Titulo :

Utilizar de la colecistoquinina para prevenir el desarrollo de parenteral

use of cholecystokinin to prevent the development of parenteral
nutrition associated cholestasis
la nutricin colestasis asociada

abstract
Background: Neonates are at high risk for the development of parenteral
nutrition-associated cholestasis when receiving a prolonged course of total
parenteral nutrition (TPN). Although this cholestasis is of unknown etiology, it
may result from a lack of gastrointestinal hormone formation, including
cholecystokinin, which normally occurs after enteral feedings. Methods: Two
groups of neonates were studied. The treatment group consisted of 21
consecutive, prospectively enlisted neonates receiving TPN for > 14 days. The
nontreatment group consisted of 21 infants from the 2 years preceding the
study who were matched to the treatment group by gestational age, diagnosis,
and duration of TPN. The major outcome determinant was direct bilirubin.
Cholestasis was defined as a direct bilirubin >2.0 mg/dL and was considered
severe if the direct bilirubin was >5.0 mg/dL after other causes were ruled
out. Results: The mean direct bilirubin levels in the nontreated group
progressively rose over time, whereas the mean direct bilirubin in the treated
group remained level. The incidence of infants with a direct bilirubin >2.0 mg/dL
was 24% and 43% in the CCK+ and CCK- groups, respectively, and was not
significant (p = .14). The percentage of infants with a direct bilirubin >5.0 mg/dL
was 9.5% and 38% in the treatment and nontreatment groups, respectively, and
was significant, p = .015. Conclusions: Levels of direct bilirubin were lower in
the treated compared with the nontreated group. These findings suggest that
cholecystokinin prophylaxis in high-risk neonates may help prevent the
development of parenteral nutrition-associated cholestasis. (journal of
Parenteral and Enteral Nutrition21:100-103, 1997)

Antecedentes: Los recin nacidos tienen un alto riesgo para el desarrollo de

colestasis asociada a nutricin parenteral cuando se recibe un curso
prolongado de la nutricin parenteral total (NPT). Aunque este colestasis es de
etiologa desconocida, que puede ser consecuencia de la falta de formacin de
la hormona gastrointestinal, incluyendo la colecistoquinina, que normalmente
se produce despus de la alimentacin enteral. Mtodos: Se estudiaron dos
grupos de recin nacidos. El grupo de tratamiento consisti en 21 casos
consecutivos, prospectivamente alistados reciben NPT durante> 14 das. El
grupo sin tratamiento consisti en 21 nios de los 2 aos anteriores al estudio,
quienes fueron agrupados para el grupo de tratamiento segn la edad
gestacional, el diagnstico, y la duracin de la NPT. El determinante principal

resultado fue la bilirrubina directa. La colestasis se defini como la bilirrubina>

2,0 mg / dl directa y se considera grave si la bilirrubina directa fue> 5,0 mg / dl
despus de otras causas se descartaron. Resultados: La media de los niveles
de bilirrubina directa en el grupo no tratado aumentaron progresivamente con el
tiempo, mientras que la media de bilirrubina directa en el grupo tratado se
mantuvo el nivel. La incidencia de los nios con una bilirrubina> 2,0 mg / dl
directa fue 24% y 43% en los grupos de CCK + y CCK, respectivamente, y no
fue significativa (p = 0,14). El porcentaje de recin nacidos con una bilirrubina>
5,0 mg / dl directa fue del 9,5% y del 38% en los grupos de tratamiento y sin
tratamiento, respectivamente, y fue significativa, p = .015. Conclusiones: Los
niveles de bilirrubina directa fueron menores en el grupo tratado en
comparacin con el grupo no tratado. Estos hallazgos sugieren que la
colecistoquinina la profilaxis en los recin nacidos de alto riesgo puede ayudar
a prevenir el desarrollo de colestasis asociada a nutricin parenteral. (Journal
of Parenteral y Enteral Nutrition 21: 100-103, 1997)

Parenteral nutrition-associated cholestasis (PNAC) is a common problem

encountered in neonates who cannot receive adequate amounts of
enteral nutrition for prolonged periods of time. 1-3 The etiology of this
disorder remains unclear. One possible explanation, however, is that a
lack of enteral feeding leads to diminished bile flow. Because
cholecystokinin (CCK) has been demonstrated to increase both
intrahepatic and extrahepatic bile flow, 4-6 we hypothesized that CCK
may prevent the development of PNAC. Our group and others have
recently reported that CCK can decrease the level of hyperbilirubinemia
in neonates who have already developed PNAC.7,8 The aim of this study
was to determine if prophylactically administered CCK would reduce the
severity of PNAC in neonates at risk for the development of this process.
recibir cantidades adecuadas de nutricin enteral durante perodos de
tiempo pro- anhelado 1-3 La etiologa de este trastorno permanece poco
claro. Una explicacin posible, sin embargo, es que la falta de
alimentacin enteral conduce a flujo biliar disminuida. Debido a la
colecistoquinina (CCK) se ha demostrado que aumentar tanto el flujo
biliar intraheptico y extraheptico, la hiptesis de que CCK puede
prevenir el desarrollo de PNAC. Nuestro grupo y otros han informado
recientemente de que la CCK puede disminuir el nivel de la
hiperbilirrubinemia en recin nacidos que ya han desarrollado PNAC. S
El objetivo de este estudio fue determinar si profilcticamente nistracin

MATERIALS AND METHODS Two groups of infants receiving total

parenteral nutrition (TPN) were studied. The treatment group (CCK+)
consisted of 26 neonates who were consecutively enrolled

*Presented at the American Pediatric Surgical Association Meeting, San

Diego, CA, May, 1996. Correspondence and reprint requests: Daniel H.
Teitelbaum, MD, Section of Pediatric Surgery, University of Michigan
Hospitals, C. S. Mott Childrens Hospital, F3970, Box 0245, Ann Arbor,
Michigan 48109.
materiasles y mtodos
Se estudiaron dos grupos de lactantes que reciben nutricin parenteral
total CTPN). El grupo de tratamiento (CCK +) consisti en 26 recin
nacidos que se incluyeron consecutivamente "Presentado en la
Asociacin Americana de Ciruga Peditrica Reunin, San Diego, CA,
Mayo, 1996. Recibido para su publicacin, 5 de agosto de 1996.
Aceptado para su publicacin 28 de octubre de 1996 . correspondencia y
de las solicitudes de reimpresin: Daniel H. Teitelbaum, MD, Seccin de
Ciruga Peditrica, Universidad de Michigan Hospitales, hospital CS Mott
de Nios, F3970, Box 0245, Ann Arbor, Michigan 48109
and followed in a prospective fashion. All patients had a disease process
(eg, prematurity [< 1500 g], gastroschisis, necrotizing enterocolitis, or
congenital diaphragmatic hernia) in which it was thought that the patient
would require at least 2 weeks of TPN. A synthetic form of
cholecystokinin-octapeptide (Sincalide; Bracco Diagnostics, Princeton,
NJ, referred to as CCK for the remainder of this paper) was given at a
dose of 0.02 pg/kg/dose IV, twice a day for 14 days. Dosing was
increased to 0.04 pg/kg/dose IV three times a day if TPN was continued
for > 14 days. CCK administration was terminated when 50% or more of
the infants nutritional intake was received by the enteral route or upon
discharge from the neonatal intensive care unit. Infants were excluded
from the study if they had liver dysfunction or hyperbilirubinemia from
other causes (eg, congenital obstruction of the biliary tree, hemolysis, or
if they were receiving a course of extracorporeal membrane oxygenation,
in which hemolysis may occur). Infants were also excluded if they had (or
were suspected of having) a metabolic defect or if they had been
receiving TPN for > 10 days prior to starting on the study. Infants were
removed from the study if they achieved >50% of their caloric intake by
the enteral route before completing at least 14 days of the study
enterocolitis necrotizante, o diafragmtica congnita su nia) en el que se
pensaba que el paciente requerira por lo menos 2 semanas ofTPN.
forma Asynthetic de cholecystoki nin (sincalide; Bracco Diagnostics,
Princeton, NJ, denominado CCK para el resto de este documento fue
dado a una dosis de 0,02 ug / kg / dosis IV, dos veces al da durante
veces al da si se continu la RPT durante 14 das. CCK ad ministracin
se termin cuando el 50% o ms de los de los lactantes ingesta
nutricional se recibi por va enteral o en el momento del alta de la
unidad neonatal bebs cuidados intensivos fueron excluidos del

studyifthey tena la funcin dys del hgado o hiperbilirrubinemia por otras

causas (por ejemplo, aire obstruccin genital del rbol biliar, hemlisis, o
si estaban recibiendo acourse de extracorprea hidrogenacin oxi
membrana, en la que se puede producir hemlisis). los bebs tambin
fueron excluidos si tenan (o se sospecha que tiene Ameta defecto bolic
o si que haban estado recibiendo alimentacin intravenosa durante 10
das antes de iniciar el estudio. los nios fueron retirados del estudio
Rym si t ao de su calorin
The nontreatment group (CCK-), consisted of 21 neonates who were
matched to the study patients by gestational age (within 1 week),
principal clinical diagnosis and duration of TPN (within 1 week). All
control neonates had been treated in the same neonatal intensive care
unit over the previous 2 years. All patients received the same type of
parenteral nutrition. The crystalline amino acid was
El grupo sin tratamiento (CCK), consisti en 21 neonatos, quienes fueron
agrupados a los pacientes del estudio por edad gestacional (dentro de 1
semana), el diagnstico clnico principal y de la duracin de la NPT
(dentro de 1 semana). Todos los neonatos de control haban sido
tratados en la misma unidad de cuidados intensivos neonatales durante
los 2 aos anteriores. Todos los pacientes recibieron el mismo tipo de
nutricin parenteral. El aminocido cristalino fue de

Aminosyn (Abbott Laboratories, Abbott Park, IL) and the lipid was
Liposyn 20% (Abbott Laboratories). The primary outcome measure was
direct bilirubin. PNAC was defined, based on previously established
definitions, as a direct bilirubin >2.0 mg/dL after a prolonged course of
TPN (ie, >2 weeks) and when other causes were ruled out. Severe
PNAC was defined as a direct bilirubin >5.0 mg/dL. Severe PNAC was
defmed by previous reports, which have demonstrated a high degree of
mortality associated with a direct bilirubin in this range. 10 Direct bilirubin
levels were obtained on a weekly basis while all infants were on the
study for both study groups. Thus, bilirubin levels were obtained at
similar time periods and intervals in each group, which allowed for a
ready comparison. Other etiologies of hyperbilirubinemia were evaluated
by clinical inspection, ultrasonography of the hepatobiliary tree, as well
as hepatitis and TORCH titers. An open liver biopsy was done in three
patients after the termination of the study in conjunction with another
operative procedure (closure of ostomies). A cholestatic histologic
appearance was present in all cases, consistent with PNAC.
La medida de resultado primario fue directo bilirrubina NAC fue definido,
basado en itions defi previamente establecidos, como la bilirrubina
directa 2,0 mg / dl despus de una prolongada ourse de la RPT (es

decir, 2 semanas) y cuando otras causas fueron ULed a cabo. Severe

PNAC se defini como una bilirrubina 5,0 mg / dl directa. Severa PNAC
fue definida por los informes anteriores que han demostrado un alto
grado de Asso mortalidad iated con una bilirrubina directa en este rango.
"Biliru directa en los niveles que se obtuvieron semanalmente mientras
que Al nfants estaban en el estudio para ambos grupos de estudio. Por
lo tanto ilirubin los niveles fueron obtenidas en perodos de tiempo
similares y frecuencia que fije en cada grupo, lo que permiti una
comparacin com listo. Otras etiologas de hyperbilirubinemiawere eva
ted mediante inspeccin clnica, la ecografa del rbol nepatobiliary XX,
as como la hepatitis y la antorcha ttulos una biopsia heptica abierta se
llev a cabo en tres pacientes despus ermination del estudio junto con
otro procedimiento op rativa (cierre de ostomas). Acholestatichis
A data acquisition sheet was maintained on each patient. Direct, indirect,
and total bilirubins, alkaline phosphatase, alanine transaminase (ALT),
asparatate transaminase (AST), and lactate dehydrogenase (LDH) were
measured on a weekly basis, starting at the initiation of the study and
ending at the completion of the study. Monitoring also included the
amount and type of parenteral and enteral nutrition. Mean total calories
and amounts of protein and lipid were calculated weekly and expressed
as the mean amount delivered each day. Additionally, clinical diagnosis,
birth weight, gestational age, daily body weights, operative procedures,
complications, and drugs administered were recorded. Adverse reactions
to CCK were monitored on a daily basis. This study was approved by the
University of Michigans Investigational Review Board as well as by the
Food and Drug Administration, which considered Sincalide an
investigational drug in the neonatal period. Informed consent was
obtained from the infants parent(s) or guardian(s) prior to beginning the
study. Results are expressed as means SD. The McNemars test,
linear regression analysis, and Fishers Exact Test were used for
statistical analysis; ap value
CAST), y lactato deshidrogenasa (LDH) se midieron sobre una base
semanal, a partir de la iniciacin del estudio y terminando en la
realizacin Ofthe estudio. Monitoringalso incluida la cantidad y el tipo de
nutricin parenteral y enteral. La media de las caloras totales y
cantidades de protenas y lpidos se calcula semanalmente y se
expresan como la cantidad media entregada cada da. Adems, sis
clnica tico, el peso al nacer, edad gestacional, peso corporal al da, los
procedimientos rativa opciones, complicaciones, y dnugs administrada
se registraron. Las reacciones adversas a la CCK se controlaron
diariamente. Este estudio fue aprobado por la Universidad de Michigan
Junta de Revisin de Investigacin, as como por la Administracin de
Alimentos y Medicamentos, que considera un frmaco Sincalida
vestigational cin en el perodo neonatal. consentimiento informado se
obtuvo de los padres (s) del nio o tutor (s) antes de comenzar el

estudio. Los resultados se expresan como medias SD. prueba de

McNemar, anlisis de regresin lineal, y la prueba exacta de Fisher
RESULTS Twenty-six neonates were recruited into the treatment group
(CCK+). Five infants were removed from the study because they
achieved >50% of nutritional intake by the enteral route before receiving
14 days of CCK. Twenty- one neonates completed the study. CCK
treatment was discontinued for one patient in the treatment group at 21 1
days of treatment because of a persistent delay in gastric emptying that
was thought to be due to the drug. Following cessation of the drug, no
improvement in feeding tolerance or gastric emptying was noted.
Patients in the CCK+ group received a mean of 34::!:: 33 days of CCK
treatment (range 14 to 116 days). Table I shows the demographic
characteristics of the two groups. The diagnoses of the patients in each
study group were as follows: gastroschisis (n = 5); necrotizing enterocoliti
rupo (CCK Cinco recin nacidos fueron retirados del estudio ebido a que
alcanzaron> 50% de la ingesta de nutrientes por va nteral antes de
recibir los 14 das de la CCK. veintin recin nacidos completaron el
estudio. CCK tratamiento se suspendi por un paciente en el grupo de
tratamiento en 21 das de tratamiento debido a un retraso persistente en
el vaciado gstrico que se cree que es debido a la droga. cesacin ng
seguimiento de la droga, ninguna mejora en la alimentacin de Rance
tol- o el vaciado gstrico se seal. los pacientes en el grupo de CK +
recibieron una significa of34: 33 das de tratamiento CCK (rango de 14 a
116 das) Tabla I muestra las caractersticas demogrficas de los dos
grupos los diagnsticos de los pacientes en cada grupo de estudio
fueron los siguientes:.. gastrosquisis (n = 5); enterocolitis necrotizante
(n = 10); congenital diaphragmatic hernia (n = 3); and lowbirth-weight
infants (n = 3). As can be seen, the majority of the neonates had an
abnormality of the gastrointestinal tract that prevented them from taking
enteral feedings. Of the 10 infants in each group who were diagnosed
with necrotizing enterocolitis (NEC), 6 were treated conservatively with
antibiotics and nasogastric decompression and 4 underwent a surgical
exploration with resection of involved intestine. Three patients died in
each group, from either their primary disease process, sepsis, or liver
failure secondary to the cholestasis. All deaths occurred >2 weeks after
the termination of the study. Two patients in both the CCK+ and the CCKgroups developed a septic episode, defined as a blood culture positive
for a bacteria, during the course of the study
de los recin nacidos tenan una anomala del tracto gastrointestinal que
les impeda tomar la alimentacin enteral. De los 10 recin nacidos en
cada grupo que fueron diagnosticados con la enterocolitis necrotizante

(NEC), 6 fueron tratados de forma conservadora con antibiticos y

descompresin nasogstrica y 1 se sometieron a una exploracin
quirrgica con reseccin del intestino CORRE PELIGRO cin. Tres
pacientes murieron en cada grupo, ya sea de su proceso de mary pri
enfermedad, sepsis, o insuficiencia heptica secundaria a la colestasis.
Todas las muertes ocurrieron> 2 semanas despus de la terminacin del
estudio. Dos pacientes tanto en el CCK + y las CCK-grupos
desarrollaron un episodio sptico, definido
Mean total calories (enteral and parenteral combined) and protein and fat
delivery (from parenteral nutrition) were not statistically different (p > .05)
between the two groups except for a higher protein delivery in the CCK+
group during the second week of the study. Bilirubin levels are shown in
Figure 1. Because of a limited number of patients remaining on the study
after 7 weeks, only the first 7 weeks of the study are shown in Figure 1.
Mean direct bilirubin showed a more rapid rise in the CCK- group as the
period of time patients received TPN increased, whereas the mean levels
of direct bilirubin were almost flat in the CCK+ group. Although these
results were not statistically different, the use of a linear regression
analysis (the lowest p = .15) revealed a trend. The percentage of infants
with a direct bilirubin >2.0 mg/ dL was 24% and 43% in the CCK+ and
CCK- groups, respectively, and was not significant (p = .14). The
percentage of infants with a direct bilirubin >5.0 mg/dL (se- . vere
cholestasis) was 9.5% and 38% in the CCK+ and CCK- . groups,
respectively, which was significant (p = .015). With ~ longer durations of
TPN, total bilirubin levels were also . noted to be higher in the CCKgroup compared with the . CCK+ group. Indirect bilirubin levels, although
somewhat higher in the CCK- group for the first 3 weeks of the ~ study,
showed no difference between groups for other 3 study time points
y la protena y la entrega de grasa (de la nutricin parenteral) no fueron
estadsticamente different.05) entre los dos grupos, excepto para una entrega de
protena ms alta en el grupo CCK + durante la segunda semana del estudio. Los
niveles de bilirrubina se muestran en la Figura 1. Debido a un nmero limitado de
pacientes que permanecen en el estudio despus de 7 semanas, slo las primeras 7
semanas del estudio se muestran en la Figura 1. bilirrubina directa Mean mostraron
un aumento ms rpido en la CCK -Grupo como el periodo de tiempo que los
pacientes recibieron nutricin parenteral total aument, mientras que los niveles
medios de la bilirrubina directa fueron casi plana en la CCK + grupo. Aunque estos
resultados no fueron estadsticamente diferentes, el uso de un anlisis de regresin
lineal (el ms bajo p.15) revel una tendencia. El porcentaje de recin nacidos con
una bilirrubina directa 2,0 mg / dl fue del 24% y el 43% en los grupos de CCK + y
CCK, re respectivamente, y no fue significativa (p.14). El porcentaje de recin
nacidos con una bilirrubina directa> 5,0 mg / dl (severa colestasis) fue 9,5% y el
38% en los grupos de CCK + y CCK, respectivamente, lo cual fue significativo
Cp-.015). Con duraciones ms largas de TPN, los niveles de bilirrubina total se
observ tambin a ser mayor en el grupo de CCK en comparacin con el grupo de
CCK. los niveles de bilirrubina indirecta, aunque algo

FIG. 1. Serum direct bilirubin levels measured weekly, in both groups

of neonates receiving total parenteral nutrition (TPN) therapy (*p < .
05). After the third week, note the rapid rise and consistently higher
levels for the nontreatment group of patients. Because of a loss of
patients in each group after week 7, only weeks 1 through 7 are
shown. No statistical differences were noted for AST, ALT, LDH, and
alkaline phosphatase levels throughout the study period. No
difference was seen in the growth characteristics of either group as
measured by weight gain throughout the study. At study week 3, body
weights were 1.91 1.1 and 2.06 1.1 kg in the CCK+ and CCKgroups, respectively. Mean serum total protein levels, measured on a
weekly basis, were virtually the same in the two groups. At study
week 3, total protein levels were 4.6 0.9 and 4.6 1.2 g/ dL in the
CCK+ and CCK- groups, respectively.
Despus de la tercera semana, tenga en cuenta el rpido aumento y niveles
consistentemente ms altos para el grupo sin tratamiento de los pacientes. Debido a la
prdida de pacientes en cada grupo despus de la semana 7, se muestran slo
semanas a 7 l. No se observaron diferencias estadsticas para la AST, ALT, LDH, y los
niveles de fosfatasa alcalina durante todo el perodo de estudio. No se observaron
diferencias en las caractersticas de crecimiento de ninguno de los grupos como se
mide por el aumento de peso durante el estudio. Al final del estudio la semana 3, los
pesos corporales fueron 1,91 y 2,06 1,1 1,1 kg en los grupos de CCK + y CCK,
respectivamente. La media de los niveles de protenas sricas totales, medidos sobre
una base semanal, eran prcticamente la misma en los dos grupos. al final del estudio

DISCUSSION Parenteral nutrition-associated cholestasis (PNAC) is a

persistent problem in newborns receiving long-term parenteral
nutrition.2,11 The etiology of PNAC has not been identified; however,
one hypothesis is that a lack of oral feedings may lead to biliary
stasis.&dquo; Biliary stasis has been observed in patients receiving
prolonged courses of TPN using ultrasonographic assessment of the
gallbladder.13 This stasis may develop secondarily to inadequate
hormonal stimulation, which is needed for gallbladder contraction and
intrahepatic bile flow. The gastrointestinal hormone cholecystokinin,
which is normally released during enteral feeding and which is
needed for bile flow, remains at very low levels during periods of
fasting. 14 Cholecystokinin has the ability to induce gallbladder
contraction as well as to increase intrahepatic bile flow. Therefore, we
hypothesized that cholecystokinin would be efficacious in the
prevention of parenteral nutrition-associated cholestasis. In our study,
we showed that the CCK-treated neonates maintained a lower level of
direct bilirubins throughout the duration of the study. The nontreated
group, on the other hand, showed a steady rise in direct bilirubin
levels, demonstrating a defmite trend over the duration of theii

un problema persistente en los recin nacidos que reciben nutricin parenteral a largo
plazo 11 La etiologa de la PNAC no ha sido identificado, sin embargo, una hiptesis es
que la falta de Ora alimentacin puede conducir a la estasis biliar 12 estasis biliar ha
cerveza observado en pacientes que reciben tratamientos prolongados de TPM
mediante la evaluacin ecogrfica de la vescula biliar. Esta inmovilizacin se puede
desarrollar en segundo lugar a insuficiente estimulacin monal hon, que es necesaria
para la vescula biliar con la traccin y el flujo biliar intraheptico. La hormona
colecistoquinina gastrointestina, que normalmente se libera du rante la alimentacin
enteral y que es necesaria para el flujo de bilis, re red a niveles muy bajos durante los
perodos de ayuno. Chole cystokinin tiene la capacidad de inducir contractio vescula
biliar, as como para aumentar el flujo biliar intraheptico. Por lo tanto la hiptesis de
que la colecistoquinina se efficaciou en la prevencin de una colestasis nutricinasociado parenteral. En nuestro estudio, hemos demostrado que los recin nacidos
tratados con CCK mantuvo un nivel inferior de bilirrubinas directas throughou la
duracin del estudio. El groun no tratado.

TPN course. A statistically significant difference was achieved in the

ability of CCK to reduce the incidence of severe cholestasis (direct
bilirubin > 5.0 mg/dL); however, significance was not attained when
examining all cases of PNAC (defined as a direct bilirubin >2.0
mg/dL). The difficulty in achieving a significant difference was due to
the fairly large standard deviations in mean direct bilirubin levels in
the control group. Further, because most neonates had started on
enteral feedings after the fourth week of the study, only 7 patients
remained in each group (CCK+ and CCK-) after the fourth week, which
made the attainment of significance more difficult. It has been shown
that higher septic rates can contribute to a worsening of PNAC and
could have contributed to the higher bilirubin levels in the control
group. 15 Septic events, however, were identical in both groups,
making this possibility unlikely. Although our current study was not
randomized, we carefully selected controls that were matched to our
study patients in terms of the greatest potential risk factors for the
development of PNAC (ie, gestational age, diagnosis, and duration of
TPN).
colestasis grave (bilirrubina directa> 5,0 mg / dl); howev importancia no fue
alcanzado al examinar todos los casos PNAC (definida como una bilirrubina directa>
2,0 mg / dl). El d difi- en el logro de una diferencia significativa fue debido a las
relativamente grandes desviaciones estndar en los niveles de bilirrubina directa
media en el grupo control. Adems, porque la mayora de los neonatos haban
comenzado en la alimentacin enteral despus de la cuarta semana del estudio,
slo 7 pacientes permanecieron en cada grupo (CCK + y CCK despus de la cuarta
semana, lo que hizo que el medio consecucin de significacin ms difcil. Ha sido
shownthat las tasas ms altas spticos pueden contribuir a un empeoramiento de
PNAC y podra haber contribuido a los altos niveles de bilirrubina en el grupo de
control. spticos eventos, sin embargo, fueron idntica en ambos grupos, lo que
hace poco probable esta posibilidad. al pesar de que nuestro estudio no fue
aleatorio , nosotros seleccionamos descuidado totalmente los controles que
coincidieron con nuestros natients de estudio en trminos de mayor riesgo
factorsfor nntential

Studies in young rats receiving TPN have demonstrated that

cholecystokinin is beneficial in reducing the degree of cholestasis.l6 In
a more recent study by Curran et ap7 on the use of Sincalide (CCK) in
prepubescent rabbits maintained on TPN, the authors demonstrated
that there was a reduction in periportal inflammation and fibrosis but
no change in the balloon degeneration of the hepatocytes. This group
also noted a significant increase in basal bile flow rates and clearance
of sulfobromophthalein in the CCK-treated rabbits. Based on these
reports, Rintala et al7 and our own group8 have successfully treated a
number of premature and postsurgical neonates who developed
significant degrees of PNAC. In each of these studies, several
neonates attained a significant decline in their direct bilirubin levels
after receiving IV cholecystokinin for 4 to 14 days. In our own study,
several infants failed to respond to CCK; all were shown to have
advanced PNAC with cirrhosis and subsequently were shown to have
liver failure. The purpose of the current study was to evaluate the use
of CCK in a prophylactic fashion to prevent the development of PNAC
and, thus, cirrhosis. Other tests of liver function failed to show any
clear trends with CCK treatment. However, no study has shown that
PNAC correlates well with any of these other reported tests.

en el uso de Sincalida (CCK) en conejos prepberes mantenidos en TPN, los

autores demostraron que hubo una reduccin en la inflamacin periportal y fibrosis
pero ningn cambio en la degeneracin del globo de los citos hepato. Este grupo
tambin seal asignificantes aumento en las tasas de flujo de la bilis basales y el
despacho de sulfobromophthalein en los conejos tratados con CCK. Sobre la base de
estos informes, Rintala et al y nuestros propios grupos han tratado con xito ber
anum de los recin nacidos prematuros y postquirrgicas que desa ses grados
significativos de PNAC. En cada uno de estos estud, varios neonatos lograron una
disminucin significativa en los niveles de bilirrubina directa despus de recibir la
colecistoquinina IV de 4 a 14 das. En nuestro propio estudio, varios bebs no
lograron responder a CCK; todos fueron demostrado tener PNAC avanzada con
cirrosis y posteriormente se demostr la presencia insuficiencia heptica. El objetivo
del presente estudio fue evaluar el uso de la CCK de manera profilctica para
prevenir el desarrollo de PNAC y, por lo tanto, cirrosis Otras pruebas de la funcin
heptica no muestran tendencias claras con el tratamiento CCK lowever ningn
estudio muestra

Several adverse reactions may occur with the administration of

cholecystokinin; these include gastrointestinal cramping and feeding
intolerance because of spasm of the pyloric sphincter. No neonate
developed any substantiated side effect during treatment with the
CCK-octapeptide. Most likely this was due to the fairly low doses of
the drug used in this study compared with our previous investigation
in which doses several times higher were used to treat clinically
advanced PNAC , In conclusion, use of cholecystokinin-octapeptide
appears to be associated with a trend toward lower direct bilirubin
levels in neonates receiving long-term TPN. Based : on this finding,
we believe that cholecystokinin-octapep- , tide may be effective in
preventing the development of, or ~ a reduction in the degree of
parenteral nutrition-associ- , ated cholestasis in neonates. Future,
randomized prospec- , tive studies should confirm the findings

presented here.
calambres y la intolerancia alimentaria debido a un espasmo del esfnter pilrico.
Noneonate desarrollado ningn efecto secundario fundamentadas durante el
tratamiento con el CCK-octapptido. Lo ms probable es que esto era debido a las
dosis relativamente bajas Ofthe drogas utilizadas en este estudio en comparacin con
nuestra investiga- cin anterior en el que las dosis varias veces superiores se utilizaron
totreat clnicamente avanzados PNAC. En conclusin, el uso de peras colecistoquininaoctapptido AP que se asocia con una tendencia hacia niveles de bilirrubina directa
inferiores en los recin nacidos de recibir a largo plazo TPN. Basndose en este
hallazgo, creemos que la marea colecistoquinina-octapep- puede ser eficaz en la
prevencin del desarrollo de, o una reduccin en el grado de colestasis parenteral ated
nutricin-aso- en neonatos. Finture. nrnsnec- aleatorizado