which have been associated with hepatic inflammation and
cholestasis [
82
,
83
]. The SO factor, stigmasterol, has also been shown in a murine model to promote
cholestasis, liver injury, and liver macrophage activation [
84
]. In 2012, Teitelbaum and colleagues
described a significant reduction in cholestasis in a cohort of pediatric IF whose SO lipid dose was
restricted to 1 g/kg/day compared to the historical dose of 3 g/kg/day [
85
]. Subsequent studies
demonstrated that this lipid reduction strategy does not decrease the incidence of IFALD, but may
slow its progression [86].
In 2018, the United States Food and Drug Administration approved a fish-oil (FO)-based lipid
emulsion (Omegaven
®)
for the treatment of pediatric intestinal failure associated liver disease
(IFALD). Unlike SO-based lipid emulsion, FO is composed primarily of anti-inflammatory omega-3
FA (docosahexaenoic and eicosapentaenoic acids) and contains a small amount of the essential FA
(linoleic and alpha-linolenic acids) [
87
]. FO-based lipids are rich in
α
-tocopherol, which scavenges
free radicals from peroxidized lipids to prevent propagation of oxidative lipid damage [
88
]. IV FO
treatment results in a biochemical reversal of cholestasis and is associated with reduction in plasma
phytosterols, cytokines, and bile acids. However, despite biochemical and histologic improvement in
cholestasis, there is persistent significant liver fibrosis on histology [
89
,
90
]. There is also concern that
because FO provides fewer essential omega-6 FAs than that recommended in children, it could cause
essential fatty acid deficiency (EFAD). However, Calkins, et al. found in a cohort of PN-dependent
children, switching from SO to FO for six months led to a decrease in essential FA concentrations, but no
evidence of EFAD [
91
]. These findings were supported in a long term study conducted over three
years by Puder, et al. [
92
]. Newer preparations such as Smoflipid
®
(Fresenius-Kabi, Uppsala, Sweden)
combine soybean oil (30%), coconut oil (30%), olive oil (25%) and fish oil (15%) and have proven to
be of benefit in patients with IFALD. Randomized controlled trials in preterm infants have shown
that Smoflipid
®
emulsion increases the content of eicosapentaenoic acid (EPA) and docosahexaenoic
acids [
93
]. Muhammed, et al. reported rapid and marked improvement in biochemical liver function
Nutrients 2020,12, 520 11 of 16
tests in children with cholestatic jaundice after switching from a SO-based ILE to Smoflipid
®
[
94
].
Smoflipid
®
has a positive impact on liver enzymes due low phytosterol and high vitamin E content;
in addition, its use leads to a decrease in lipid peroxidation and an improvement on the
ω
-3:
ω
-6 PUFA
ratio, producing a less proinflammatory profile [95].
5. Conclusions
Providing infants breast milk has been the mainstay of nutritional therapy in NEC prevention
and is also beneficial for infants following surgery in stage III NEC [
19
,
20
,
46
]. Unfortunately, there
have been no feeding strategies proven to prevent NEC, such as initiating feeds later, advancing feeds
more slowly, or bolus versus continuous feeds; however, it is safe to start feeds within 96 hours of
birth, advance more rapidly, and bolus feed [
7
,
9
,
12
]. Because there is great variability in individual
feeding practices, it is important that each NICU has a standardized protocol to approaching feeds in
order to ensure appropriate nutrition and minimize complications. Additional studies focusing on
more premature and smaller infants should be conducted, as most studies that are currently available
are limited to infants >1000 g and between 28–32 weeks. Younger and smaller infants may respond
differently than older infants to alternate feeding approaches. Additionally, identifying more specific
biomarkers for NEC severity and intestinal recovery is necessary to provide appropriate treatment and
assist clinicians in determining intestinal recovery after disease.
Finally, more diet studies on the effect of macronutrients on recovery after surgical NEC are
required. The majority of current data on intestinal adaptation shows the benefit of a high fat diet but
is limited to animal studies [
61
]. Using hydrolyzed formula in patients with SBS is common but has
only been studied in a small population and lacks robust evidence [
69
]. Since parenteral nutrition is
often required following resection, it is important to understand its complications. Omegaven
®
and
Smoflipid
®
both are less likely to lead to cholestasis and IFALD without causing essential fatty acid
deficiency and may be more beneficial as a fat source than the traditionally used intralipids [92,95].
Author Contributions:
J.O., C.M.C., A.E.S., and M.E.T. contributed to the writing—original draft preparation,
review, and editing of the initial version manuscript. J.O., C.M.C., and B.W.W. edited and revised the manuscript.
All authors have read and agreed to the published version of the manuscript.
Funding:
B.W. is funded by NIHR01DK104698, R01DK112378, and the Children’s Surgical Sciences Research
Institute of St. Louis Children’s Hospital Foundation CMC is supported by the Marion and van Black Research
Fellowship. AES is funded by T32DK077653-28. MET is funded by T32DK007120.
Conflicts of Interest: The authors declare no conflict of interest.
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