Content uploaded by Nadja Haiden
Author content
All content in this area was uploaded by Nadja Haiden on Jan 30, 2015
Content may be subject to copyright.
DOI: 10.1542/peds.2011-3634
; originally published online November 26, 2012; 2012;130;e1600Pediatrics Bernd Jilma, Angelika Berger and Andreas Repa
Nadja Haiden, Florentine Norooz, Kathrin Klebermass-Schrehof, Anna Sophie Horak,
Preterm Infants
The Effect of an Osmotic Contrast Agent on Complete Meconium Evacuation in
http://pediatrics.aappublications.org/content/130/6/e1600.full.html
located on the World Wide Web at:
The online version of this article, along with updated information and services, is
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
publication, it has been published continuously since 1948. PEDIATRICS is owned,
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
at Bibliothek der MedUniWien (309961) on December 27, 2012pediatrics.aappublications.orgDownloaded from
The Effect of an Osmotic Contrast Agent on Complete
Meconium Evacuation in Preterm Infants
WHAT’S KNOWN ON THIS SUBJECT: Delayed meconium passage
impairs gastrointestinal function in premature infants. No
intervention has been identified that accelerates meconium
passage sufficiently. Gastrografin is an osmotic contrast agent
used for radiologic examination of the bowel or for conservative
treatment of uncomplicated meconium ileus.
WHAT THIS STUDY ADDS: Gastrografin did not accelerate
complete meconium evacuation but stimulated gastrointestinal
motility in a randomized, placebo-controlled trial in premature
infants. Application shortened the time to full enteral feedings
and hospital stay but was associated with necrotizing
enterocolitis as a possible adverse event.
abstract
OBJECTIVE: To determine whether enteral application of the osmotic
contrast agent Gastrografin accelerates complete meconium excre-
tion and improves feeding tolerance in very low birth weight infants.
METHODS: This study was a stratified, randomized, placebo-controlled
trial in premature infants with a birth weight ,1500 g and
a gestational age ,32 weeks who received 3 mL/kg Gastrografin
diluted 1:3 with water within their first 24 hours of life, or placebo.
RESULTS: Passage of last meconium occurred after a median of 7 days
(95% confidence interval: 6–9 days, n= 39) in the intervention group
and after 8 days (95% confidence interval: 7–10 days, n= 39) in the
control group (P= .61); however, Gastrografin application was asso-
ciated with a 7.5-day shorter time to full enteral feedings, a 24-day
shorter stay in the NICU, and a 17-day reduction in the overall hospital
stay in the intervention group compared with the control group. A
numerically higher incidence of necrotizing enterocolitis (21%) was
observed in the intervention group, however.
CONCLUSIONS: Gastrografin application did not accelerate meconium
evacuation, but the higher stool frequency during the first week of life
had a beneficial effect on the time to full enteral feedings and later
hospital stay; however, it may increase the necrotizing enterocolitis
risk. Further investigations are needed with modified protocols, and
the prophylactic use of Gastrografin cannot currently be recommended
without further clinical trials. Pediatrics 2012;130:e1600–e1606
AUTHORS: Nadja Haiden, MD,
a
Florentine Norooz, MD,
a
Kathrin Klebermass-Schrehof, MD,
a
Anna Sophie Horak,
MD,
a
Bernd Jilma, MD,
b
Angelika Berger, MD,
a
and Andreas
Repa, MD
a
a
Division of Neonatology, Intensive Care and Neuropediatrics,
Department of Pediatrics, and
b
Department of Clinical
Pharmacology, Medical University of Vienna, Vienna, Austria
KEY WORDS
premature infant, Gastrografin, meconium passage, enteral
feedings, hospital stay
ABBREVIATIONS
CI—confidence interval
GA—gestational age
ITT—intention-to-treat
NEC—necrotizing enterocolitis
PP—per protocol
VLBW—very low birth weight
This trial has been registered at www.clinicaltrials.gov (identifier
NCT01515696) and at Eudract (identifier 2007-00851-33).
www.pediatrics.org/cgi/doi/10.1543/peds.2011-3634
doi:10.1543/peds.2011-3634
Accepted for publication Aug 31, 2012
Address correspondence to Nadja Haiden, MD, Department of
Pediatrics, Division of Neonatology, Intensive Care Medicine and
Neuropediatrics, Medical University of Vienna, Waehringer Guertel
18-20, A-1090 Vienna, Austria. E-mail: nadja.haiden@meduniwien.ac.at
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2012 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
e1600 HAIDEN et al at Bibliothek der MedUniWien (309961) on December 27, 2012pediatrics.aappublications.orgDownloaded from
In premature infants the establishment
of proper gastrointestinal function is
challenging and often associated with
delayed meconium passage. Meconium
evacuation depends on gestational age
(GA) and birth weight
1
: the more im-
mature an infant is, the later meco-
nium passage starts, and the longer
meconium passage lasts. The mean
duration of meconium evacuation in
premature infants with a GA ,30 weeks
is 8 days, whereas mature infants ex-
crete their meconium in 2 days.
1
The
obstruction of deep intestinal segments
by tenacious, sticky meconium fre-
quently leads to gastric residuals, a dis-
tended abdomen, and delayed food
passage,
2
whichextendsthetimeto
reach full enteral feedings. As a conse-
quence, it prolongs the probability of
acquiring infections due to intravenous
access for parenteral nutrition and
increases the duration of the hospital
stay of the infant. The relation between
meconium passage and feeding toler-
ance remains controversial, however.
Although 1 study revealed that there is
little concordance between first meco-
nium passage and feeding tolerance,
3
Mihatsch et al showed that rapid and
complete excretion of meconium is cru-
cial for oral feeding tolerance and has
a positive effect on it.
4
Recently, we per-
formed a prospective randomized trial
to determine whether repeated pro-
phylactic applications of small-volume
glycerin enemas accelerate passage of
meconium in very low birth weight
(VLBW) infants.
5
Disappointingly, appli-
cation of enemas did not accelerate me-
conium evacuation. A possible reason for
the ineffectiveness of glycerin enemas is
that the volume used was too small to
mobilize tenacious meconium sufficiently
from the colon and small bowel.
Gastrografin is a radiopaque contrast
agent for the gastrointestinal tract that
can be administered orally or rectally. In
neonatal intensive care, Gastrografinis
used for the treatment of meconium
ileus.
6,7
Gastrografin has a strong os-
motic effect and leads to water influx
into the intestinal lumen. It may be hy-
pothesized that the peristaltic move-
ment is accelerated, and the premature
infant excretes stool during the hours
after application. Gastrografinmightbe
more effective in mobilizing meconium
from the small bowel and deep parts of
the colon. We hypothesized that enteral
application of Gastrografin accelerates
meconium evacuation in premature infants
and thereby enhances feeding tolerance in
this population.
METHODS
Study Design
The study design was a randomized,
double-blind, placebo-controlled trial
performed at the NICUof the Department
of Pediatrics, Medical University of
Vienna/Austria from October 2007 to
February 2011. Premature infants with a
birth weight #1500 g and a GA #32
weeks were eligible for inclusion in the
study. Randomization lists were gener-
ated by using a Web-based program
8
by a clinical pharmacologist (B.J.) not
otherwise involved in the conduct of the
trial. Randomization assignment was
performed by using sealed opaque en-
velopes. Block sizes of 10 contained 5
subjects of each group. Infants were
stratified according to their GA (,28 vs
$28 weeks) and assigned randomly to
the intervention or control group. The
study was approved by the ethics com-
mittee of the Medical University of Vienna.
After full explanation of the procedure,
written informed consent was obtained
from the parents.
Exclusion Criteria
Exclusion criteria were defined as
major congenital disorders, chromo-
somal aberrations, systemic metabolic
disease, and preexisting gastrointestinal
abnormalities (ie, Morbus Hirschsprung).
Because Gastrografinisanosmoticcon-
trast agent, it is possible that Gastrografin
can aggravate preexisting conditions of
severe hypotension.
9
Severe hypotension
was defined as persisting hypotension
even under catecholamine (eg, adrena-
line, epinephrine) support for .3hours.
Study Medication
Gastrografin (Bayer, Leverkusen, Ger-
many) is an osmotic, ionic contrast
agent with an osmolarity of 2150 mOsmol/
L. One hundred milliliters of gastroenteral
solution contain 10 g of sodium amido-
trizoate and 66 g of meglumine amido-
trizoate. The iodine concentration is 370
mg/mL. The contrast-enhancing sub-
stance of Gastrografinisasaltofthe
amido (dia-) trizoic acid in which the
radiograph-absorbing iodine is present
in a stable chemical bond. Absorption of
amidotrizoic acid, the radiopaque agent
of Gastrografin, after oral administra-
tion is only 3%. In newborn infants, the
manufacturer recommends diluting
Gastrografin 1:3, with water for in-
jection
10
resulting in a final osmolarity
of 717 mOsmol/L. Thyrotropin levels
were measured on the fourth, 14th,
and 28th days of life to monitor possi-
ble systemic adverse effects of the
study medication on thyroid function.
Study Groups
Infants in the intervention group were
administered 3 mL/kg of Gastrografin
orally via gastric tube, diluted 1:3 with
water (total 9 mL/kg) within the first 6 to
24 hours of life. As the primary end point
was time to complete meconium evac-
uation, starting as early as possible was
assumed to increase assay sensitivity.
The control group received the equiva-
lent amountof water (9 mL/kg). Basedon
the order in which infants entered the
study, infants were assigned a random-
ization number (whereby stratification
was applied for GA at randomization).
The details of the randomization were
unknown to the investigator and the site
staff except for the study nurse, who
ARTICLE
PEDIATRICS Volume 130, Number 6, December 2012 e1601
at Bibliothek der MedUniWien (309961) on December 27, 2012pediatrics.aappublications.orgDownloaded from
prepared and applied all the study
medication and was not otherwise in-
volved in the conduct of the trial.
After admission of the patient to the
NICU, the infant received primary care
according to standard principles of
neonatal intensive care (monitoring of
oxygen saturation, heart rate, blood
pressure, temperature, fluid intake, and
urine rate, and intravenous access by
peripheral or central venous line).
To exclude an already existing perfora-
tion or a gastrointestinal abnormality,
a plain abdominal radiograph was per-
formedbefore the beginning ofthe study.
Duringthe study,unblindingwasavoided
by covering the abdomen of the infants
with a small lead gown used for pre-
mature infa nts when they receiv ed chest
radiographs. The nursing staff assessed
the quality of stools as “meconium”
(black,thick,sticky)or“nonmeconium”
by appearance and documented data
into the patient documentation system.
The time to complete meconium evacu-
ation was defined as the day of life on
which the last meconium was passed.
Documentation of stool consistency, color,
and amount was continued until the end
of each infant’s stay at the NICU. The ob-
servation period ended when the infant
was transferred or discharged.
11
Feeding Schedules
Standardized Feeding Regimen
All preterm infants routinely received
a gastric tube during the first hour of
life. Within the first 12 hours of life,
minimal enteral nutrition was started,
definedas1mLofnutrition(preterm
formula or breast milk) every 3 hours.
The introduction of enteral feedings
was achieved by using colostrum of
the premature infant’s mother.
12
If no
breast milk was available, undiluted hy-
drolyzed preterm formula (Prematil HA;
Milupa, Puch bei Hallein, Austria) or Beba
F (Nestle, Vevey, Switzerland) was used.
13
As soon as breast milk was available,
nutrition was changed to breast milk.
The daily amount of nutrition was in-
creased by 20 mL/kg/d.
14,15
Full enteral
feedings were defined as 140 mL/kg.
16
At
an enteral intake of 100 mL/kg, breast
milk was supplemented with breast milk
fortifier, such as Aptamil FMS (Milupa),
FM 85 (Nestle). If the concentration of the
fortifier was increased, the volume of
feedings remained the same for 2 days.
16
Gastric Residuals and Feeding
Intolerance
Detailed information concerning gas-
tric residuals and feeding intolerance is
given in the Supplemental Information.
Data Collection
Demographic data were recorded for all
infants. Infants were monitored, with
documentation of clinical condition of
the abdomen (size, tension, peristalsis,
apparent standing intestinal loops),
stooling pattern, ventilation, and venti-
lator support (positive end-expiratory
pressure) every hour during the first
48 hours after Gastrografinadminis-
tration. Blood pressure was monitored
continuously by an arterial line during
the first 3 days of life. Electrolytes and
urinary output in milliliter per kilogram
per hour were monitored every 12
hours. During the further study peri-
od, the following parameters were re-
corded daily: body weight, volume of
enteral and parenteral fluids, volume
and color of gastric residuals before
every meal, abdominal girth, presence
of gross abdominal distension, pres-
ence of persistent visible loops without
peristalsis, presence of abdominal ten-
derness, stool pattern, and respiratory
support. Concomitant application of
suppositories and enemas were re-
corded as well as laboratory parame-
ters of infection (complete blood cell
count, C-reactive protein, interleukin-8,
blood culture), and antibiotic therapy.
Necrotizing enterocolitis (NEC) was de-
fined according to the stages by Bell as
proven NEC grade 2a.
17
The physician
assessing the NEC radiographs was
blinded to the treatment assignment.
Sample Size Calculation and
Statistical Analysis
We hypothesized that the enteral ap-
plication of Gastrografin during the first
24 hours of life can accelerate meco-
nium evacuation, defined as the time
until the last meconium was passed in
days (primary outcome).
Chart reviews of previouspatients at our
department indicated that the mean
time to meconium evacuation was 9.32
days (SD 65.1). We performed an open
pilot study in 20 subjects: in the in-
tervention group, we observed 7.38 days
to meconium evacuation (SD 61.8); in
the control group, we observed 8.91
days to meconium evacuation (SD 6
1.2). The pilot study suggested a 17%
difference between groups, so we cal-
culated to have a power of 95%, if we are
able to include 37 subjects in each
group of the per protocol (PP) analysis.
Secondary outcome variables were
feeding tolerance as evidenced by “start
of enteral feeding,”“amount of nutrition
on the 14th day of life,”and “day of full
enteral feedings”(defined as 140 mL/kg
of supplemented breast milk or formula).
To evaluate the efficacy of Gastrografin,
the stooling frequency during the first 2
weeks of life was calculated.
Results of primary and secondary out-
come variables are expressed as the
median and the range in tables and as
median and 95% confidence intervals
(CIs) in the text. Given non-normal dis-
tribution of the data, all comparisons
were performed by using nonparamet-
ric tests. The x
2
test was used for di-
chotomous (demographic) variables.
The Mann–Whitney Utest was used to
evaluate differences in the primary and
secondary outcome. Multivariate logis-
tic regression models (including these
variables: birth weight, group, NEC, and
persistent ductus arteriosus) were used
e1602 HAIDEN et al at Bibliothek der MedUniWien (309961) on December 27, 2012pediatrics.aappublications.orgDownloaded from
to identify the possible influence of
predictors. For all tests, a Pvalue ,.05
was considered as statistically signifi-
cant. SPSS statistical software system
(version 16.0; SPSS Inc, Chicago, IL) was
used for all calculations.
RESULTS
Study Population
During a 3-year study period, 789 infants
were eligible for enrollment in the study.
Six hundred ninety-three infants were
excluded for the following reasons: in-
formedconsent was not obtained intime
(n= 660), parental refusal (n=21),and
12 infants died before randomization.
The final cohort included 96 infants.
Owing to protocol violations for 18 infants
(study medication was not administered
or the infant vomited, n=5;transfer
before the 14th day of life/primary out-
come could not be evaluated, n= 13),
recruitment in excess of the calculated
sample size was necessary. Because of
the protocol violations, both the PP and
intention-to-treat (ITT) population were
analyzed. The PP population included 78
infants. Both analyses led to comparable
results, suggesting that the protocol
violations did not introduce any bias.
Baseline Characteristics and
Outcome Data
Baseline characteristics and outcome
data between study groups were
balanced and are summarized in
Table 1. No differences between the
groups or between the ITT and PP
population were observed; however,
in the PP population, 8 treated infants
(21%) and 3 control infants (8%) de-
veloped NEC. In the intervention group,
the mortality related to NEC was 13%
(n= 5) vs 0% in the control group.
Onset of NEC was between the 12th
and the 27th days of life and not con-
founded by type of enteral feedings
(breast milk or formula).
Primary and Secondary Outcome
Clinical characteristics, including feed-
ing and stooling variables of study
patients, are given in Table 2. In the PP
group, the primary end point meconium
evacuation lasted a median of 7 days
(95% CI: 6–9 days) in the intervention
group and8 days (95% CI: 7–10 days; not
significant) in the control group. A post-
hoc subgroup analysis showed no dif-
ference in meconium evacuation be-
tween infants with a birth weight ,1000
g and those with birth weights of 1001 to
1500 g. Time tofull enteral feedings was
7.5 days shorter in the intervention group
(median, 19 days; 95% CI: 12–33 days)
than in the control group (median, 26.5
days; 95% CI: 26–42 days; P= .05). This
reduction was associated with a 24-day
shorter stay in the NICU and a 17-day
reduction in the overall hospital stay in
the intervention group compared with
the control group (Table 2). A detailed
analysis of the stool pattern showed
that infants in the intervention group
produced significantly more stools dur-
ing the first week of life than infants in
the control group (controls: 7.5 stools
versus intervention: 10.5 stools, P= .013;
Table 3). The mean daily stool frequency
also was higher in the intervention group.
In a multivariate analysis (logistic re-
gression model), treatment group
remained a significant independent
predictor of the duration of hospitali-
zation at our tertiary care center, when
days to total enteral nutrition were
entered in the model (P,.05, b= .31).
Side Effects After Administration of
Study Medication
No pathologic results were observed
in baseline radiograph films obtained
before Gastrografin use. Gastric resid-
uals were analyzed separately during
the first 24 hours after administration of
the study medication, and data are given
in Table 4. Infants in the control group had
significantly more frequent bloody gastric
residuals (18%) than in the intervention
group (3%; P= .03). These data indicate
that the application of Gastrografin
caused no local mucous irritations in the
stomach. None of the infants developed
hypotension with Gastrografinuseor
within 24 hours after Gastrografinad-
ministration. Furthermore, no infant in
either group developed pathologic thyro-
tropin values.
TABLE 1 Demographic Characteristics and Outcome Data Concerning the Study Population, Divided Into ITT and PP Populations
ITT PP
Control Group, N= 49 Intervention Group, N= 47 Control Group, N= 39 Intervention Group, N=39
Birth weight, g; median (range) 900 (480 to 1414) 870 (490 to 1440) 795 (480 to 1414) 870 (490 to 1440)
GA, wk; median (range) 27 + 3 (23 + 4 to 31 + 2) 26 + 6 (24 + 1 to 30 + 5) 26 + 6 (23 + 4 to 31 + 2) 26 + 6 (24 + 1 to 30 + 5)
GA, d; median (range) 192 (165 to 219) 188 (169 to 215) 188 (165 to 219) 188 (169 to 215)
Male gender, N(%) 29 (59) 20 (42) 22 (56) 14 (26)
Deceased, N(%) 7 (14) 8 (17) 6 (15) 7 (18)
NEC, N(%) 4 (8) 10 (21) 3 (8) 8 (21)
NEC surgery, N(%) 1 (2) 6 (13) 1(3) 6 (15)
Intraventricular hemorrhage I + II, N(%) 13 (27) 9 (19) 9 (23) 6 (15)
Intraventricular hemorrhage III + IV, N(%) 3 (6) 3 (6) 3(8) 3 (8)
Persistent ductus arteriosus, N(%) 28 (57) 22 (46) 24 (61) 18 (46)
The x
2
test was used for dichotomous (demographic) variables. The Mann–Whitney Utest was used to evaluate differences in the primary and secondary outcome. There were no significant
differences in baseline characteristics or outcome data between groups (P..05).
ARTICLE
PEDIATRICS Volume 130, Number 6, December 2012 e1603
at Bibliothek der MedUniWien (309961) on December 27, 2012pediatrics.aappublications.orgDownloaded from
Periods of Feeding Intolerance and
Use of Suppositories and Enemas
No differences were observed between
groups in periods of mild or severe feeding
tolerance until full enteral feedings
(Table 5); however, infants in the control
group received significantly more glyc-
erin suppositories until complete meco-
nium excretion was achieved (P= .008).
DISCUSSION
This double-blind, randomized, placebo-
controlled trial examined the effect of
enterally applied Gastrografinonmeco-
nium evacuation in VLBW infants. The re-
sults indicate that the osmotic contrast
agent Gastrografin did not accelerate
completemeconium excretion; however,
the stool frequency was significantly
higher during the first week of life, in-
dicating that gastrointestinal mobility
was enhanced. Time to full enteral feed-
ings and hospital stay in the NICU were
significantly shorter in the Gastrografin
group as compared with the group re-
ceiving placebo.
Gastrointestinal Function
In the literature, the relationship be-
tween meconium evacuation and feed-
ing tolerance in premature infants is
controversial. Although some authors
showed a link between feeding toler-
ance and meconium passage,
4
others
could not prove a causality.
3
The estab-
lishment of proper gastrointestinal func-
tion is characterized by feeding tolerance
and a normal, regular stool pattern,
however. The so-called “meconium ob-
struction of prematurity”
18,19
is a distinct
clinical condition in VLBW infants with
obstructive symptoms such as abdominal
distension occurring several days after
having passed some initial meconium.
15
This meconium obstruction should be
avoided by all means, but so far it
remains unclear if meconium passage
can be influenced prophylactically (eg,
by enemas). For therapeutic purposes,
agents such as N-acetylcysteine and
Gastrografin (an osmotic contrast
agent) are proven to be effective in
solving gastrointestinal obstructions
caused by meconium.
18
Gastrografin
can be administered orally or as an
enema and is used as a contrast me-
dium for the radiologic examination of
the gastrointestinal tract. Gastrografin
can be given by enema for conservative
treatment of an uncomplicated meco-
nium ileus. There is an advantage to the
high osmotic pressure of the contrast
medium; the surrounding tissue is
forced to release considerable amounts
of fluid, which then flows into the gut
and dissolves the inspissated (thickened
or hardened) meconium. The intention
of this trial was to investigate if Gastro-
grafin also can be used prophylactically
to accelerate complete meconium ex-
cretion. Although Gastrografindidnot
accelerate meconium evacuation, the
TABLE 2 Clinical Characteristics of the Study Population, Including Feeding and Stooling Pattern Divided Into ITT and PP Populations
ITT PP
Control Group, Median
(Range); N=49
Intervention Group, Median
(Range); N=47
PControl Group, Median
(Range); N=39
Intervention Group, Median
(Range); N=39
P
Duration of stay in the NICU, d 62 (3–179) 54 (4–161) .48 78 (4–179) 54 (4–161) .02*
Duration of hospital stay, d 70 (4–179) 61 (4–209) .35 78 (4–179) 61 (4–209) .09
Wt at discharge home, g 2380 (1614–4650) 2271 (1650–6720) .64 2328 (1614–4070) 2256 (1650–6720) .61
Introduction of oral feedings, day of life 2 (1–6) 1 (1–8) .92 2 (1–6) 2 (1–8) .68
Feeding amount on 14th day of life, mL/kg 48.15 (0–156) 59 (0–166) .40 62.5 (0–156) 67 (0–166) .97
Full enteral feedings, day of life 26 (9–109) 19 (10–115) .15 26.5 (9–109) 19 (10–68) .05*
Passage of first meconium, day of life 2 (1–5) 2 (1–4) .38 2 (1–5) 2 (1–4) .57
Passage of last meconium, day of life 7.5 (1–24) 8 (3–16) .67 8 (1–24) 7 (3–16) .61
The Mann–Whitney Utest was used to evaluate differences in the primary and secondary outcome.
*5P,.05.
TABLE 3 Stool Pattern
Control Group,
Mean (SD); N=39
Intervention Group,
Mean (SD); N=39
P
Sum of stools, days 1–14 20.05 (10.13) 23.97 (9.29) .26
Sum of stools, days 1–7 7.56 (4.04) 10.50 (4.09) .013*
Sum of stools, days 8–14 12.49 (7.08) 13.47 (6.26) .84
Mean daily stools, days 1–14 1.46 (0.69) 1.74 (0.63) .07
Mean daily stools, days 1–7 1.09 (0.57) 1.52 (0.57) .02*
Mean daily stools, days 8–14 1.93 (0.9) 1.98 (0.85) .96
The Mann–Whitney Utest was used to evaluate differences in the primary and secondary outcome.
*5P,.05.
TABLE 4 Possible Side Effects of Gastrografin
Gastric Residuals Within 24 h After
Gastrografin Application
Control Group, N(%);
N=39
Intervention Group, N(%);
N=39
P
Bloody 7 (18) 1 (3) .03*
More than 1 time .3 mL/kg 22 (56) 26 (67) .36
Bilious 10 (26) 11 (28) .80
The x
2
test was used for dichotomous (demographic) variables.
*5P,.05.
e1604 HAIDEN et al at Bibliothek der MedUniWien (309961) on December 27, 2012pediatrics.aappublications.orgDownloaded from
stool frequency was significantly higher
in the intervention group compared with
placeboduringthefirst week of life.
These data indicate that gastrointestinal
mobility was enhanced by Gastrografin,
which could have accelerated the time to
enteral feedings. Full enteral feedings
were achieved 7.5 days earlier in the
Gastrografin group compared with the
placebo group, and consequently par-
enteral feedings and intravenous cathe-
ter days were reduced by the same
amount of time. This reduction also was
associated with a shortened hospital
stay. In the Gastrografin group, infants
were discharged from the hospital 17
days earlier than in the placebo
group.
Side Effects and Adverse Events
No severe adverse events were ob-
served in direct context to Gastrografin
application. In 5 infants, problems with
the volume of study medication oc-
curred. The quantity of Gastrografin/
water mixture was 9 mL/kg, which is
a large feeding volume for a premature
infant on his or her first day of life. Three
infants reacted with emesis of study
medication, and 2 infants developed
bradycardia after instillation of 4 to 5
mL. Although nausea and vomiting are
reported to be frequent side effects of
enteral Gastrografin administration,
these problems were observed only in
infants with a birth weight between 500
and 650 g. These smallest premature
infants seemed to be more sensitive to
high feeding volumes than larger neo-
nates. A numerically higher proportion
of infants in the Gastrografin group
(21%) developed NEC, as compared with
the control group (8%). Although this
difference is not significant, an NEC
incidence of 21% in the treatment group
is alarming. A detailed analysis of the
NEC cases showed that all NEC infec-
tions occurred between the end of the
second and the end of the fourth week of
the infant’s life, which is consistent
with the literature.
20
Thus, the de-
velopment of NEC occurred well after
the end of Gastrografin administration;
however, this finding does not exclude
the possibility that Gastrografin might
be a risk factor for the development of
later NEC. Tuladhar et al
21
report a case
of severe Gram-negative sepsis caused
by complete breakdown of mucosal
integrity after enteral Gastrografin
application. In this report, undiluted
Gastrografin was given to a premature
infant for gut stimulation for 6 con-
secutive days; 3 days after the last
dose, the mucosal integrity of the
bowel collapsed, and the infant de-
veloped Gram-negative sepsis. Irre-
versible damage to the mucosa of the
small intestine also was reported in an
animal model, in which newborn rats
received undiluted Gastrografin twice
a day to investigate bacterial trans-
location of Klebsiella bacteria
22
; how-
ever, in neonates Gastrografin should
always be diluted (according to the
summary of product characteristics),
otherwise severe gastrointestinal side
effects may occur. If not only a chance
finding, one may speculate that a base-
line mucosal injury that acts as a nidus
may perhaps be responsible for the
Gastrografin-associated incidence of
NEC occurring many days after its use.
This study raises the question, “Where is
the ‘safety cutoff point’of osmolarity for
the premature gut?”The American
Academy of Pediatrics
23
recommended
that osmolarity of milk or formula
should not exceed 400 mOsmol/L. This
osmolarity is easily exceeded when
therapeutic supplements, such as mul-
tivitamins, are added. The osmolarity of
milk is then increased up to 700 to 1000
mOsmol/L, depending on the supple-
ment added.
24
Supplementation of hu-
man milk or formula is a common
practice in neonatology, even in the
smallest infants, but it usually starts
when premature infants tolerate a mini-
mum of half-enteral feeds.
16
In the cur-
rent study, we used a drug with an
osmolarity of 717 mOsmol/L, which is
comparable to supplemented human
milk, but we administered it during the
first hours of life. It is possible that the
mucosa is much more vulnerable early
after birth than later in life. Factors re-
lated to premature birth, such as selec-
tive mesenteric ischemia in response
to perinatal stress,
25
may aggravate
mucosal damage caused by high os-
molarity.
CONCLUSIONS
Gastrografin did not accelerate com-
plete meconium evacuation in premature
infants but stimulated gastrointestinal
motility, as evidenced by a significantly
higher stool frequency during the first
week of life. This finding was associated
with accelerated full enteral feedings
and shortened stay in the NICU in infants
treated with Gastrografin. Although the
results are of clinical interest, the ob-
served numerical increase in NEC is
a concern that strongly argues against
prophylactic routine use of Gastrografin.
Further clinical trials may be warranted
to examine the safety and efficacy of
Gastrografin at higher dilution.
TABLE 5 Feeding Intolerance, Suppositories, and Enemas
Control Group,
Mean (SD);
N=39
Intervention Group,
Mean (SD);
N=39
P
Periods of mild feeding intolerance until full enteral feedings 1.23 (0.84) 1.13 (0.89) .55
Periods of severe feeding intolerance until full enteral feedings 0.71 (1.03) 0.69 (1.08) .92
No. of glycerine suppositories until complete meconium
evacuation
0.67 (0.77) 0.26 (0.55) .008*
No. of enemas until complete meconium evacuation 1.38 (0.78) 1.15 (0.87) .25
The Mann–Whitney Utest was used to evaluate differences in the primary and secondary outcome.
*5P,.05.
ARTICLE
PEDIATRICS Volume 130, Number 6, December 2012 e1605
at Bibliothek der MedUniWien (309961) on December 27, 2012pediatrics.aappublications.orgDownloaded from
REFERENCES
1. Bekkali N, Hamers SL, Schipperus MR, et al.
Duration of meconium passage in preterm
and term infants. Arch Dis Child Fetal
Neonatal Ed. 2008;93(5):F376–F379
2. Weaver LT, Lucas A. Development of bowel
habit in preterm infants. Arch Dis Child.
1993;68(3):317–320
3. Meetze WH, Palazzolo VL, Bowling D, Behnke
M, Burchfield DJ, Neu J. Meconium passage
in very-low-birth-weight infants. JPEN J
Parenter Enteral Nutr. 1993;17(6):537–540
4. Mihatsch WA, Franz AR, Lindner W, Pohlandt
F. Meconium passage in extremely low
birthweight infants and its relation to very
early enteral nutrition. Acta Paediatr. 2001;
90(4):409–411
5. Haiden N, Jilma B, Gerhold B, et al. Small
volume enemas do not accelerate meco-
nium evacuation in very low birth weight
infants. J Pediatr Gastroenterol Nutr. 2007;
44(2):270–273
6. Emil S, Nguyen T, Sills J, Padilla G. Meconium
obstruction in extremely low-birth-weight
neonates: guidelines for diagnosis and man-
agement. JPediatrSurg. 2004;39(5):731–737
7. O’Halloran SM, Gilbert J, McKendrick OM,
Carty HM, Heaf DP. Gastrografin in acute
meconium ileus equivalent. Arch Dis Child.
1986;61(11):1128–1130
8. Randomization Web site. Available at: www.
randomization.com. Accessed September 30,
2007
9. Rowe MI, Furst AJ, Altman DH, Poole CA. The
neonatal response to gastrografin enema.
Pediatrics. 1971;48(1):29–35
10. Schering. Summary of product: Gastro-
grafin. 2005
11. American Academy of Pediatrics Committee
on Fetus and Newborn. Hospital discharge
of the high-risk neonate. Pediatrics. 2008;
122(5):1119–1126
12. Tsang RC, Uauy R, Koletzko B, Zlotkin SH,
eds. Nutrition of the Pre-term Infant: Sci-
entific Basis and Practical Guidelines. 2nd
ed. Cincinnati, OH: Digital Educational Pub-
lishing, Inc; 2005
13. Mihatsch WA, Högel J, Pohlandt F. Hydro-
lysed protein accelerates the gastrointes-
tinal transport of formula in preterm
infants. Acta Paediatr.2001;90(2):196–198
14. McGuire W, Bombell S. Slow advancement of
enteral feed volumes to prevent necrotising
enterocolitis in very low birth weight in-
fants. Cochrane Database Syst Rev. 2008;(2):
CD001241
15. Morgan J, Young L, McGuire W. Slow ad-
vancement of enteral feed volumes to
prevent necrotising enterocolitis in very
low birth weight infants. Cochrane Data-
base Syst Rev. 2011;(3):CD001241
16. Agostoni C, Buonocore G, Carnielli VP, et al;
ESPGHAN Committee on Nutrition. Enteral
nutrient supply for preterm infants: com-
mentary from the European Society of
Paediatric Gastroenterology, Hepatology
and Nutrition Committee on Nutrition. J
Pediatr Gastroenterol Nutr. 2010;50(1):85–
91
17. Bell MJ. Neonatal necrotizing enterocolitis.
N Engl J Med. 1978;298(5):281–282
18. Garza-Cox S, Keeney SE, Angel CA,
Thompson LL, Swischuk LE. Meconium ob-
struction in the very low birth weight
premature infant. Pediatrics. 2004;114(1):
285–290
19. Siddiqui MMF, Drewett M, Burge DM. Me-
conium obstruction of prematurity. Arch
Dis Child Fetal Neonatal Ed. 2012;97(2):
F147–F150
20. Berman L, Moss RL. Necrotizing enteroco-
litis: an update. Semin Fetal Neonatal Med.
2011;16(3):145–150
21. Tuladhar R, Daftary A, Patole SK, Whitehall
JS. Oral gastrografin in neonates: a note of
caution. Int J Clin Pract. 1999;53(7):565
22. Feigenberg Z, Levavi H, Ben-Baruch D,
Abramovici A. Translocation of bacteria
due to direct mucosal damage caused by
Gastrografin: an experimental study in
newborn rats. Dig Dis Sci. 1994;39(1):157–
160
23. American Academy of Pediatrics. Com-
mentary on breast-feeding and infant
formulas, including proposed standards
for formulas. Pediatrics. 1976;57(2):278–
285
24. Srinivasan L, Bokiniec R, King C, Weaver G,
Edwards AD. Increased osmolality of breast
milk with therapeutic additives. Arch Dis
Child Fetal Neonatal Ed. 2004;89(6):F514–
F517
25. Pearson F, Johnson MJ, Leaf AA. Milk os-
molality: does it matter [published online
ahead of print September 19, 2011]? Arch
Dis Child Fetal Neonatal Ed.
e1606 HAIDEN et al at Bibliothek der MedUniWien (309961) on December 27, 2012pediatrics.aappublications.orgDownloaded from
DOI: 10.1542/peds.2011-3634
; originally published online November 26, 2012; 2012;130;e1600Pediatrics Bernd Jilma, Angelika Berger and Andreas Repa
Nadja Haiden, Florentine Norooz, Kathrin Klebermass-Schrehof, Anna Sophie Horak,
Preterm Infants
The Effect of an Osmotic Contrast Agent on Complete Meconium Evacuation in
Services
Updated Information &
html
http://pediatrics.aappublications.org/content/130/6/e1600.full.
including high resolution figures, can be found at:
Supplementary Material
9/peds.2011-3634.DCSupplemental.html
http://pediatrics.aappublications.org/content/suppl/2012/11/1
Supplementary material can be found at:
References
html#ref-list-1
http://pediatrics.aappublications.org/content/130/6/e1600.full.
at:
This article cites 21 articles, 10 of which can be accessed free
Rs)
3
Peer Reviews (P
Post-Publication
http://pediatrics.aappublications.org/cgi/eletters/130/6/e1600
R has been posted to this article:
3
One P
Subspecialty Collections
_and_newborn
http://pediatrics.aappublications.org/cgi/collection/premature
Premature & Newborn
the following collection(s):
This article, along with others on similar topics, appears in
Permissions & Licensing
tml
http://pediatrics.aappublications.org/site/misc/Permissions.xh
tables) or in its entirety can be found online at:
Information about reproducing this article in parts (figures,
Reprints http://pediatrics.aappublications.org/site/misc/reprints.xhtml
Information about ordering reprints can be found online:
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy of Pediatrics. All
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
at Bibliothek der MedUniWien (309961) on December 27, 2012pediatrics.aappublications.orgDownloaded from