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## Complete Summary

#### GUIDELINE TITLE

Evidence-based care guideline for necrotizing enterocolitis (NEC) among
very low birth weight infants.

#### BIBLIOGRAPHIC SOURCE(S)

Cincinnati Children\'s Hospital Medical Center. Evidence-based care
guideline for necrotizing enterocolitis (NEC) among very low birth
weight infants. Cincinnati (OH): Cincinnati Children\'s Hospital Medical
Center; 2007 Feb. 12 p. \[95 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Cincinnati Children\'s
Hospital Medical Center. Evidence-based care guideline for necrotizing
enterocolitis (NEC) among very low birth weight infants. Cincinnati
(OH): Cincinnati Children\'s Hospital Medical Center; 2005 Jul 14. 12 p.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Necrotizing enterocolitis (NEC)

#### GUIDELINE CATEGORY

Diagnosis\
Evaluation\
Management\
Prevention\
Treatment

#### CLINICAL SPECIALTY

Family Practice\
Gastroenterology\
Nutrition\
Pediatrics\
Surgery

#### INTENDED USERS

Advanced Practice Nurses\
Allied Health Personnel\
Health Care Providers\
Nurses\
Patients\
Physician Assistants\
Physicians

#### GUIDELINE OBJECTIVE(S)

-   To provide evidence based recommendations for the evaluation and
    management of necrotizing enterocolitis (NEC) among very low birth
    weight infants

-   To improve diagnostic accuracy, treatment outcomes, and
    patient/parent satisfaction

#### TARGET POPULATION

Preterm infants less than 1500 grams birth weight

This guideline is **not** intended for use in:

-   Term and near term infants

-   Infants with major congenital anomalies (e.g., congenital heart
    disease, Trisomy 21)

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Prevention**

1.  Encourage mothers to supply breast milk

2.  Consider donor milk, if mother\'s milk is unavailable

3.  Cautious use of histamine-2 receptor blocker therapy for gastric
    acidity

**Note**: Guideline developers considered but did not find sufficient
evidence to make recommendations on the following preventive
interventions:

-   Minimal enteral feeding

-   Early or delayed initiation of feeding

-   Specific rate of feeding volume

-   Transpyloric versus gastric feeding

-   Bolus versus continuous feeding

-   Specific location for umbilical artery catheters

-   Probiotics

-   Supplemental vitamin E

-   Prenatal and postnatal indomethacin

**Note**: No preventive benefits have been shown for amino acid
supplementation, immunoglobulins, and antibiotics

**Diagnosis/Evaluation**

1.  Bell\'s necrotizing enterocolitis (NEC) staging system

2.  Abdominal radiograph

**Note**: Guideline developers considered but did not find sufficient
evidence to make recommendations for the following measures: using stool
patterns, presence of occult blood or presence of specific pathogens as
indicators of NEC risk, or gastric residuals as a predictor of
necrotizing enterocolitis.

**Treatment**

1.  Medications - antibiotics

> **Note**: There is insufficient evidence on benefit or risk regarding
> choice of antibiotic regimen or duration of treatment

2.  Nutrition

> **Note**: There is insufficient evidence on benefit or risk regarding
> the timing of reinitiating feeding

3.  Abdominal paracentesis

**Surgical Management**

1.  Transfer neonates with suspected necrotizing enterocolitis to a
    facility that can meet their surgical needs

2.  Evaluation by surgeon

3.  Surgical intervention decisions based on both the clinical and
    radiologic presentation

4.  Percutaneous drainage versus exploratory laparotomy

#### MAJOR OUTCOMES CONSIDERED

-   Diagnostic accuracy

-   Efficacy of interventions at decreasing the risk of or preventing
    necrotizing enterocolitis

-   Risks and rates of necrotizing enterocolitis

-   Benefits and risks of treatment interventions

-   Patient/parent satisfaction

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Cincinnati clinicians responsible for the care of patients with
necrotizing enterocolitis (NEC) were asked to submit clinical questions
using the PICO (patient, intervention, comparison, outcome) format.
Using these questions as guides, two independent computerized, OVID,
literature searches of Medline and the Cochrane databases were
performed. Searches employed a combination of Boolean searching on
human-indexed thesaurus terms (Medical Subject Heading \[MeSH\] headings
using an OVID Medline interface) and \"natural language\" searching on
words in the title, abstract, and indexing terms. The citations were
reduced by eliminating duplicates, most review articles, non-English
articles, and articles on NEC in adults. The resulting abstracts were
reviewed by a methodologist to eliminate low quality citations.

The following search strategies were used: Necrotizing enterocolitis as
a phrase in the title or as a subject heading was combined with
established filters for clinical articles in the diagnosis, therapy,
etiology, or prognosis domains. The search was limited to human,
English, infants as an age group, and 1980 through May 2003. During the
course of the guideline development, additional clinical questions were
generated and subjected to the search process.

Titles and abstracts of the identified citations (619) were initially
categorized independently by two guideline team leaders as definitely
included in guideline development (all randomized controlled trials
\[RCTs\], all meta-analyses, all systematic reviews and all
observational studies with comparison groups and sample sizes greater
than 50), definitely not included (case reports, letters, observational
studies without control groups, and/or sample size less than 30) and
those possibly included. Studies in the included and possibly included
categories were re-reviewed by the methodologist and other guideline
team members to assure that studies to be appraised in detail were
relevant to the clinical questions that were used to develop search
terms. Complete copies of the remaining articles were organized by
question and distributed to the team according to each member\'s
expressed interest and area of expertise. All selected studies were
appraised by the methodologist and at least two team members using a
standardized form for evaluating design, sample size, methods, and
findings.

A search using the above criteria was conducted for dates of May, 2003
through July, 2006. Four of these citations have been added to the
document, and one of these references was determined to require a change
to the 2005 version of the guideline (recommendation #12 in the original
guideline document). Thirty-four additional relevant articles were
selected as potential future citations for the guideline.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Not applicable

#### METHODS USED TO ANALYZE THE EVIDENCE

Review\
Review of Published Meta-Analyses

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

During formulation of these guidelines, the team members have remained
cognizant of controversies and disagreements over the management of
these patients. They have tried to resolve controversial issues by
consensus where possible and, when not possible, to offer optional
approaches to care in the form of information that includes best
supporting evidence of efficacy for alternative choices.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Not applicable

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

The guidelines have been reviewed and approved by clinical experts not
involved in the development process, and other individuals as
appropriate to their intended purposes.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

Each recommendation is followed by evidence classification (A-X)
identifying the type of supporting evidence. Definitions for the types
of evidence are presented at the end of the \"Major Recommendations\"
field.

**Prevention**

**Type of Milk**

1.  It is recommended that mothers of infants at risk for necrotizing
    enterocolitis (NEC) be encouraged to supply breast milk as the
    optimal enteral nutrition to decrease risk. Infants who received
    human milk were 4 times less likely to have confirmed NEC compared
    to infants who received formula (relative risk \[RR\] 0.25, 95%
    confidence interval \[CI\*\] 0.06 to 0.98) (McGuire & Anthony,
    \"Formula milk versus term human milk,\" 2003 \[M\]; Schanler et
    al., 1999 \[A\]; Lucas & Cole, 1990 \[A\]; Gross, 1983 \[B\]; Tyson
    et al., 1983 \[B\]; Svenningsen, Lindroth, & Lindquist, 1982 \[B\]).

> **Note 1**: Studies show that providing human milk to twenty preterm
> infants will prevent one case of NEC (McGuire & Anthony, \"Formula
> milk versus preterm human milk,\" 2003 \[M\]).
>
> **Note 2**: Although the benefits of human milk to decrease NEC risk
> have been demonstrated primarily with donor milk, it is reasonable to
> encourage use of mother\'s own milk (Schanler et al., 2005 \[A\];
> Local Expert Consensus \[E\]).
>
> **Note 3**: Conditions that would contraindicate the use of breast
> milk are detailed in the Pediatric Nutrition Handbook 5th Ed. American
> Academy of Pediatrics (Kleinman, 2004 \[O\]).
>
> \*95%CI: 95% Confidence Interval expresses the uncertainty (precision)
> of a measured value; it is the range of values within which we can be
> 95% sure that the true value lies. A study with a larger sample size
> will generate more precise measurements, resulting in a narrower
> confidence interval.

2.  It is recommended that donor milk be considered, if available and
    affordable, as an alternative, when mother\'s own milk is
    unavailable (Schanler et al., 2005 \[A\]; Local Expert Consensus
    \[E\]).

> **Note 1**: Current cost of donor milk is 4 to 5 times higher than
> formula designed for premature infants.
>
> **Note 2**: When recommending the use of donor milk, reimbursement
> issues may need to be considered and discussed with the family. Donor
> milk may not be covered by insurance. For more information see
> [www.hmbana.org](http://www.hmbana.org/).

**Feeding Strategies**

Available studies were reviewed for use of minimal enteral feeds, timing
of initiation of feeds, and rates for advancing feeds (see Table below).

**Table: Definitions Used in Studies of Feeding Issues**

  ------------------- ---------------------------------------------------
  **Minimal Enteral   Dilute or full strength formula feedings providing
  Feeding**           \<25 kcal/kg/day (37 cc/kg/day) for \>5 days (Tyson
                      & Kennedy, 2003 \[M\])\
                      \
                      0.5 to 1 mL/hr to extubation (McClure & Newell,
                      2000 \[A\])\
                      \
                      20 mL/kg/day, day 4 to 14 (Schanler et al., 1999
                      \[A\])\
                      \
                      In all studies, controls were not fed by mouth

  **Timing of         Definitions of early versus late initiation varied
  Initiation of       among studies reviewed.\
  Feeds**             \
                      Early \-- day 1 to 5\
                      \
                      Late \-- day 5 to 14 (Kennedy, Tyson, &
                      Chamnanvanikij, \"Early versus delayed,\" 2003
                      \[M\])

  **Rate of           Rates of advancement varied with overlapping
  Advancement of      categories from study to study\
  Feeds**             \
                      10-20 cc/kg/day slow\
                      \
                      20-35 cc/kg/day fast (Kennedy, Tyson, &
                      Chamnanvanikij, \"Rapid versus slow,\" 2003 \[M\])\
                      \
                      20 mL/kg/day X 10 day versus increase by 20
                      mL/kg/day to 140 mL/kg/day (Berseth, Bisquera, &
                      Paje, 2003 \[A\])
  ------------------- ---------------------------------------------------

**Minimal Enteral Feeding**

3.  There is insufficient evidence regarding the role of minimal enteral
    feedings in preventing NEC.

> **Note 1**: A meta-analysis reviewing 6 studies showed use of minimal
> feeds had no effect on risk of NEC (Tyson & Kennedy, 2003 \[M\]).
>
> **Note 2**: Inclusion of two additional randomized controlled trials
> (RCTs) did not alter results of the meta-analysis (McClure & Newell,
> 2000 \[A\]; Schanler et al., 1999 \[A\]).

**Timing of Initiation of Feeds**

4.  There is insufficient evidence to support either early or delayed
    initiation of feeding relative to risk for NEC (Kennedy, Tyson, &
    Chamnanvanikij, \"Early versus delayed,\" 2003 \[M\]; Wilson et al.,
    1997 \[A\]; LaGamma, Ostertag, & Birenbaum, 1985 \[C\]; McKeown et
    al., 1992 \[D\]).

**Rate of Advancement of Feeds**

5.  There is insufficient evidence to recommend a specific rate of
    feeding volume advancement in relation to NEC risk.

> **Note 1**: No difference in NEC risk was observed in studies
> advancement as low as 10 cc/kg/day and as high as 35 cc/kg/day
> (Kennedy, Tyson, & Chamnanvanikij, \"Rapid versus slow,\" 2003 \[M\];
> Kamitsuka, Horton, & Williams, 2000 \[D\]).
>
> **Note 2**: One large study showed a decreased rate of NEC in infants
> maintained at 20 cc compared to those children advanced. Inclusion of
> this study did not alter results of the meta-analysis (Berseth,
> Bisquera, & Paje, 2003 \[A\]).

**Transpyloric Versus Gastric Feeding**

6.  There is insufficient evidence to support either transpyloric or
    gastric feeding methods relative to the risk of NEC (McGuire &
    Anthony, \"Formula milk versus term human milk,\" 2003 \[M\]).

**Bolus Versus Continuous Feeding**

7.  There is insufficient evidence to support either bolus or continuous
    tube feeding as a method to reduce the risk of NEC (Premji &
    Chessell, 2003 \[M\]).

**Umbilical Artery Catheters (UAC)**

8.  There is insufficient evidence to recommend a specific placement
    location for the tip of the umbilical artery catheter. Umbilical
    artery catheter position (high versus low) has not been found to
    affect the incidence of NEC (Barrington, 2003 \[M\]).

9.  There is insufficient evidence to evaluate the risk of NEC
    associated with enteral feeding while an umbilical artery catheter
    is in place.

> **Note**: One small randomized trial found no difference in the
> incidence of NEC between infants fed early, with a UAC in place, and
> those in which feeds were delayed until 24 hours after UAC removal
> (Davey et al., 1994 \[B\]).

**Probiotics**

10. There is insufficient evidence to recommend either use or avoidance
    of probiotics. Clinical trials of the effects of probiotics on the
    risk of NEC have not consistently shown benefit.

> **Note 1**: One large observational study showed a significant
> decrease in NEC compared to historical controls when infants were
> treated with lactobacillus and bifidobacterium (Hoyos, 1999 \[D\]).
>
> **Note 2**: One large RCT of lactobacillus GG found no significant
> effect on the incidence of NEC in very low birth weight (VLBW) infants
> (Dani et al., 2002 \[A\]).
>
> **Note 3**: A second large RCT of lactobacillus and bifidobacterium in
> VLBW infants found a significant reduction in NEC incidence among
> treated infants (Lin et al., 2005 \[A\]).
>
> **Note 4**: Issues regarding the safety of probiotic use in
> immunodeficient hosts such as preterm infants have been raised,
> particularly the potential for sepsis. None of the clinical trials
> reported harmful side effects although they were not powered to
> evaluate safety (Land et al., 2005 \[O\]).

**Additional Prevention Strategies**

11. The following prevention strategies have been evaluated in large
    sample size, randomized, controlled trials or meta-analyses with no
    statistically significant effects on NEC risk.

> *Amino Acid Supplementation*

-   Enteral glutamine (Vaughn et al., 2003 \[A\])

-   Intravenous (IV) glutamine (Poindexter et al., 2004 \[A\])

-   Enteral arginine (Amin et al., 2002 \[A\])

> *Immunoglobulins*

-   Oral immunoglobulin G (IgG) or IgA/IgG combination (Foster & Cole,
    2004 \[M\]; Rubaltelli, Benini, & Sala, 1991 \[A\]; Eibl et al.,
    1988 \[A\])\
    Note: There is no RCT of IgA alone for the prevention of NEC.

-   Intravenous IgG (Fanaroff et al., 1994 \[A\])

> *Antibiotics*

-   Results from a meta-analysis of 5 studies suggest that oral
    aminoglycosides decrease the incidence of NEC. However, lack of
    information on other outcomes including mortality and development of
    resistant bacteria precludes any recommendation (Bury & Tudehope,
    2003 \[M\]).

-   Oral or intravenous erythromycin (Ng & Shah, 2003 \[M\])

Where evidence is present but sparse, information is shared below for
purposes of awareness even if conclusions can not be made.

**Acidification**

12. It is recommended that histamine-2 receptor (H2) blocker therapy for
    gastric acidity be used with caution. Two studies suggest that
    gastric pH alters risk for NEC.

> **Note 1**: One small RCT showed that acidification of feeds was
> associated with decreased risk of NEC (Carrion & Egan, 1990 \[B\]).
>
> **Note 2**: One large retrospective case-control study showed a
> significant association between H2-blocker therapy and higher rates of
> NEC (Guillet et al., 2006 \[D\]).

**Supplemental Vitamin E**

13. In those at greatest risk for NEC, studies suggest that supplemental
    vitamin E may increase the risk of NEC with no effect on other
    outcomes with the exception of risk of severe retinopathy of
    prematurity which may be less (Brion, Bell, & Raghuveer, 2003 \[M\];
    Johnson et al., 1985 \[A\]; Finer et al., 1984 \[D\]).

**Prenatal Indomethacin**

14. There is insufficient evidence to recommend either use or avoidance
    of prenatal indomethacin related to risk of NEC (Parilla et al.,
    2000 \[D\]; Vermillion & Newman, 1999 \[D\]; Major et al., 1994
    \[D\]; Norton et al., 1993 \[D\]).

**Postnatal Indomethacin**

15. Evidence does not support an altered risk of NEC with use of
    indomethacin for prevention of intraventricular hemorrhage (Fowlie &
    Davis, 2003 \[M\]) or treatment of patent ductus arteriosus (PDA)
    (Malviya, Ohlsson, & Shah, 2003 \[M\]; Gersony et al., 1983 \[A\];
    Cooke & Embleton, 2000 \[S\]).

> **Note 1**: Although the number of infants \<1,000 gm birth weight was
> small, a collaborative trial showed no difference on NEC risk using
> surgical versus indomethacin treatment for PDA (Gersony et al., 1983
> \[A\]).
>
> **Note 2**: No difference in NEC risk has been noted between ibuprofen
> and indomethacin used for PDA treatment or prevention (Shah & Ohlsson,
> 2003 \[M\]).

**Medical Management**

**Evaluation**

*Clinical Assessment and Diagnosis*

16. Bell\'s NEC staging system is commonly used to assess NEC severity
    (Bell et al., 1978 \[C\]). Studies to firmly establish assessment
    and diagnosis criteria are not available (see Table below).

**Table: Bell\'s Staging for NEC**

  ------------------------------------------------------------------------------
  **Stage I: Suspect**           **Stage II: Definite**   **Stage III:
                                                          Advanced**
  ------------------------------ ------------------------ ----------------------
  Any one or more historical     Any one or more          Any one or more
  factors producing perinatal    historical factors       historical factors
  stress                                                  

  Systemic                       Signs and symptoms as in Signs and symptoms as
  manifestations\--temperature   **Stage I plus**         in **Stage II plus**
  instability, lethargy, apnea,  persistent occult or     deterioration of vital
  bradycardia                    gross gastrointestinal   signs, evidence of
                                 bleeding; marked         septic shock, or
                                 abdominal distention     marked
                                                          gastrointestinal
                                                          hemorrhage

  Gastrointestinal               Abdominal radiographs    Abdominal radiographs
  manifestations\--poor feeding, show significant         may show
  increasing pre-gavage          intestinal distension    pneumoperitoneum in
  residuals, emesis (may be      with ileus; small bowel  addition to signs
  bilious or test positive for   separation (edema in     listed for Stage II
  occult blood), mild abdominal  bowel wall or peritoneal 
  distention, occult blood may   fluid), unchanging or    
  be present in stool (no        persistent \"rigid\"     
  fissure)                       bowel loops, pneumatosis 
                                 intestinalis, portal     
                                 vein gas                 

  Exclude other disorders via                             
  bacterial cultures,                                     
  electrolyte analysis, maternal                          
  drug history, coagulation                               
  studies, and contrast studies                           
  ------------------------------------------------------------------------------

*Diagnostics*

[Laboratory Studies]{.underline}

17. While specific pathogens have been isolated from stools and
    abdominal fluid during outbreaks of NEC, no specific pathogen has
    been found to have a consistent causal relationship with NEC (de la
    Cochetiere et al., 2004 \[C\]; Peter et al., 1999 \[C\]; Millar et
    al., 1996 \[C\]; Rotbart et al., 1988 \[C\]; Blakey et al., 1985
    \[C\]; Thomas et al., 1984 \[C\]; Gupta, Burke, & Herson, 1994
    \[D\]; Keller et al., 1991 \[D\]; Sherertz & Sarubbi, 1982 \[D\]).

18. There is insufficient evidence to support the use of stool patterns,
    presence of occult blood, or presence of specific pathogens as
    clinical indicators of NEC risk (Peter et al., 1999 \[C\]; Abramo et
    al., 1988 \[C\]; Andrews & Krowchuk, 1997 \[D\]).

19. There is insufficient evidence for use of gastric residuals as a
    predictor of NEC. Gastric residuals in infants who developed NEC
    tended to be larger, but significant overlap in the amount of
    residual precludes its use as a marker for NEC (Cobb, Carlo, &
    Ambalavanan, 2004 \[D\]).

[Radiologic Studies]{.underline}

20. It is recommended that an abdominal radiograph be performed in
    infants with clinical suspicion of NEC (Bell et al., 1978 \[C\]).
    The influences on infant outcome and diagnostic validity of the
    number of abdominal x-rays, the type of view(s) or the frequency or
    timing of abdominal radiographs have not been systematically
    studied.

> **Note 1**: Inter-observer reliability of radiographic signs of NEC is
> low (Napoli et al., 2004 \[D\]).
>
> **Note 2**: While positive radiographic findings have good predictive
> value, negative studies must be interpreted with caution (Tam,
> Camberos, & Applebaum, 2002 \[D\]; Kosloske, 1994 \[D\]).

**Intervention**

*Medications*

21. There is insufficient evidence on benefit or risk regarding choice
    of antibiotic regimens or duration of antibiotic treatment of NEC
    (Faix, Polley, & Grasela, 1988 \[B\]; Scheifele et al., 1987 \[C\]).

> **Note**: Decisions regarding antibiotic choice and duration might
> best be guided by:

-   Culture results

-   Antibiotic resistance patterns present within nurseries

> (Local Expert Consensus \[E\])

22. There is insufficient evidence on benefit or risk of routine
    clindamycin use for treatment of NEC (Faix, Polley, & Grasela, 1988
    \[B\]).

> **Note**: One small randomized controlled trial using clindamycin
> showed an increase in bowel strictures (Faix, Polley, & Grasela, 1988
> \[B\]).

23. There is insufficient evidence on benefit or risk of oral
    aminoglycoside use for the treatment of NEC (Hansen et al., 1980
    \[B\]).

*Nutrition*

24. There is insufficient evidence on benefit or risk regarding the
    timing of reinitiating feeding once the diagnosis of NEC has been
    made.

> **Note**: One retrospective study evaluating the impact of early
> initiation of feeding (\<10 days from diagnosis) suggests a positive
> impact. Early feeding was associated with a shorter time to full
> feeds, less catheter related sepsis, and a shorter hospital stay. The
> study was underpowered to evaluate recurrence risk of NEC (Bohnhorst
> et al., 2003 \[C\]).

*Paracentesis*

25. Abdominal paracentesis may be helpful to confirm the presence of
    intestinal gangrene in infants with NEC (Ricketts, 1986 \[D\];
    Kosloske & Goldthorn, 1982 \[D\]). Indications for paracentesis are
    absence of pneumoperitoneum and one of the following:

    -   Portal venous gas

    -   Erythema of abdominal wall

    -   Fixed, tender abdominal mass

    -   Persistently dilated intestinal segment

    -   Clinical deterioration (see Table \"Relative indications for
        surgical consultation,\" below)

> **Note**: Positive results reliably predict the presence of intestinal
> gangrene (accuracy 90% to 97.5%). A \"positive\" result is considered
> an aspiration of 0.5 mL of peritoneal fluid and one of the following:

-   Yellow-brown or brown staining fluid

-   Gram stain positive for bacteria

> However, a negative result does not reliably exclude the presence of
> intestinal gangrene (40% false negative rate) (Kosloske, 1994 \[D\];
> Ricketts, 1986 \[D\]).

**Surgical Management**

**Site of Care**

26. It is recommended that neonates with suspected NEC be transferred to
    a facility that can meet their possible surgical needs if surgical
    services are not available within the admitting institution. A safe
    transfer is best achieved when the child is hemodynamically stable.
    Indications for transfer might include:

    -   Pneumoperitoneum

    -   Radiographic evidence of portal venous gas (Buras et al., 1986
        \[D\])

> (Local Expert Consensus \[E\]).
>
> **Note**: Evidence suggests that portal gas or diffuse pneumatosis is
> associated with more severe disease (see Evaluation and Intervention
> Recommendation #28 below).

**Evaluation and Intervention**

27. It is recommended that neonates with clinical/radiographic evidence
    of pneumoperitoneum be evaluated by a surgeon in a center in which
    operative intervention can be performed if indicated.
    Pneumoperitoneum represents an **absolute** indication for surgical
    intervention (Tam, Camberos, & Applebaum, 2002 \[D\]; Kosloske, 1994
    \[D\]; Kosloske, Papile, & Burstein, 1980 \[D\]).

28. It is recommended that neonates with clinical/radiographic evidence
    of intrahepatic venous gas (portal venous gas) be evaluated by a
    surgeon in a center in which operative intervention can be performed
    if indicated (Molik et al., 2001 \[C\]; Tam, Camberos, & Applebaum,
    2002 \[D\]; Kosloske, 1994 \[D\]; Rowe et al., 1994 \[D\]; Kennedy,
    Holt, & Ricketts, 1987 \[D\]; Buras et al., 1986 \[D\]).

29. The following conditions may be considered as **relative**
    indications for surgical consultation in a center in which operative
    intervention can be performed if indicated:

    -   Abdominal wall cellulitis

    -   Fixed dilated intestinal segment by x-ray

    -   Tender abdominal mass

    -   Clinical deterioration refractory to medical management (see
        Table below)

> (Local Expert Consensus \[E\])

**Table 3: Relative Indications for Surgical Consultation**

+-----------------------------------------------------------------------+
| -   Persistent metabolic acidosis                                     |
|                                                                       |
| -   Persistent thrombocytopenia                                       |
|                                                                       |
| -   Increasing respiratory support                                    |
|                                                                       |
| -   Increased third-space fluid losses, hypovolemia, oliguria         |
|                                                                       |
| -   Leukopenia, leukocytosis                                          |
+-----------------------------------------------------------------------+

(Ververidis et al., 2001 \[D\]; Gupta, Burke, & Herson, 1994 \[D\];
Buras et al., 1986 \[D\]; Local Expert Consensus \[E\])

30. Radiographic signs of NEC have high specificity but low sensitivity,
    with poor negative predictive values. It is recommended that the
    decisions regarding surgical intervention be based on both the
    clinical and radiological presentation. It is recommended that
    decisions regarding the need for surgical intervention not be made
    solely on the basis of absent radiographic signs (Tam, Camberos, &
    Applebaum, 2002 \[D\]; Kosloske, 1994 \[D\]).

31. One retrospective study compared the use of the neonatal intensive
    care unit for surgery versus transport to an operating room setting
    for neonates weighing less than 1,500 g with severe NEC. Transport
    of neonates less than 1,500 g from an intensive care unit to an
    operating room is associated with deterioration in physiologic
    parameters (Frawley, Bayley, & Chondros, 1999 \[D\]).

32. The role of percutaneous drainage versus exploratory laparotomy is
    controversial (Moss et al., 2001 \[M\]; Ahmed, Ein, & Moore, 1998
    \[D\]; Azarow et al., 1997 \[D\]; Morgan, Shochat, & Hartman, 1994
    \[D\]; Cheu, Sukarochana, & Lloyd, 1988 \[D\]). A multicenter,
    prospective, randomized trial of percutaneous drainage compared to
    laparotomy, in 117 very low birth weight newborns with NEC and
    intestinal perforation, demonstrated no difference in short term
    outcomes (Moss et al., 2006 \[A\]).  No recommendation can be made
    on surgical approach at the time of publication of this guideline.

**Definitions**:

**Evidence Based Classifications**:

M: Meta-analysis or Systematic Review\
A: Randomized controlled trial: large sample\
B: Randomized controlled trial: small sample\
C: Prospective trial or large case series\
D: Retrospective analysis\
O: Other evidence\
S: Review article\
E: Expert opinion or consensus\
F: Basic laboratory research\
L: Legal requirement\
Q: Decision analysis\
X: No evidence

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### REFERENCES SUPPORTING THE RECOMMENDATIONS

[References open in a new
window](http://www.guideline.gov/summary/select_ref.aspx?doc_id=10578)

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is classified for the recommendations
(see \"Major Recommendations\").

**Evidence Based Classifications**:

M: Meta-analysis or Systematic Review\
A: Randomized controlled trial: large sample\
B: Randomized controlled trial: small sample\
C: Prospective trial or large case series\
D: Retrospective analysis\
O: Other evidence\
S: Review article\
E: Expert opinion or consensus\
F: Basic laboratory research\
L: Legal requirement\
Q: Decision analysis\
X: No evidence

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

**Overall Potential Benefits**

-   Decreased incidence of necrotizing enterocolitis (NEC)

-   Decreased NEC-associated mortality

-   Decreased incidence of NEC-associated morbidity

**Specific Potential Benefits**

Infants who received human milk were 4 times less likely to have
confirmed NEC compared to infants who received formula. Studies show
that providing human milk to twenty preterm infants will prevent one
case of NEC.

#### POTENTIAL HARMS

-   Transport of neonates less than 1500 g from an intensive care unit
    to an operating room is associated with deterioration in physiologic
    parameters.

-   Abdominal paracentesis has a 40% false negative rate for the
    presence of intestinal gangrene.

-   Although radiographic signs of necrotizing enterocolitis (NEC) have
    high specificity, they also have low sensitivity with poor
    predictive value.

-   Histamine-2 receptor (H2) blocker therapy for gastric acidity should
    be used with caution. One large retrospective case-control study
    showed a significant association between H2-blocker therapy and
    higher rates of NEC.

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

Conditions that would contraindicate the use of breast milk are detailed
in the Pediatric Nutrition Handbook 5th Ed. American Academy of
Pediatrics.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

These recommendations result from review of literature and practices
current at the time of their formulations. This guideline does not
preclude using care modalities proven efficacious in studies published
subsequent to the current revision of this document. This document is
not intended to impose standards of care preventing selective variances
from the recommendations to meet the specific and unique requirements of
individual patients. Adherence to this guideline is voluntary. The
physician in light of the individual circumstances presented by the
patient must make the ultimate judgment regarding the priority of any
specific procedure.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

Building upon this guideline, a multi-organizational improvement team
that includes representatives of Cincinnati\'s three Level 3 Neonatal
Intensive Care Units (NICUs) was chartered in spring 2005 to work as a
team to decrease NEC incidence through increased human milk (HM)
consumption.

The NEC Improvement team is applying a quality improvement (QI) approach
to the implementation of recommendations in the guideline. The team is
using the Model for Improvement developed by the Institute for
Healthcare Improvement, which guides users through developing aims for
improvement in NEC rates, HM consumption, and other process measures;
testing good ideas on a small scale to see if they lead to improvement;
and using simple data collection and analysis strategies to understand
the impact of the tests of change. With the support of the National
Institute of Child Health and Human Development (NICHD) Neonatal
Network, the team will be tracking data related to both NEC incidence
and human milk consumption in nearly 100% of very low birth weight
(VLBW) babies admitted to the three NICUs. HM data will provide a better
understanding whether the team\'s quality improvement work is leading to
improvement in HM consumption, and will also further the knowledge
regarding the potential relationship between HM, other factors, and NEC.

#### IMPLEMENTATION TOOLS

Patient Resources

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Staying Healthy

#### IOM DOMAIN

Effectiveness\
Patient-centeredness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Cincinnati Children\'s Hospital Medical Center. Evidence-based care
guideline for necrotizing enterocolitis (NEC) among very low birth
weight infants. Cincinnati (OH): Cincinnati Children\'s Hospital Medical
Center; 2007 Feb. 12 p. \[95 references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2005 Jul 14 (revised 2007 Feb)

#### GUIDELINE DEVELOPER(S)

Cincinnati Children\'s Hospital Medical Center - Hospital/Medical Center

#### SOURCE(S) OF FUNDING

Cincinnati Children\'s Hospital Medical Center

#### GUIDELINE COMMITTEE

Necrotizing Enterocolitis Team 2007

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Cincinnati Children\'s Hospital Medical Center Physicians*: Barbara
Warner, MD, Chair, Neonatology; Rebeccah Brown, MD, Pediatric Surgery;
Michael Crossman, MD, Neonatology; Samuel Kocoshis, MD,
Gastroenterology; Frederick Ryckman, MD, Pediatric Surgery; Kurt
Schibler, MD, Neonatology; Greg Tiao, MD, Pediatric Surgery; Brad
Warner, MD, Pediatric Surgery; Nada Yazigi, MD, Gastroenterology

*Nursing/Patient Services*: Dawn Butler, Pharm D, Pharmacy; Jeanne
Harjo, RN, RCNIC Care Coordinator; Gayle Hertenstein, RN, RCNIC Staff;
Nancy Roberto, RN, MSN, RCNIC-NNP; Jackie Wessel, Med, RD, RCNIC
Dietitian

*Other Services*: Jareen Meinzen-Derr, Center for Epidemiology and
Biostatistics

*Parent Advisors*: Traci Fitch; Kim & Rob Latham; Rejena Rizzuto; Craig
& Amanda Green; Barbara Rose

*Clinical Effectiveness Services*: Edward Donovan, MD, Medical Director,
Clinical Effectiveness; Danette Stanko, MA, MPH, Epidemiologist; Kate
Rich, BA, Lead Decision Support Analyst; Debbie Hacker, RN, Medical
Reviewer; Ed Mendez, RN, MPH, Dir. Evidence Based Care; Uma Kotagal,
MBBS, MSc., VP, Division Director; Eloise Clark, MPH, MBA, Guideline
Program Administrator

*Ad Hoc Advisory*: Richard Azizkhan, MD, Surgeon in Chief, General and
Thoracic Surgery; William Balistreri, MD, Director
Gastroenterology/Nutrition; Michael Farrell, MD, Chief of Staff; Michael
Farrell, MD, Chief of Staff; Cheryl Hoying, R.N., PhD, VP Patient
Services; James Greenberg, MD, Director Neonatology; Barbarie Hill,
Pratt Library; Kim Collins, Medical Education

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

The guideline was developed without external funding. All Team Members
and Clinical Effectiveness support staff listed have declared whether
they have any conflict of interest.

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Cincinnati Children\'s
Hospital Medical Center. Evidence-based care guideline for necrotizing
enterocolitis (NEC) among very low birth weight infants. Cincinnati
(OH): Cincinnati Children\'s Hospital Medical Center; 2005 Jul 14. 12 p.

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Portable Document Format (PDF) from the
[Cincinnati Children\'s Hospital Medical Center Web
site](http://www.cincinnatichildrens.org/svc/alpha/h/health-policy/ev-based/).

Print copies: For information regarding the full-text guideline, print
copies, or evidence-based practice support services contact the
Children\'s Hospital Medical Center Health Policy and Clinical
Effectiveness Department at <HPCEInfo@chmcc.org>.

#### AVAILABILITY OF COMPANION DOCUMENTS

None available

#### PATIENT RESOURCES

The following Health Topics is available:

-   Necrotizing enterocolitis. Cincinnati Children\'s Hospital Medical
    Center, 2005 Oct. Electronic copies: Available from the [Cincinnati
    Children\'s Hospital Medical Center Web
    site](http://www.cincinnatichildrens.org/health/info/abdomen/diagnose/nec.htm).

Please note: This patient information is intended to provide health
professionals with information to share with their patients to help them
better understand their health and their diagnosed disorders. By
providing access to this patient information, it is not the intention of
NGC to provide specific medical advice for particular patients. Rather
we urge patients and their representatives to review this material and
then to consult with a licensed health professional for evaluation of
treatment options suitable for them as well as for diagnosis and answers
to their personal medical questions. This patient information has been
derived and prepared from a guideline for health care professionals
included on NGC by the authors or publishers of that original guideline.
The patient information is not reviewed by NGC to establish whether or
not it accurately reflects the original guideline\'s content.

#### NGC STATUS

This NGC summary was completed by ECRI on September 14, 2005. The
information was verified by the guideline developer on October 10, 2005.
This NGC summary was updated by ECRI Institute on July 23, 2007.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original full-text guideline, which is
subject to the following copyright restrictions:

Copies of [Cincinnati Children´s Hospital Medical Center
(CCHMC)](http://www.cincinnatichildrens.org/svc/alpha/h/health-policy/ev-based/default.htm)
Evidence-Based Clinical Practice Guidelines (EBCG) are available online
and may be distributed by any organization for the global purpose of
improving child health outcomes. Examples of approved uses of CCHMC´s
EBCG include the following:

-   Copies may be provided to anyone involved in the organization\'s
    process for developing and implementing evidence-based care
    guidelines.

-   Hyperlinks to the CCHMC website may be placed on the organization\'s
    website.

-   The EBCG may be adopted or adapted for use within the organization,
    provided that CCHMC receives appropriate attribution on all written
    or electronic documents.

-   Copies may be provided to patients and the clinicians who manage
    their care.

Notification of CCHMC at <HPCEInfo@cchmc.org> for any EBCG adopted,
adapted, implemented or hyperlinked to by a given organization and/or
user, is appreciated.

### DISCLAIMER

#### NGC DISCLAIMER

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Date Modified: 11/10/2008