Transcript Things we do that cause gut disease in neonates

Phillip Gordon
Tulane
Topics we will cover
 NEC (overview)
 Term NEC
 Preterm NEC
NEC associated with transfusions
NEC associated with cows milk intolerance
Catastrophic NEC
 Spontaneous Intestinal Perforations
NEC is increasing
Incidence of NEC in Level C NICUs over time
Inborn - Level C NICUs
25th % Inborns
20.00%
75th % Inborns
Outborn - Level C NICU
25th % Outborns
16.00%
Percent of Total
75th % Outborns
12.00%
8.00%
4.00%
0.00%
1996
1998
2000
2002
2004
2006
The data suggests that nationally, current trends in prematurity and neonatal care have resulted
in increased NEC incidence in lower level units. This situation calls for more proactive regional
NICUs who can provide support and education to surrounding units.
What is NEC?
It’s not just inflammation,
it’s hemorrhagic necrosis
Normal
NEC
The reason that this
distinction is important is
that the neonatal bowel is
utilizing the innate
immune system to
modulate inflammation
rather than adaptive
immunity (which kicks in
weeks to months later as
we introduce food)
It is the innate immune system in combination with
external factors that creates a permissive situation for NEC
 Hemorrhagic necrosis is a common end point that allows
us to give an umbrella diagnosis of NEC, but infants with
widely variable presentation and severity of disease all have
the same pathology – i.e. it’s not a very useful differentiator
 There are variable combinations of factors and triggers that
each distinctly increase the risk of progression to NEC
 Large cohort analyses have allowed recognition of distinct
NEC subgroups, based on their etiologic risk factors, and
have been key to new strategies for NEC prevention
Review of term NEC risk factors
Hypoxia / Ischemia
Feeding a
colonized
gut
Term NEC
An
immature
and naive
gut
The Classic NEC Triad
NEC risk factors with prematurity
Hypoxia / Ischemia
Feeding a
colonized
gut
Term NEC
Preterm NEC
Bacterial Overgrowth
An
immature
and naive
gut
The Key differences are:
The principle mechanistic difference between term and
preterm NEC is that one is triggered by hypoxicischemic pre-events, the other by bacterial overgrowth
that the bowel cannot contain or tolerate.
However, the circumstances in which NEC evolves is
quite different in the two populations and thus
understanding the co-morbidities and evolution of
NEC in each distinct disease process can help us
understand the rationale behind prevention strategies.
How do clinical databases see “NEC”?
 These are the Diagnostic Categories currently available in
the Pediatrix Database:
 Rule out NEC
 Suspected NEC
 Medical NEC
 Surgical NEC
 Which of these are truly NEC? Clinically, NEC is diagnosed
in any child with bowel pneumatosis on x-ray
This is the distribution of NEC and SIP by
gestational age. Most NEC is preterm NEC.
Preterm NEC Pathogenesis (1)
Feeding Intolerance of Prematurity / Ileus
Intermittent
aspirates
Loopy
Formula
< 80 mL/kg/day
Irregular stooling
Preterm NEC Pathogenesis (2)
Pneumatosis / NEC
Stacking Aspirates
Ileus
Pneumatosis (x-ray)
Formula
80-120 mL/kg/day
Not stooling
Can we cut the incidence of (preterm) NEC in half today?
1
Human Milk
Christensen, Gordon,
Besner , 2010
2
A Standardized
Feeding Protocol
Nurse Ratched
3
What is different about term NEC?
 They are fed at full feeds almost immediately
 They have intact G.I. motility (more or less)
 They are able to feed P.O.
 Parents have more input into the child’s feeding
Lambert , et al., 2007
Perinatal factors associated with term NEC
Out of 5877 infants > 36 weeks, 30 had NEC diagnosed by pneumatosis
The were 4 common
NEC preconditions:
Other = perinatal
hypoxia / ischemia,
sepsis or respiratory
distress
1- cong. heart disease
(incidence = 1.5%)
2- shock/sepsis
(incidence = 50%)
3- hypoxia/ischemia
(incidence = 9%)
4- polycythemia
(incidence = 13%)
These variables were
significantly higher in the
NEC cohort than controls
All infants but one were rapidly advanced with formula (that infant was fed breast milk
fortified with human milk fortifier – thus had the potential for bacterial overgrowth)
Lambert , et al., 2007
Outcomes for Ischemic NEC
Feature
M/MD (sd, rg, %)
Age (days) when NEC was diagnosed
15 12; (12; 1–46)
Location of patient when NEC developed
Home=2, NICU=28
Transferred to children's hospital for
surgical management
8 (27%)
Surgery for NEC
7 (23%)
Bowel perforation and resection
5 (17%)
Total bowel necrosis diagnosed
2 (7%)
Survival (%)
26/30 (87%)
Length of hospital stay (days) – all 30
patientsb
(32; 2–244)
Length of hospital stay (days) – 26
survivors
(37; 7–145)
Preventing term NEC
 Term NEC has preconditions that place patient’s at risk.
Exclusive feeding of human milk may reduce risk, but
this population is rarer and more challenging to capture
for standardized feeding protocols (especially in nontertiary NICUs) and thus may not be as amenable to
prevention when compared to preterm NEC.
 A high index of suspicion for a co-morbid, perinatal risk
factors should prompt a controlled feeding advance (50
ml/kg/day on day 1 -> 100 ml/kg/day on day 2 -> 150
ml/kg/day on day 3) to facilitate observation during the
period of greatest risk
Transfusion Associated NEC is a subset
of Preterm NEC
Pneumatosis
associated with
IVIG
38
36
n=3
n = 11
34
Gestation age
(weeks) 32
n = 72
NEC not
associated with
transfusion
n = 40
30
n=6
28
Transfusion
associated NEC
n=3
26
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24
500
1000
1500
2000
2500
Birth weight (grams)
3000
What are the co-travelers with
transfusion-associated NEC?
 Incidence is decreased in infants receiving breast milk
 Incidence is decreased in infants whose feedings are held
during the time of transfusion
 Incidence is increased in infants with lowest HCTs
 Incidence is increased in infants on exclusive formula feeds
 Incidence is increased in infants who have had a previous
transfusion
 There is no relation to the age of the pRBCs at time of
transfusion
Cows Milk Allergy versus NEC
We have known for some time that infants with cows
milk allergy can present with pneumatosis. More
recently, we have seen case studies and case series
demonstrating premature infants with multiple
episodes of pneumatosis that finally resolve with
elemental formula and that are highlighted by
eosinophilia in the stool and/or blood which also
resolve with elemental formula. These infants have a
milder form of NEC that is precipitated principally
by relatively early onset of milk allergy (usually not
before 4 weeks of life).
Gordon et al. J. Perinatol, 2008
Infants who have NEC with
eosinophilia are less likely to die
Eosinophils
N Lived
N Died
<5
(76.8%)
5 -10
(13.8%)
>10
(9.4%)
1821
(78%)
328
(81%)
223
(85.2%)
514
(22%)
77
(19%)
45
(16.8%)
Patients extracted from the Pediatrix database of preterm neonates (< 36 weeks
with a diagnosis of medical or surgical NEC from 1997-2009 and also had a
reported CBC on the day of diagnosis)
Catastrophic NEC
Catastrophic NEC
This is the NEC subgroup we know the least about…
NEC (n = 7099)
PERINATAL VARIABLES
Lived
Died
< 7 days
Died
Died
> 7 days
Median
10-90th
Median
10-90th
p value
Median
10-90th
Median
10-90th
p value
Maternal Age
26
(19-36)
26
(18-36)
NS
26
(18-36)
26
(18-36)
0.3
Gestational
30
(25-35)
26
(24-32)
0.001
26
(24-32)
25
(23-31)
0.01
0.82 (0.55-1.6)
0.001
0.86
(0.6-1.7)
0.74 (0.5-1.4)
0.001
Birth weight
1.32 (0.72-2.5)
APGAR 1 min
7
(2-8)
5
(1-8)
0.001
5
(1-8)
5
(1-8)
NS
APGAR 5 min
8
(6-9)
7
(4-9)
NS
8
(5-9)
7
(4-9)
0.001
15
(4-40)
18
(7-42)
0.01
18
(7-40)
19
(7-47)
NS
Age at diagnosis
Patients extracted from the Pediatrix database of preterm neonates (< 36 weeks with
a diagnosis of medical or surgical NEC from 1997-2009 for whom discharge data was
available)
There is a trend towards lymphocytosis
at presentation in catastrophic NEC
NEC
CBC data (n)
Avg of WBC
Avg of Hgb
Avg of Hct
Avg of Plat
Avg of Seg
Avg of Band
Avg of Lymph
Lived
5569
Died p value Died < 7 days
Died > 7 days
p value
1494
11
(4.9-20.7)
12.8
(9.9-16.9)
11.2
(4.3-25.9)
12.1
(9.3-15)
37.4
(29-49)
288
(117-506)
35
(13-61)
8
(1-29)
37
(16-59.3)
35.6
(27.6-44.4)
178
(56-409.3)
31
(8.5-59)
13
(2.55-33)
34.8
(13.5-62.2)
0.001
0.001
0.001
0.001
0.001
0.001
NS
10.5
(3.9-25)
11.8
(9-14.9)
12.1
(4.9-27.2)
12.5
(9.9-15.2)
35.1
(27.1-44.2)
198
(59-422)
29
(7-56)
13
(3-32)
37.8
(14.5-65)
36.2
(29.2-44.7)
150
(54-375)
36.3
(12-65.5)
12
(2-33.45)
29
(11-57.35)
0.004
0.004
0.001
0.001
0.001
NS
0.001
We don’t yet know what causes
catastrophic NEC but, if I had to guess…
These would be the etiologies highest on my list of possibilities:
 Viral-triggered NEC (Rotavirus, Adenovirus, Norwalk virus, etc.).
 Some may be coincident with transfusion, therefore some may
actually be transfusion-associated NEC
 Some may be a combination: emerging cows milk allergy, viral
challenge and/or transfusion associated, in other words, these
sub-group designations are not mutually exclusive
The only new potentially preventative measure here is the possible
viral aspect, because infants who are part of a NEC cluster need
to be quarantined to prevent further spread.
Spontaneous Intestinal Perforations
SIP presents as a single or a few isolated perforations most commonly in the ileum
of distal jejunum in infants < 1000 grams birth weight. The average day of life 0f
presentation is 7 days and the clinical finding is pneumoperitoneum in most cases.
Spontaneous Intestinal Perforations
SIP is not NEC. The simplest evidence for this is the histology. NEC has mucosal
necrosis, SIP doesn’t. SIP has focal muscularis necrosis, NEC doesn’t. Even in cases of
SIP that are occult and the perforation has gone undiagnosed for days to weeks, this
histopathology remains remarkably consistent (with only minimal total tissue necrosis
at the peforation margins.
Normal
NEC
SIP
Risk factors associated with SIP
 Extreme prematurity / low birth weight (< 100o grams)
 Early postnatal steroids (dexamethasone or hydrocortisone)
 Early postnatal indomethacin (in the first 4 days of life)
 The combination of early steroids and early indomethacin
 Early postnatal ibuprofen
 Prenatal indomethacin, given shortly before delivery of an
extremely premature infant (for tocolysis)
 SGA infants who are also premature.
 High endogenous cortisol levels in the first days of life
 Candida chorioamnionitis
Summary of surgical outcomes data
for SIP & NEC
 SIP preferentially treated by drain is associated with
increased cPVL and likely increased neurodevelopmental
insult (NDI) compared to age matched controls
 Surgical NEC has a higher mortality than SIP and has a
greater risk of NDI when compared to SIP cohorts and
controls, but all available data suffers from SIP
contamination in currently published NEC cohorts.
 It is probable that NDI associated with NEC and SIP could
be improved by choosing primary laparotomy rather
than drain.
 It is imperative that future outcome studies differentiate
SIP from NEC in the primary disease cohorts
SIP and NEC are preventable diseases







No early steroids or NSAIDs
Use feeding guidelines, initiate feeding advances early
Promote breast milk feeding at every opportunity
Use glycerin as appropriate
Minimize blood draws and transfusions (draw retics with HCTs)
Wash your hands between babies
Pay attention to aspirates that “stack”, ignore those that don’t,
ignore all colors but dark green.
 Don’t over wean the respiratory support or the isolette temp
while advancing feeds
 Quarantine infants with NEC to minimize the chance of NEC
clusters (contact precautions).
The End