JOURNAL

APPRAISAL
A Requirement in Department of Pediatrics

By

CC HUEVOS, HAZIEL M.

July 2022
Hypothetical Scenario
This is a 14 day old infant female born to a 24 year old G1P1 mother at 30 weeks
gestation via spontaneous vaginal delivery. Birthweight was 1340 g. APGAR scores were
6 and 7 at 1 and 5 minutes respectively. Her early hospital course was remarkable for
respiratory distress syndrome and patent ductus arteriosus. Recent problems include
apnea and bradycardia of prematurity and feeding intolerance. Her nutritional needs have
been met by advancing enteral feedings of preterm formula supplemented with parenteral
hyperalimentation. On the day prior to the onset of symptoms, she was no longer
receiving hyperalimentation and she was feeding 30 cc every 3 hours. Today she
presents with abdominal distention and bilious vomiting. Her stool color has darkened
and her urine output is reduced. She is also having more apnea and bradycardia events.

Vital signs show T 36, HR 180, RR 60, BP 63/40, weight 1425 grams. She is
lethargic, slightly toxic, and poorly perfused. Cardiac exam demonstrates tachycardia and
no murmurs. Lungs are clear. Her abdomen is tympanitic, distended, and questionably
tender, with hypoactive bowel sounds. Stool is guaiac positive.

Abdominal radiographs demonstrate pneumatosis intestinalis. She is made NPO

and a nasogastric tube is placed to suction. Following an intravenous bolus of normal
saline, her tachycardia resolves and she is placed on maintenance intravenous fluids at
150 cc/kg/day. Empiric antibiotic therapy of ampicillin and gentamicin is started. Serial
abdominal radiographs and examinations are regularly performed to monitor her status.
She begins to show improvement shortly after the initiation of therapy, and enteral feeding
is reintroduced 10 days later. Her feedings are slowly advanced. She is discharged from
the hospital at 6 weeks of age. She is evaluated for intestinal stricture later in infancy and
none is found.
Background
Necrotizing enterocolitis (NEC) is a fulminant syndrome causing bowel wall
necrosis, which can lead to air in the intestinal wall, portal venous system, or peritoneal
cavity. It occurs in 1-5% of neonatal intensive care unit admissions and is the most
common GI emergency in neonates. NEC may affect the gastrointestinal (GI) tract from
the stomach to the rectum, although the distal ileum and proximal colon are the segments
most commonly involved. The incidence of this disease is 1 to 3 per 1000 live births, with
75-95% of cases occurring in premature infants. Onset is most common between 3 to 10
days of age, with the age of onset inversely related to gestational age at birth. The overall
mortality rate in NEC may be as high as 30%. NEC in full-term infants is associated with
a lower mortality rate than that of premature infants.

Clinical Question
An initial question was phrased as: What strategies can be employed to preterm
neonates to prevent them from developing NEC?

A search for medical literature was conducted through research database PubMed using
the following keywords, “prevention of necrotizing enterocolitis” with search results filtered
to Randomized Controlled Trials and 5-year publication date. A research article entitled,
“Erythropoietin prevents necrotizing enterocolitis in very preterm infants: a randomized
controlled trial” was then encountered.
Summary of Evidence
Appraising Directness
Clinical Question Research Question
Population Preterm infants Very late preterm infants
Exposures Pharmacologic or preventive Recombinant human
strategies erythropoietin (rhEPO) vs.
Saline
Outcome Incidence of NEC in preterm Incidence of NEC in very
infants preterm infants at 36wks of
corrected gestational age
Methods Randomized controlled trial Prospective randomized
controlled trial

Appraising Validity
Criteria Complied with?
1. Were patients randomly assigned to treatment Yes
groups?
2. Was allocation concealed? Yes
3. Were baseline characteristics similar at the start of Yes
the trial?
4. Were patients blinded to treatment assignment? Yes
5. Were caregivers blinded to treatment assignment? Yes
6. Were outcome assessors blinded to treatment Yes
assignment?
7. Were all patients analyzed in the groups to which Yes
they were originally randomized?
8. Was follow-up rate adequate? Yes
 1. Were patients randomly assigned to treatment groups?
Yes. The preterm infants were randomly assigned to the recombinant human
erythropoietin (rhEPO) or control group by the trial investigators in a 1:1 allocation using
a simple randomization plan by a computer- based random-number generator in each
NICU center.

2. Was allocation concealed?

Yes. The preterm infants were randomly assigned to the rhEPO or control group by the
trial investigators in a 1:1 allocation using a simple randomization plan by a computer-
based random-number generator in each NICU center. Additionally, the researchers
have also assigned a third party, the doctors and nurses in the NICU, to assign the
patient treatment groups.

3. Were baseline characteristics similar at the start of the trial?

Yes. There were no significant differences between the control and treatment groups for
any of the baseline parameters (p > 0.05).

4. Were patients blinded to treatment assignment?

Blinding of patients to the treatment assigned was not explicitly stated but a clue to this
is whether the researchers used identical preparations of the treatments. In this study,
infants in the rhEPO group were given rhEPO (500 IU/kg dissolved in 2 ml saline,
intravenously once every other day for 2 weeks for a cumulative dose of 3500 IU/kg)
starting within 72 h after birth. Infants in the control group were given saline with the
same volume and timing.

5. Were caregivers blinded to treatment assignment?

Blinding of the caregivers to the treatment assigned was not explicitly stated but a clue
to this is the same as above, that is, if the researchers used identical preparations of the
treatments.

6. Were outcome assessors blinded to treatment assignment?

Yes. The investigators performing quality control, data collection, and analysis were
blinded to the treatment groups.

7. Were all patients analyzed in the groups to which they were originally
randomized?
Whether the patients were analyzed in their original groups where not explicitly stated.
However, the number of patients randomized is equal to the number of patients
analyzed at the end of the study.
 8. Was follow-up rate adequate?
Adequacy of follow-up refers to minimization of the number of patients who drop out
from a study. As seen from the image above, although there are patient deaths, there
are no patient drop-outs and the number of patients analyzed at the end were same as
in the beginning of the study.

Appraising Results
1. How large was the effect of treatment?

A total of 51 infants (3.8%) of the 1285 very preterm infants developed confirmed
NEC (Stage II and III). rhEPO treatment reduced the incidence of NEC (stage I, II and
III) and confirmed NEC (stage II and III) compared to controls. However, rhEPO did not
have a significant effect on NEC stage I, NEC stage II, or NEC stage III, or on fulminant
NEC. No side effects were observed with rhEPO treatment.
 2. How precise was the estimate of the treatment effect??

Precision of treatment effect is determined by the level of confidence. This study

used a confidence interval of 95%.

Appraising Applicability
1. Are there biological issues that may affect the applicability of treatment?

The researchers stressed that if the infants developed polycythemia, hypertension,

thrombosis, shock, or any other emergency conditions, the rhEPO administration would
be stopped immediately and appropriate emergency treatment would be given.
Furthermore, this study is only limited to very late preterm infants. Application to other
categories of preterm infants should be used with caution.

2. Are there socio-economic issue that may affect applicability of treatment?

Yes. Erythropoietin prices here in the Philippines are not exactly cheap. It may cost
around Php 1,000 per 4,000 IU/0.5mL solution and very low-income parents may not be
able to afford this easily. However, putting it into perspective against the possible cost
should their child develop NEC, rhEPO is a cost-effective preventive strategy and must
be offered to the parents.

3. Can the results help me in caring for my patients?

Yes. The results of this study strongly suggest that rhEPO is a potential promising
therapeutic target for the prevention and/or treatment of NEC in very preterm infants.
Furthermore, this study shows that rhEPO could reduce the number of RBC transfusion
in confirmed NEC, and that rhEPO could be beneficial for preterm infants against NEC,
especially in those with Hb < 90 g/l.

Conclusion
Repeated low-dose rhEPO treatment reduced the risk of NEC compared with
controls and without obvious adverse effects. This indicates that prophylactic early rhEPO
treatment has multiple beneficial effects in very preterm infants and that rhEPO could be
recommended for infants at risk of NEC. Whether such treatment improves long-term
outcomes of NEC patients remains to be determined.

Reference
Wang Y, Song J, Sun H, Xu F, Li K, Nie C, Zhang X, Peng X, Xia L, Shen Z, Yuan X. Erythropoietin
prevents necrotizing enterocolitis in very preterm infants: a randomized controlled trial. Journal of
Translational Medicine. 2020 Dec;18(1):1-9.