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Note: Tables and figures
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Introduction
Necrotizing enterocolitis (NEC)
is a common neonatal gastrointestinal disease that
affects approximately 11% of premature neonates weighing
less than 1500 g (Berseth 1990, Uauy et. al., 1991). The
average mortality is 20% to 40%, and survivors after
either medical or surgical therapy can present with
failure to thrive (Berseth 1990), feeding abnormalities
(Uauy et. al., 1991), diarrhea, or bowel obstruction (Berseth
1990, Eibl et al., 1988). The etiology of NEC is
multifactorial, and the most important risk factors are
prematurity, hypoxia and/or intestinal ischemia, and
enteral feeding and gastrointestinal bacteria
colonization (Halac et al., 1990). The association of
such risk factors might trigger a local inflammatory
cascade with release of inflammatory mediators,
resulting in NEC (Siu et al., 1998). Early signs of NEC
are indistinguishable from sepsis neonatorum (Walsh,
Kliegman, & Hack 1989). The usual presentation includes
abdominal distension, gastric residuals, bilious
vomiting, and bloody stools. Lethargy, apnea, and
hypoperfusion also may be a prominent feature (Halac et
al., 1990, Siu et al., 1998, Walsh, Kliegman, & Hack
1989, Sonntag et al., 2000).
Since
prematurity is the most important risk factor associated
with NEC, possible therapeutic approaches that promote
maturation of the gastrointestinal mucosal barrier (Vohr
et al., 2000), such as the prenatal administration of
corticosteroids (Rabinowitz et al., 2001), have been
explored. With the increased survival of very low birth
weight (VLBW) and premature infants, the incidence of
NEC has been increasing (Berseth 1990, Halac et al.,
1990, Siu et al., 1998, Walsh, Kliegman, & Hack 1989,
Sonntag et al., 2000, Rabinowitz et al., 2001) and at
present ranges between 1-5% of all admissions in the
neonatal intensive care unit. Inspite of appreciable
medical and surgical therapy, the mortality has ranged
between 20-50 percent. Since a combination of factors
initiate and propagate the disease and the pathogenesis
is incompletely understood (Eibl et al., 1988, Sonntag
et al., 2000, Rabinowitz et al., 2001, Edelson 1999)
.various preventive measures have been unsuccessful (Berseth
1990, Eibl et al., 1988, Walsh, Kliegman, & Hack 1989,
Sonntag et al., 2000, Rabinowitz et al., 2001). Greater
emphasis is placed on the early recognition of disease,
so that prompt management may be initiated to lessen the
severity and complication of this disease.
Preterm
infants are at increased risk of adverse neonatal
outcomes (Edelson 1999, Dimmitt et al., 2003). However
they frequently demonstrate intolerance of milk feeds
and have been shown to have an increased incidence of
necrotizing enterocolitis (NEC) (Maalouf et al., 2000).
Since NEC is an infant disease it is necessary to
identify disease burden in hospital setting. The
purposes of our study were: 1) to provide
epidemiological statistics of necrotizing enterocolitis
in university hospital, and 2) to determine the clinical
outcome of TPN in necrotizing enterocolitis treatment.
Lastly, but not least, we seek to identify the
likelihood associated with necrotizing enterocolitis
among pediatric patients.
Study
significance lies under the potential evaluation of
current and past clinical practices for the management
of NEC. Given the increase of mortality and morbidity
per annum with increased risk among preterm infants, our
emphasis is to review the teaching university practice
regarding the therapeutic effectiveness of care and
clinical outcomes. The majority of cases in NICU require
TPN because of either gastrointestinal (GI)
malformations or necrotizing enterocolitis. TPN is the
main source of nutrients during the transition period
and should be started in the first 48 hours of life when
possible.
Methodology
Study description and location:
Study was done in University Hospital
(HUSM), Kuban Kerian, Kelantan, Malaysia. A descriptive
cross-sectional observational study was designed on
cases of necrotizing enterocolitis. Study was conducted
as five-year retrospective review from January 2003 till
August 2007. Patient medical records were reviewed and
data extracted by using a standardized data
collection form. Study scope was based on the patients
diagnosed with NEC between the duration of January 2003
to December 2007.
Sampling Technique:
Universal sampling technique was employed as to include
all the cases being identified in the five years of
retrospective study frame. Vehicle of the study was
records of medication profile of patients available in
record office of the Hospital. The patient records were
sorted out according to the inclusion and exclusion
criteria employed in this study allowing us to include
all the registered cases for NEC in the NICU (all term,
preterm and post-term neonates) from January 2003 till
December 2007.
Ethical approval:
Study protocol was approved from the Ministry of Health
Malaysia and also with the local Clinical Research
Committee.
Data Analysis:
Collected data were then analyzed by using statistics
software name Statistical Package for Social Science,
(SPSS®12.0). Descriptive statistic was used as
appropriate against the prelimary identification of the
problem. For categorical data, the correlation chi
squire test was used to test levels of significance (p <
0.05). For the secondary evaluation of risk (likely to
develop), relative risk interval (with 95% confidence
interval (CI)) was calculated against risk ratio.
Confidence interval 95 % was taken for level of
significance with 5% margin of error.
Results & Discussions
Demographic Data
By
the end of the study period, 46 patients were
identified. Majority of the patients were Malays 44
(95.6%) patients. This is followed by Chinese 1 (2.2%)
patient and 1 (2.2%) others. Gender distribution was
equivalent with 22 (47.8%) females and 24 (52.8%) males.
Birthweight is recognized as one of the high predictor
for NEC among neonates (Siu et al., 1998, Sonntag 2000,
Vohr et al., 2000, Rabinowitz et al., 1990, Brown &
Sweet 1978, Rayyis et al., 1999). We found that the
majority, 39 (84.8%) of neonates, were under the range
of ≤ 2500 g. While the distribution pattern showed that
among these 39 birthweight cases about 24 (61.5%) of
them were in between 2000gms – 2500 g (Maalouf et al.,
2000, Brown & Sweet 1978, Kamitsuka, Horton & Williams.
2000). By using modified Bell’s (Bell & Acarregui 2001)
classification of NEC, we found that 26 (56.5%) had
stage I of suspected disease, 14 (30.4%) had on
definitive stage II and 3 (13.1%) were on advanced stage
III.
We
compared the per annum incidence of necrotizing
enterocolitis among NICU neonates. We reviewed the
number of admissions on a yearly basis to the NICU and
second set of information reflects the number of NEC
cases among these NICU admission. We found that
admission to the NICU does not predict the NEC
susceptibility as 1.34% (Rayyis et al., 1999) incidence
was found in 2005 among 1119 neonates, while only 0.42%
(Siu et al., 1998) among 1187 in 2006. Similarly 1.16% (Maalouf
et al., 2000) among 1031 were identified in year 2003.
We identified that NICU admission load is not matter of
concern against the susceptibility of NEC among neonates
(Table 02). Overall indicators of nutritional support
and feeding practices such as: total parenteral volume,
number of days to regain birth weight (Dimmitt et al.,
2003, Caplan et al., 1997, Juul, Joyce, Zhao & Ledbetter
1999, Ledbetter & Juul 2000), days to reach full enteral
feeds, duration of parenteral nutrition and days to
reach 1800-2000g weight among others, serve to
underscore the variation in clinical practices that may
directly or indirectly affect NEC prevalence (Kliegman
1990).
Duration of TPN used among the gender distribution
showed no significant difference between male and female
neonates as majority of both (58.3% vs 72.7%) remained
on TPN more than 9 days. But it was found that male
neonates were more prone to develop renal and liver
complications as compared to females. On other hand
female neonates showed increased recovery with
complications as with male neonates with low mortality
ratio, Robert et al., (1997) found that the necrotizing
enterocolitis infant mortality rate was higher for males
than females. But birth weight showed no significant
association with duration of TPN and outcomes but we
observed a significant increase in complication
(bacterial sepsis, thrombocytopenia and renal
complications) among VLBW neonates (1000g to 2000g).
Secondly we found an inverse relationship between
gestational age and duration of TPN. For the clinical
outcomes of NEC, we observed a high rate of recovery
with complication in suspected disease, but high rate of
deaths with definitive disease. (Table 03). A
significant relationship
was found between
gestational
age and duration of TPN with p-value
<0.001, Birth weight and complication
was
significant with p-value
= 0.041 and NEC cases and outcomes
were
significant with p-value
= 0.005 (Table
03).
Our
study identified that infants born at less than 32
weeks gestational age and who survived for at least five
days have a higher incidence of NEC as compared to
patients born at more than 32 weeks of gestation (Kovacs
& Papageorgiou 2007 ). While doing the comparison
between the birthweight and gestational age we found
that a gestational age of more than 32 weeks were found
in all domain of birthweights but with highest value in
between 2000g – 2500g, followed by 1500 g-1999g (fig
01). Very low birth weight infants growing poorly tend
to have higher prevalence of impaired immune
system(Rayyis et al., 1999, Berseth, Bisquera & Paje
2003, Schanler et al., 1999, Lopez, Taeusch, Findlay &
Walther 1995). We sought to identify potential medical
complications found among neonates with NEC, and we used
descriptive statistics and found abdominal distention 43
(93.5%), jaundice 36 (78.3%), gastric aspiration 34
(73.9%), failure to tolerate feeding 30 (65.2%), and
dilated bowel 27 (58.7%). We also identified that
pneumotosis intestinalis was present in all 46 NEC
cases. Most premature infants that require nutritional
support need TPN because of the immaturity of the
gastrointestinal tract. Parenteral nutrition was however
not free of complications; infections, mucosal atrophy,
hepatic damage and cholestasis. In addition osteopenia
of prematurity have been associated with prolonged use
of TPN (Arant, Friis-Hansen,
Hay 1993).
Majority (58.7%) of the neonates received solution A,
followed by 23.9% with AB1, then 13.1% with AB2 and 4.3%
with Sol. C (Solution A: glucose + calcium, Solution B:
amino acid + electrolytes, Solution C: lipid, AB1= 85%
of A + 15% of B and AB2= 75% of A + 25% of B). Duration
of therapy ranged from a minimum of 5 days to more than
14 days (Figure 02). Recommendations on nutrient intake
from enteral and parenteral sources (Caplan, Hedlund,
Adler & Hsueh 1994) in preterm infant are usually
established based on needs for growth and optimal
development (Walker 1997, Caplan, Hedlund, Adler & Hsueh
1994); in addition we should consider the need to
prevent the health risks associated with nutritional
deficiency or excess (Juul, Joyce, Zhao, Ledbetter 1994,
Ledbetter & Juul 2000, Lawrence et al., 1997). The
information base to scientifically support (Ledbetter &
Juul 2000, Lucas, Bloom & Aynsley-Green 1986) the
definition of nutritional needs of neonates, especially
for extremely low birth weight (ELBW) ( < 1000 gram )
neonate is quite limited for most specific nutrients
(Gross et al., 1993).
Reasons
for discontinuation of TPN in our study were ability to
tolerate oral feeding among 29 (63.04%) infants, disease
recovery among 4 (8.7%) and others reasons for 13
(28.26%) including death, cyanosis, shock, liver and
renal complications (Sonntag et al., 2000, Edelson et
al., 1999, Heird 1999, Arant,
Friis-Hansen & Hay 1993, Eyal,
Sagi, Arad & Avital 1982). The clinical outcomes
following the use of TPN were that 15 (32.6%) infants
recovered without complications,
18 (39.1%) were recovery with complications
and 13 (28.3%) died. The medical
complications included
bacterial sepsis 20 (60.6%), thrombocytopenia 10
(30.3%), liver
complications 2 (6%) and renal
complications 1 (3%).
Unfortunately, the achievement of appropriate
therapeutic goal was not an easy task considering the
special needs of the premature infants resulting from
the immaturity of the gastrointestinal tract (Caplan et
al., 1999), difficulties in metabolic adaptations and
the concomitant neonatal medical disease conditions (Kliegman
1990, Walker 1997). The rate of death was quite high
(28.3%) in our study similar to finding identified by
Wiswell et al in 1988. The death rate of 61.5% among
male infants was significantly higher as compared to
female infants (Brown & Sweet 1978, Heird 1999, Eyal,
Sagi, Arad & Avital 1982). Majority of deaths (76.2% )
were found with birth weight less than 2000g, among them
60.0% deaths were between the range of <1000g to 1499g
and 40.0% in the range of 1500g to 1999g (Eyal, Sagi,
Arad & Avital 1982, Kovacs & Papageorgiou 2007).
It was
prevailed that 84.6% of infant deaths after 14 days of
TPN use may be associated with the significant use of
either solution A and AB1 alone or in combinations.
Hence, all VLBW infants should be closely monitored for
early signs of NEC independent of feeding strategy used
(Sonntag et al., 2000, Edelson et al., 1999). As we
managed to find out that birth weight had no influence
on NEC class, but gestational age <30 weeks was
associated with a higher number of deaths than > 30
weeks gestational age babies. Males with pre-term
delivery were more prone to definitive class of disease,
than females with more advanced status. Mode of delivery
either simple vaginal labor or emergency lower segment
caesarian section had no clinical impact on the number
of deaths/ NEC class. Major causes of deaths were
septicaemia (38.5%), thromboembolic events (30.7%),
cyanosis (15.4%), and others (15.4%) (40). All death
cases showed no breast feeding or intolerance of enteral
feeding similar with the findings of Pickard et al
(2009).
Conclusion
We concluded that use of TPN for
more than 14 days with low birth weight / gestational
age less than 30 weeks highlighted a risk of developing
clinical manifestation as well as death.
Majority patient was treated with Sol.A
and duration of TPN > 14 days.
Providing TPN was wrought with unique
potential risks and complications to these fragile
infants and calls for a diligent interdisciplinary team
approach. The implementation of standardized feeding
protocols by birth weight categories (e.g., <750 g;
750-1000; 1000-1250;1250-1500) decreases the variability
in feeding practice and lowers the risk of NEC,
limiting the use of riskier feeding methods.
Recommendation
Current knowledge on nutritional
needs of premature infants underscores the importance of
providing appropriate nutrients to premature infants for
immediate survival, growth and neurodevelopment, and for
long-term health. Gastrointestinal priming has emerged
as a safe and effective practice with demonstrable
beneficial effects for the VLBW by allowing earlier
establishment of enteral nutrition, decreasing time of
exclusive total parenteral nutrition and improving
weight gain. Although TPN has not demonstrated to
enhance the risk of NEC, we should be concerned with
avoiding gut atrophy and thus should start early trophic
feeds even in the smallest and sickest infants
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