Keywords
hypertrophic pyloric stenosis - conservative treatment - atropine sulfate - pyloromyotomy
Introduction
Hypertrophic pyloric stenosis (HPS) is the most common surgical cause of vomiting
in newborns. Conservative management of the condition remains controversial. The Fredet-Ramstedt
operative technique is easy for a skilled pediatric surgeon to perform, with both
classical and laparoscopic approaches yielding excellent results and fast recovery
of patients. The cause of HPS is unknown; it is generally accepted that the condition
results from a pronounced pylorospasm, with rare and immature ganglion cells in the
pylorus wall having some potential role. Progredient stenosis of the pyloric channel
causes intensive peristaltic gastric waves, which lead to antral elongation and thickening
of the pyloric channel wall.[1]
Since there is a prevailing opinion that a muscle spasm underlies its etiology,[2]
[3] the success of medical-oral or venous therapy using the antispasmodic atropine sulfate
has been reinvestigated. Medical treatment of HPS with oral antispasmodics was abandoned
in the mid-1960s, but reappraised in the 1990s mainly by a group from Osaka, Japan.[4]
[5]
Here, we analyze the justification of the treatment and role of oral atropine sulfate
therapy in comparison to surgical treatment using the classical technique, (extramucosal
pyloromyotomy by Fredet-Ramstedt), the gold standard for the treatment of HPS since
the mid-1960s.
Materials and Methods
We performed a retrospective cohort study, in the period between January 2006 and
December 2011, with 66 patients, divided into two groups according to the mode of
treatment: conservative and surgical. The prerequisite for inclusion was an ultrasonographically
verified diagnosis of HPS according to the criteria by Haller and Cohen.[6] HPS was defined if the thickness of the pyloric muscle was 4 mm or more, diameter
was 15 mm or more, and length was 18 mm or more.
The parents were previously informed of the therapeutic options of both conservative
and surgical treatment, as well as the attitude of the attending surgeon toward the
specific type of treatment. Both treatment protocols were presented to the parents
in detail, and their informed consent for the chosen method was obtained. Patients
in the conservative group were administered oral atropine sulfate solution. The surgical
group underwent extramucosal pyloromyotomy (Fredet-Ramstedt). The conservative and
surgical treatment involved 40 (33 boys and 7 girls) and 26 (20 boys and 6 girls)
patients, respectively. On admission, all patients underwent complete laboratory analyses
(blood count with differential, acid-base status, electrolytes, bilirubin, glycemia,
C-reactive protein (CRP), transaminases, urea, and creatinine level). No patient had
associated abnormalities of the gastrointestinal tract.
The atropine sulfate protocol of treatment included the insertion of a nasogastric
tube (NG), and decompression of the stomach on admission, followed by an initial correction
of water and electrolyte imbalance as per the patient. A total daily dose of atropine
sulfate was divided into 8 carefully titrated equal doses comprising of 1 mL of solution.
Atropine was given in the form of an aqueous solution via the NG tube at the initial
dose of 0.05 mg/kg/day, 20 minutes before feed, following aspiration of gastric content
and measurement of residual food. If the meal was tolerated, indicated by the amount
and appearance of residual feed (up to 10% of previous feed volume, without evidence
of milk, was considered normal and returned through the tube), the same atropine dose
would be repeated in 3 hours. Vomiting was tolerated a maximum of two times a day.
The initial meal was 10 mL of 5% glucose solution, and subsequent meals included breast
milk or formula. The newborns who responded well to therapy were gradually given bigger
meals, with feed volumes increased by increments of 10 mL for each meal until an oral
intake of 120 mL/kg/24 hours was achieved. If vomiting occurred, the atropine dose
would be increased in the following meal by 0.01 mg/kg/day without changing the oral
intake, up to 0.18 mg/kg/day. If the subsequent meal was tolerated, progressive increase
of intake would be continued.
The patients were discharged for home treatment when they tolerated feeds for 2 days
without vomiting, and parents were trained for continuation of oral drug administration
at home. The patients were clinically assessed once a week during drug administration,
together with an ultrasound examination and body weight measurement. Atropine was
used for 6 to 8 weeks after the vomiting ceased, irrespective of the degree of reduction
of the pyloric muscle hypertrophy. The atropine sulfate concentration on discharge
was given without any dose adjustment if oral feed was tolerated. If posseting occurred,
the dose was adjusted to body weight. Newborns for whom a maximal daily dose of 0.18
mg/kg/day had been attained but who still experienced postprandial projectile vomiting
were withdrawn from therapy.
Ten newborns from the conservatively treated group (eight males and two females) had
an inadequate response to therapy and thus were excluded from further follow-up. They
underwent surgical treatment by pyloromyotomy in less than 5 to 7 days from the onset
of treatment to finish the therapy. Pyloromyotomy was performed via a supraumbilical
right transverse incision. The NG tube was left for 12 hours after surgery in the
operated patients, and feeds were started 3 hours after its withdrawal: initially
with 10 mL of 5% glucose solution, and subsequently replaced by breast milk or formula.
If the meal was tolerated, it was progressively increased; otherwise, the previously
tolerated volume was re-introduced.
The Board of Experts of the University Children's Hospital approved the application
of oral atropine sulfate as a therapeutic option in 2000.
The significance of difference by distribution of sex and age was analyzed by means
of nonparametric χ2 test. For analyzing the difference in the outcome of HPS treatment between the conservatively
and surgically treated groups, the nonparametric χ2 test modified by Yates was used.
Results
HPS was managed by oral atropine sulfate therapy in 40 patients, including 33 boys
and 7 girls. The patients were assessed on a daily basis by a neonatal surgeon and
neonatologist. Until they had attained full oral intake, they had fluid and electrolyte
supplementation, Vaminolact (amino acid solution for intravenous nutrition). The mean
age of this group was 22 days. The primary surgically treated group included 26 newborns
(20 boys and 6 girls; mean age, 21 days). The distribution by sex of the patients,
53 boys and 13 girls, was statistically significant, in a ratio of 4:1 (p < 0.01). There was no significant difference (p value, χ2 test) in distribution by age, weight (on admission and discharge), and pyloric measures
(length and thickness of pyloric muscle) between the atropine and pyloromyotomy group
([Table 1]).
Table 1
Summary of patients with HPS
|
Atropine sulfate group
(n = 40)
|
Pyloromyotomy group
(n = 26)
|
p value
|
|
Number of males
|
33
|
20
|
0.06[b]
|
|
Number of females
|
7
|
6
|
|
Male to female ratio
|
11:4
|
10:3
|
|
|
Age on admission (days)
|
22.25 ± 6.75
|
20.86 ± 6.14
|
0.40[a]
|
|
Weight on admission (g)
|
3,680.2 ± 510.6
|
3,560 ± 523.3
|
0.36[a]
|
|
Weight on discharge (g)
|
3,870 ± 505.2
|
3,610 ± 533.1
|
0.05
[a]
|
|
Pyloric muscle thickness US (mm)
|
4.9 ± 0.5
|
4.9 ± 0.7
|
1.00[a]
|
|
Pyloric muscle length US (mm)
|
17.2 ± 2.8
|
17.6 ± 2.5
|
0.56[a]
|
|
Successful therapy
|
30 (75%)
|
26 (100%)
|
0.02[b]
|
Abbreviations: HPS, hypertropic pyloric stenosis; US, ultrasonography.
a
t test.
b χ2 test.
It appeared that oral atropine sulfate was well tolerated in all patients. In the
medically managed-group, 30 cases were successfully treated with oral therapy (25
boys and 5 girls, 75%). No patient required surgical treatment after discharge, and
the established oral intake was continued at home for a duration of 6 to 8 weeks.
No significant complications during medical treatment were reported. Serial ultrasound
controls performed on days 7, 14, 21, and 6 weeks from the beginning of treatment
did not show regression of the pyloric muscle wall to normal, although the passage
of content from stomach to duodenum was unobstructed. Once a week, parents were supplied
with a prepared solution of atropine sulfate, and its concentration was adjusted to
the patient's body weight in the first 4 weeks. After 4 weeks, atropine concentration
remained the same and given the increase in the patient's body weight, it was gradually
decreased, and was completely discontinued at week 6.
Vomiting did not cease and there was no satisfactory oral intake in 10 out of 40 (8
boys and 2 girls, 25%) patients from the conservatively treated group in the expected
interval of 7 days, and therefore, surgical treatment by the Fredet-Ramstedt technique
was performed. The atropine sulfate therapy originally planned for 7 days was terminated
in 2 patients at day 5, as parents requested for surgery. Both patients were discharged
on postoperative day 3 upon re-establishment of full oral intake.
The Fredet-Ramstedt technique, used for the 26 primary surgically treated patients,
included a supraumbilical incision in the right upper quadrant. Experienced pediatric
surgeons operated on all patients. Full oral intake (120 mL/kg/day) was achieved between
postoperative days 2 and 3, and the patients were discharged between postoperative
days 3 and 5. The postoperative period was uneventful.
Statistical analysis showed that at the significance level of p < 0.05, there was
a difference in the choice of method of treatment in relation to its outcome (Yates
χ2 = 5.839); however, at the significance level of p < 0.01 (Yates χ2 = 7.661), these methods demonstrate a difference in favor of surgical treatment.
Discussion
After 40 years of almost exclusive domination by surgical treatment of HPS, medical
therapy with atropine sulfate has been sporadically employed in some institutions[7] worldwide, and has mostly generated a negative view among the majority of pediatric
surgeons.[8] Given the excellent results of the Fredet-Ramstedt surgical technique—with few complications
if performed by a competent pediatric surgeon, and complete cure in a short period
of time—it still represents the method of choice for HPS treatment. In the last ten
years, laparoscopy-assisted pyloromyotomy, a minimally invasive procedure, has been
advocated by many experts, although one meta-analysis[9] shows that an open method has less complications and higher effectiveness.
Atropine sulfate has been used for HPS treatment at the University Children's Hospital
since 2000,[10] and has been applied by a group of pediatric surgeons who practice neonatal surgery
and cooperate with a team of neonatologists engaged in the treatment of these patients.
The success of patients exclusively treated by oral atropine sulfate in our study
(initial dose of 0.05 mg/kg/24 hours, progressively increased to 0.18 mg/kg/24 hours)
was 75%. This proportion of 75% of treated patients by oral atropine sulfate therapy
in our study was smaller in comparison to data from other studies using combined oral
and intravenous therapy.[11]
[12]
[13] Nevertheless, opting for exclusively oral administration, we wished to evade the
possibility of side effects, which are more probable in intravenous atropine sulfate
injection.
Other studies have combined oral and intravenous atropine sulfate administration and
the percentage of success has been higher. Yamataka et al[11] reported 85% success with medical treatment of patients (initial oral atropine sulfate
dose 0.05 mg/kg/24 hours, adjusted in case of continual vomiting to 0.1 mg/kg/24 hours).
Two patients were converted to intravenous injection on day 3, because the atropine
was not tolerated. Kawahara et al[12] reported that the success of a combination of intravenous atropine followed by oral
intake (initial injection dose of 0.01 mg/kg six times a day, until vomiting stopped,
and afterward oral 0.02 mg/kg six times a day with progressive reduction until the
patient was cured) was 87%. The difference in maximal oral doses is remarkable, for
instance in our study, it was 0.18 mg/kg/24 hours. The upper limit in our study was
not exceeded, but in cases where atropine failed, and vomiting could not be stopped
till day 7 (in our series—25% of patients), the disease was managed by surgical procedure.
Out of the 12 patients treated, conversion to surgery was required in 2 (on day 5,
according to the parent's wishes). No side-effects of atropine sulfate were reported
in any of cases.
No recurrence of disease was recorded in our conservative treatment group after successful
completion of therapy, comparable with the other available data.[10]
[11]
[12]
[13] The mean hospital stay was 4 to 8 days for surgical and medical treatment, respectively.
A shorter hospitalization in the operated group of patients and quicker time to achieve
full enteral intake have been consistently found in all studies dealing with either
oral or venous atropine sulfate administration.[10]
[11]
[13]
Ultrasonographic follow up was done in all cases on days 7, 14, and 21, but there
were no significant changes in the pyloric muscle thickness or channel length. However,
an improvement in the passage of content from the stomach to the duodenum was apparent.
Further ultrasound controls were sporadic because the clinical condition of patients
was stable, vomiting-free, and characterized by weight gain.
When classical or laparoscopy-assisted pyloromyotomy is used, the major advantages
are the success of the operation, shorter hospitalization, and few complications.
Nevertheless, the postoperative length of stay varies in different parts of the world
(in western countries, the stay is only 1 day, while in Serbia, it is 4 days, i.e.,
until complete cessation of vomiting). In our study, the operated group (all patients
were operated by qualified surgeons mostly engaged in neonatal problems, and with
over 10 years of experience in surgical practice), had no postoperative complications.
However, reference data report that the percentage of incomplete pyloromyotomy ranges
from 0 to 5.5% in laparoscopic interventions, and from 0 to 0.9% in open pyloromyotomy
cases.[14]
[15]
[16]
[17]
Langer and To,[15] as well as Safford et al[18] found that the length of postoperative treatment and a lower degree of duodenal
perforation depended on the surgeon's experience. The percentage of postoperative
complications varies in relation to institutions and the surgeon's expertise and experience.
The major disadvantage of atropine sulfate application is that it requires an experienced
and motivated team to observe and monitor the patient's condition, and follow changes
of the disease process—for instance, adjust the dose regime in case of vomiting. From
the perspective of the pediatric surgeon, an HPS operation is easier and less time
consuming than conservative treatment, whose prognosis is additionally uncertain.
For the parents, there is broad satisfaction across all 75% of parents whose children
were successfully treated by medical therapy, thus avoiding surgery and its associated
risks, no matter how small they might be.
The value and place of oral, intravenous or combined atropine sulfate treatment for
HPS must be investigated. A multicenter prospective randomized study is necessary
to provide a uniform and safe protocol that will resolve the dilemma about the most
successful application of the drug (oral, venous, or combined), and its optimal dose.
Further investigations of oral or intravenous atropine treatment may clarify its position
as an alternative to pyloromyotomy.
