Octreotide for the treatment of chylothorax in neonates (Review) The Cochrane Library

Octreotide for the treatment of chylothorax in neonates
(Review)
Das A, Shah PS
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 9
http://www.thecochranelibrary.com
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . .
AUTHORS’ CONCLUSIONS . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . .
ADDITIONAL TABLES . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
INDEX TERMS
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Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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i
[Intervention Review]
Octreotide for the treatment of chylothorax in neonates
Animitra Das2 , Prakeshkumar S Shah1
1 Department of Paediatrics and Department of Health Policy, Management and Evaluation, Rm 775A, University of Toronto,
Toronto,
Canada. 2 Department of Pediatrics, Waterford Regional Hospital, Waterford, Ireland
Contact address: Prakeshkumar S Shah, Department of Paediatrics and Department of Health Policy, Management and Evaluation,
Rm 775A, University of Toronto, 600 University Avenue, Toronto, Ontario, M5G 1XB, Canada. [email protected]
Editorial group: Cochrane Neonatal Group.
Publication status and date: New, published in Issue 9, 2010.
Review content assessed as up-to-date: 5 July 2010.
Citation: Das A, Shah PS. Octreotide for the treatment of chylothorax in neonates. Cochrane Database of Systematic Reviews 2010,
Issue 9. Art. No.: CD006388. DOI: 10.1002/14651858.CD006388.pub2.
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
Routine care for chylothorax in neonate includes either conservative or surgical approaches. Octreotide, a somatostatin analogue, has
been used for the management of patients with refractory chylothorax not responding to conservative management.
Objectives
To assess the efficacy and safety of octreotide in the treatment of chylothorax in neonates.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE and EMBASE (to
March 7, 2010). We assessed the reference lists of identified trials and abstracts from the annual meetings of the Pediatric Academic
Societies published in Pediatric Research (2002 to 2009) without language restrictions.
Selection criteria
We planned to include randomised or quasi-randomised controlled trials of octreotide in the treatment of congenital or acquired
chylothorax in term or preterm neonates, with any dose, duration or route of administration.
Data collection and analysis
Data on primary (amount of fluid drainage, respiratory support, mortality) and secondary outcomes (side effects) were planned to be
collected and analysed using mean difference, relative risk and risk difference with 95% confidence intervals.
Main results
No randomised controlled trials were identified. Nineteen case reports of 20 neonates with chylothorax in whom octreotide was used
either subcutaneously or intravenously were identified. Fourteen case reports described successful use (resolution of chylothorax), four
reported failure (no resolution) and one reported equivocal results following use of octreotide. The timing of initiation, dose, duration
and frequency of doses varied markedly. Gastrointestinal intolerance and clinical presentations suggestive of necrotizing enterocolitis
and transient hypothyroidism were reported as side effects.
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1
Authors’ conclusions
No practice recommendation can be made based on the evidence identified in this review. A prospective registry of chylothorax patients
and a subsequent multicenter randomised controlled trial are needed to assess the safety and efficacy of octreotide in the treatment of
chylothorax in neonates.
PLAIN LANGUAGE SUMMARY
Octreotide for treatment of chylothorax in newborns
Collection of lymphatic fluid in the chest cavity is called chylothorax. Routine management of this condition involves treatment of the
underlying condition, draining of fluid, putting a tube in the chest wall until all the fluid is drained and rarely surgery. Octreotide is a
drug that may reduce the production and accumulation of fluid and allow babies to recover faster. No trials have evaluated the safety
and efficacy of this drug in babies and only case reports are available. Future studies are needed.
BACKGROUND
Description of the condition
Chylothorax is defined as accumulation of lymphatic fluid or chyle
in the pleural space. Chyle is composed of fats (phospholipids,
cholesterol and triglycerides), proteins (albumin, immunoglobulins and fibrinogen), electrolytes, fat soluble vitamins and lymphocytes. The diagnosis of chylothorax is considered when pleural fluid assay has a triglyceride level > 1.1 mmol/L and total cell
count of > 1000 cells/ml with > 80% lymphocytes. Without oral
fat intake, the distinction between chylous and non-chylous effusion is difficult because chylomicrons are absent in the pleural fluid (Buttiker 1999). In non-feeding infants, the diagnosis of
chylothorax is made by identifying the presence of a high number
of lymphocytes in serous fluid.
Chylothorax can be unilateral or bilateral and congenital or acquired. Congenital chylothorax is associated with abnormalities of
the lymphatic system such as lymphangiomatosis and lymphangiectasia, congenital heart disease, mediastinal malignancies, chromosomal abnormalities (trisomy 21, Turners and Noonan syndromes) and H-type of tracheoesophageal fistula (Rasiah 2004).
Acquired chylothorax is usually due to trauma to the thoracic
duct during cardiac or thoracic surgery. The incidence of congenital chylothorax is reported to be 1 in 10,000 births (Rennie
1999). Many cases of chylothorax have no clear etiology and are
considered as idiopathic congenital chylothorax (Au 2003). The
reported case fatality rate is 15% to 57%; however mortality is
higher when there is associated hydrops fetalis (Brissaud 2003 ).
Significant in-utero chylothoraces may impair lung development
and result in pulmonary hypoplasia. Attempts to treat chylothorax
by drainage may lead to malnutrition, electrolyte imbalance and
infection (Wasmuth 2004).
Antenatal management of chylothorax consists of thoracentesis
or pleuro-amniotic shunts to prevent pulmonary hypoplasia. In
the postnatal period, the management of the pleural effusion can
be either conservative or surgical. The conservative approach includes management of underlying disease, repeated thoracentesis, continuous drainage, dietary modifications (medium chain
triglyceride diet or total parental nutrition), use of positive end
expiratory pressure during mechanical ventilation and chemical
or mechanical pleurodesis. The surgical approach includes thoracoscopic pleurodesis, pleuroperitoneal pump, surgical abrasion,
ligation of the thoracic duct and creation of a thoracic duct to azygous vein anastomosis (Brissaud 2003). None of these therapeutic
modalities have undergone controlled clinical trials; however these
treatments are commonly used in the clinical setting.
Description of the intervention
Octreotide, a somatostatin analogue, is used for the management
of patients with refractory chylothorax, not responding to conservative management (Goto 2003). The use of octreotide in the
treatment of chylothorax in infants and children has been reviewed
(Helin 2006; Roehr 2006). Both reviews suggested that octreotide
has the potential to be a potent and effective therapy for chylous
pleural effusion. However, it has not been studied in randomised
trials. Octreotide has been used for a variety of indications in adults
and older children including acromegaly, carcinoid tumour, acute
variceal bleeding, gastrointestinal fistulae and intractable diarrhoea
(Lamberts 1996). In neonates, octreotide has been used for the
management of persistent hyperinsulinaemic states (Glaser 1993).
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
2
How the intervention might work
The mechanism of action of octreotide in chylothorax is uncertain. It is proposed that octreotide causes mild vasoconstriction
of splanchnic vessels, including hepatic venous flow. This leads to
reduction in gastric, pancreatic and intestinal secretions as well as
intestinal absorption. These mechanisms collectively reduce the
flow of chyle (Rasiah 2004). Animal studies have shown that octreotide is effective in treating thoracic duct injury by reducing the
chyle drainage and allowing early fistula closure (Markham 2000).
However, octreotide is associated with adverse effects such as arrhythmias, injection site pain, nausea, vomiting, constipation or
diarrhoea, hyperglycaemia, hypoglycaemia, dizziness and fatigue
(Buck 2004). Other adverse effects include transient impairment
of liver function, transient hypothyroidism and necrotizing enterocolitis (Mohseni-Bod 2004; Maayan-Metzaer 2005). Arevalo et
al reported octreotide induced hypoxaemia and pulmonary hypertension in preterm neonates (Arevalo 2003).
Randomised or quasi-randomised controlled trials of octreotide
in the treatment of chylothorax in neonates were to be included.
Cross-over trials were not included. Unpublished data and abstracts were eligible for inclusion provided adequate information
regarding primary or secondary outcomes could be obtained.
Types of participants
Both term and preterm (< 37 weeks gestation at birth) infants up
to 28 days of postnatal age who had either congenital or acquired
chylothorax were included. Studies were included if pleural fluid
was confirmed to be of chylous origin. If feeds had not been initiated, infants were included if pleural fluid showed more than 80%
lymphocytes in the absence of high triglyceride levels. In milk-fed
infants, the standard criteria for laboratory diagnosis of chyle were
used.
Types of interventions
Why it is important to do this review
Despite the reported benefit in reduction of chyle production in
uncontrolled case studies, octreotide has not been systematically
evaluated in newborns with chylothorax. Moreover, the safety profile in relation to adverse effects, dosing schedule, route of administration and duration of therapy has not been evaluated.
Octreotide versus placebo or no treatment added to the current
conservative management. Studies of any route of administration,
any dose and any duration of administration of octreotide were
considered.
Types of outcome measures
Primary outcomes
OBJECTIVES
Our primary objective was to assess the efficacy and safety of octreotide in the treatment of chylothorax in neonates.
Our secondary objective was to perform subgroup analyses based
on:
(1) gestation (preterm or term);
(2) route of administration of octreotide;
(1) Change in the amount of chyle production from baseline to
end of treatment (ml/day).
(2) Number of days of respiratory support after initiation of octreotide therapy:
a. number of days of mechanical ventilation,
b. number of days of continuous positive airway pressure (CPAP),
c. number of days of oxygen therapy.
(3) Duration of hospital stay (days).
(4) Mortality before 28 days of age.
(3) congenital or acquired chylothorax;
(4) timing of introduction of octreotide (< 7 days or ≥ 7 days of
diagnosis).
METHODS
Criteria for considering studies for this review
Types of studies
Secondary outcomes
(1) Total number of days of chest drain insertion (removal of both
chest drains in cases of bilateral effusion).
(2) Number of infants requiring surgical intervention:
a. thoracoscopic pleurodesis,
b. pleuroperitoneal pump,
c. ligation of the thoracic duct,
d. creation of a thoracic duct to azygous vein anastomosis.
(3) Number of days to reach full enteral feeds.
(4) Sepsis.
(5) Necrotizing enterocolitis (Bell’s criteria, Stage 2).
(6) Adverse effects of octreotide, number of infants with:
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
3
a. abnormal glucose homeostasis (serum glucose of < 2.6 mmol/L
or > 7 mmol/L),
b. diarrhoea,
c. elevated liver enzymes (aspartate transaminase (AST)/alanine
aminotransferase (ALT) > 40 IU/ml),
d. transient hypothyroidism (thyroid stimulating hormone (TSH)
< 10 mIU/ml, thyroxine 4 (T4) 6 to 12.8 µg/dl).
(7) Clinically important adverse effects reported by authors (not
pre-specified).
(8) Any clinically important outcome reported by authors (not
pre-specified).
or validation studies as topic/ or evaluation study.pt. or validation
study.pt. or case-control studies/ or retrospective studies/ or cohort
studies/ or longitudinal studies/ or follow-up studies/ or prospective studies/ or cross-sectional studies/ or double-blind method/ or
random allocation/ or single-blind method/ or ((singl* or doubl*
or tripl* or trebl*) adj5 (blin or mask or blinded or masked)).ti,ab.
(1900654)
5 3 and 4 (41)
6 from 5 keep 1-41 (41)
7 3 not 5 (156)
8 from 7 keep 1-156 (156)
9 from 8 keep 156 (1)
Search methods for identification of studies
Electronic searches
The Cochrane Central Register of Controlled Trials (CENTRAL)
(The Cochrane Library 2010, Issue 1), MEDLINE (1950 to March
7, 2010) and EMBASE (1980 to March 7, 2010) were searched
using the following search strategy.
Database: Ovid MEDLINE(R) (1950 to present)
Search strategy:
1 infant, newborn/ or infant, low birth weight/ or infant, small
for gestational age/ or infant, very low birth weight/ or infant,
premature/ or pregnancy, high-risk/ or quadruplets/ or quintuplets/ or superfetation/ or triplets/ or twins/ or twins, dizygotic/
or twins, monozygotic/ or (infan: or neonat: or newborn: or prematur: or iugr or sga or vlbw or lbw or elbw).ti,ab. or ((intrauterine adj2 growth adj2 restrict:) or (intrauterine adj2 growth adj2
retard:)).ti,ab. (717200)
2
Octreotide/ or (octreotide* or “sms 201-995” or “sms 201
995” or “sms 201995” or “sms201995” or “san 201-995” or “san
201 995” or “san 201995” or “sm 201-995” or “sm 201 995”
or “sm 201995” or “compound 201-995” or “compound 201
995” or “compound 201995” or “sandoz 201-995” or “sandoz
201 995” or “sandoz 201995” or sandostatine* or sandostatin* or
longastatin or longastatina or oncolar or samilstin or sandstatin
or “sdz 201995” or “sdz201995” or “sms201995” or “sms995” or
pentetreotide* or octreoscan* or “mp 1727” or “mp1727”).mp.
(7166)
3 1 and 2 (197)
4 (“clinical trial, all” or clinical trial).pt. or clinical trials as topic/
or clinical trial, phase i.pt. or clinical trials, phase i as topic/ or clinical trial, phase iii.pt. or clinical trials, phase iii as topic/ or clinical
trial, phase iv.pt. or clinical trials, phase iv as topic/ or controlled
clinical trial.pt. or controlled clinical trials as topic/ or meta-analysis.pt. or meta-analysis as topic/ or multicenter study.pt. or multicenter studies as topic/ or randomized controlled trial.pt. or randomized controlled trials as topic/ or evaluation studies as topic/
Database: EBM Reviews - Cochrane Central Register of
Controlled Trials (CENTRAL) (The Cochrane Library Issue
1, 2010)
Search strategy:
1 infant, newborn/ or infant, low birth weight/ or infant, small
for gestational age/ or infant, very low birth weight/ or infant, premature/ or infant, newborn/ or infant, low birth weight/ or infant,
small for gestational age/ or infant, very low birth weight/ or infant,
premature/ or exp Infant, Newborn, Diseases/ or pregnancy, highrisk/ or quadruplets/ or quintuplets/ or superfetation/ or triplets/
or twins/ or twins, dizygotic/ or twins, monozygotic/ or (infan:
or neonat: or newborn: or prematur: or iugr or sga or vlbw or
lbw or elbw).ti,ab. or ((intrauterine adj2 growth adj2 restrict:) or
(intrauterine adj2 growth adj2 retard:)).ti,ab.or pregnancy, highrisk/ or quadruplets/ or quintuplets/ or superfetation/ or triplets/
or twins/ or twins, dizygotic/ or twins, monozygotic/ or (infan:
or neonat: or newborn: or prematur: or iugr or sga or vlbw or
lbw or elbw).ti,ab. or ((intrauterine adj2 growth adj2 restrict:) or
(intrauterine adj2 growth adj2 retard:)).ti,ab. (23255)
2
Octreotide/ or (octreotide* or “sms 201-995” or “sms 201
995” or “sms 201995” or “sms201995” or “san 201-995” or “san
201 995” or “san 201995” or “sm 201-995” or “sm 201 995”
or “sm 201995” or “compound 201-995” or “compound 201
995” or “compound 201995” or “sandoz 201-995” or “sandoz
201 995” or “sandoz 201995” or sandostatine* or sandostatin* or
longastatin or longastatina or oncolar or samilstin or sandstatin
or “sdz 201995” or “sdz201995” or “sms201995” or “sms995” or
pentetreotide* or octreoscan* or “mp 1727” or “mp1727”).mp.
(775)
3 1 and 2 (1)
Database: Ovid EMBASE <1980 to 2010 Week 09>
Search Strategy:
1
newborn/ or newborn period/ or low birth weight/ or extremely low birth weight/ or small for date infant/ or very low
birth weight/ or Prematurity/ or multiple pregnancy/ or twin pregnancy/ or twins/ or dizygotic twins/ or monozygotic twins/ or human triplets/ or intrauterine growth retardation/ or small for date
infant/ or (infan: or neonat: or newborn: or prematur: or iugr or
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
4
sga or vlbw or lbw or elbw or (intrauterine adj2 growth adj2 restrict:) or (intrauterine adj2 growth adj2 retard:)).ti,ab. (452585)
2
Octreotide/ or (octreotide* or “sms 201-995” or “sms 201
995” or “sms 201995” or “sms201995” or “san 201-995” or “san
201 995” or “san 201995” or “sm 201-995” or “sm 201 995”
or “sm 201995” or “compound 201-995” or “compound 201
995” or “compound 201995” or “sandoz 201-995” or “sandoz
201 995” or “sandoz 201995” or sandostatine* or sandostatin* or
longastatin or longastatina or oncolar or samilstin or sandstatin
or “sdz 201995” or “sdz201995” or “sms201995” or “sms995” or
pentetreotide* or octreoscan* or “mp 1727” or “mp1727”).mp.
or (83150-76-9 or 138661-02-6 or 139096-04-1).rn. (12805)
3 1 and 2 (365)
4 ct.fs. or clinical trial/ or controlled clinical trial/ or multicenter
study/ or phase 1 clinical trial/ or phase 2 clinical trial/ or phase
3 clinical trial/ or phase 4 clinical trial/ or cohort analysis/ or
double blind procedure/ or single blind procedure/ or triple blind
procedure/ or meta analysis/ or randomized controlled trial/ or
“systematic review”/ or case control study/ or longitudinal study/
or prospective study/ or retrospective study/ or multicenter study/
or validation study/ or (((evaluation or validation) adj2 study) or
((evaluation or validation) adj2 studies)).ti,ab. (882179)
5 3 and 4 (63)
6 from 5 keep 1-63 (63)
7 3 not 5 (302)
We assessed the reference lists of identified studies (reviewed 42
titles), abstracts from the annual meetings of the Society for Pediatric Research, American Pediatric Society and Pediatric Academic
Societies published in Pediatric Research (2002 to 2009) (reviewed
25 titles). We searched clinical trial registries for ongoing or recently completed trials (www.clinicaltrials.gov; www.controlledtrials.com; and www.who.int/ictrp). No study was identified from
these registries. No language restrictions were applied.
The following types of articles were excluded: letters (which do
not contain original data), editorials, commentaries, reviews and
lectures.
Data collection and analysis
Selection of studies
All published articles identified as potentially relevant by the literature search were assessed for inclusion in the review by both
review authors (AD and PS). Data from authors were to be obtained where published data provided inadequate information for
the review or where relevant data could not be abstracted. Both
authors contributed to the literature search and article review. Retrieved articles were assessed and data were abstracted. Discrepancies regarding inclusion and exclusion of the studies were resolved
by consensus.
Data extraction and management
If studies were selected for inclusion, we planned to collect information regarding study methodology (including the method
of randomisation, blinding, drug intervention, stratification and
whether the trial was single or multicenter) and information regarding trial participants (including birth weight criteria and other
inclusion or exclusion criteria).
Assessment of risk of bias in included studies
We planned to independently review the methodological quality
of each trial. We planned to assess each identified trial for methodological quality with respect to: a) masking of allocation, b) masking of intervention, c) completeness of follow up, d) masking of
outcome assessment. This information was to be included in the
’Characteristics of included studies’ table.
In addition, we planned to complete the ’Risk of bias’ table addressing the following methodological issues.
1. Sequence generation: was the allocation sequence adequately
generated?
For each included study, we planned to describe the method used
to generate the allocation sequence as: adequate (any truly random process for example random number table, computer random number generator); inadequate (any non-random process for
example odd or even date of birth, hospital or clinic record number); or unclear.
2. Allocation concealment: was allocation adequately concealed?
For each included study, we planned to describe the method used
to conceal the allocation sequence as: adequate (for example telephone or central randomisation, consecutively numbered sealed
opaque envelopes); inadequate (open random allocation, unsealed
or non-opaque envelopes, alternation, date of birth); or unclear.
3. Blinding of participants, personnel and outcome assessors: was
knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
For each included study, we planned to describe the methods
used to blind study participants and personnel from knowledge of
which intervention a participant received. We planned to assess the
methods as: adequate, inadequate or unclear for participants; adequate, inadequate or unclear for study personnel; and adequate,
inadequate or unclear for outcome assessors and the specific outcomes assessed.
4. Incomplete outcome data: were incomplete outcome data adequately addressed?
For each included study and for each outcome, we planned to describe the completeness of data including attrition and exclusions
from the analysis. We planned to address whether attrition and
exclusions were reported, the numbers included in the analysis at
each stage (compared with the total number of randomised participants), reasons for attrition or exclusion where reported, and
whether missing data were balanced across groups or were related
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
5
to outcomes. We planned to assess methods as: adequate (< 20%
missing data); inadequate (≥ 20% missing data) or unclear.
5. Selective outcome reporting: were reports of the study free of
suggestion of selective outcome reporting?
For each included study, we planned to assess the possibility of selective outcome reporting bias as: adequate (where it was clear that
all of the study’s pre-specified outcomes and all expected outcomes
of interest to the review were reported); inadequate (where not all
the study’s pre-specified outcomes were reported, one or more of
the reported primary outcomes was not pre-specified, outcomes
of interest were reported incompletely and so could not be used,
study failed to include results of a key outcome that would have
been expected to have been reported); or unclear.
6. Other sources of bias: was the study apparently free of other
problems that could put it at a high risk of bias?
For each included study, we planned to note any important concerns regarding other possible sources of bias (for example whether
there was a potential source of bias related to the specific study
design or whether the trial was stopped early due to some datadependent process). We planned to assess whether each study was
free of other problems that could put it at risk of bias, as: yes; no;
or unclear.
(3) congenital and acquired causes of chylothorax;
(4) timing of introduction of octreotide (< 7 days or ≥ 7 days after
diagnosis if data are available).
RESULTS
Description of studies
The literature search identified 287 potential titles which were
screened by checking titles and abstracts. Screening of titles and
abstracts led to 43 articles which were identified for further review.
Two of these were reviews on the subject, published in Spanish
(Gonzalez 2005) and Portugese (Rocha 2007). They were not retrieved for further assessment because the abstracts clearly indicated that these were not eligible for inclusion. Of the remaining
41 articles retrieved for full assessment, none of them were eligible
for inclusion in this review as none of the studies met the eligibility
criteria for this review. All were case reports of neonates, infants
and children.
Measures of treatment effect
We planned to use RevMan 5.0 for statistical analysis. Planned
statistical parameters were relative risk (RR), risk difference
(RD), number needed to treat (NNT), number needed to harm
(NNH) and weighted mean difference (WMD), when appropriate. Ninety-five per cent confidence intervals (CI) were to be reported for estimates of treatment effects.
Risk of bias in included studies
We did not assess risk of bias as no studies were eligible for inclusion.
Effects of interventions
Assessment of heterogeneity
Tests for between study heterogeneity, including the I2 statistic,
were to be applied to assess the statistical heterogeneity. If heterogeneity was identified, further exploration would be performed to
identify the cause.
Data synthesis
If multiple studies were identified, meta-analysis was planned using Review Manager software (RevMan 5, The Cochrane Collaboration). For estimates of relative risk and risk difference, we
planned to use the Mantel-Haenszel method. For measured quantities, we planned to use the inverse variance method. We planned
to conduct all meta-analyses using the fixed-effect model.
The effects of the intervention were studied in case reports only.
We have summarized the results of case reports in a table below
(Table 1). Of the 19 case reports of 20 neonates, 14 reported successful resolution of chylothorax whereas four reported failure of
resolution of chylothorax with octreotide. One report indicated
equivocal results. Octreotide was initiated between the second and
109th day after birth. It was given either subcutaneously or intravenously. The dose ranged between 10 to 70 µg/kg/day when used
subcutaneously and between 0.3 and 10 µg/kg/h when used as
an intravenous infusion. The frequency of administration ranged
from six hourly to 24 hourly for subcutaneous administration and
was mostly by continuous infusion for intravenous administration.
The duration of administration in cases of successful resolution
varied between four and 21 days; however, it was mostly guided
by response to therapy.
Subgroup analysis and investigation of heterogeneity
A priori subgroup analyses were planned based on:
(1) gestational age (term and preterm);
(2) route of administration of octreotide;
DISCUSSION
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
6
The safety and efficacy of octreotide in the treatment of chylothorax in neonates has not been evaluated properly. The rarity of the condition is the main rate limiting step. Case reports
of the use of octreotide have shown promising results; however,
methodological bias prevails. If reports of unsuccessful usage of
octeotride are less likely to be submitted or accepted for publication than are reports of successful usage, then publication bias will
result. With reports of potential side effects such as necrotizing enterocolitis (Reck-Burneo 2008), persistent pulmonary hypertension (Arevalo 2003), transient hyperthyroxinemia (Mohseni-Bod
2004), cholelithiasis (Radetti 2000; Andreou 2005) and inhibition of retinal neo-vascularization (Higgins 2002; Qu 2009), it
is important that octreotide is evaluated properly before its use
becomes routine practice. The natural history of chylothorax includes spontaneous postnatal resolution over a few days. An effect
observed in certain cases of effectiveness, in terms of reduction
in chest fluid, could well fit in this category and unless properly
evaluated the question regarding efficacy remains.
Due to the rarity of this condition, multicenter efforts will be
needed. In order to design proper trials to evaluate efficacy, we
need to identify the natural history of this condition. A prospective
multicenter registry of such cases would be the best way to assess
the duration of chylous drainage, amount of chylous drainage
and its impact on respiratory outcomes. Once these outcomes
are known, a multicenter randomised clinical trial is needed to
evaluate the safety and efficacy of octreotide.
Referral centres for prenatal diagnosis would be ideal sites for such
a study. Based on published reports, the population of interest
should be those with idiopathic chylothoraces, which could be
stratified to include postoperative chylothoraces. Included infants
should be managed with routine care and those who do not respond to therapy by five days should be the target population.
It appears that early, high doses were most beneficial; however,
it would need to be monitored closely (Helin 2006). Octreotide
should be given subcutaneously or intravenously; however, the
preferable route will be by intravenous infusion as the presence
of subcutaneous edema in some infants with associated hydrops
may lead to variable absorption of the medication. Outcomes of
interest can be mean change in the fluid drainage over a specified
time, duration of respiratory support and resolution of chylothorax. Safety should also be of importance and side effects such as
pulmonary hypertension, development of intestinal complications
and, if used in preterm neonates, the incidence of retinopathy of
prematurity should be monitored.
AUTHORS’ CONCLUSIONS
Implications for practice
No practice recommendation can be made based on the evidence
identified in this review.
Implications for research
A multicenter randomised controlled trial is needed to assess the
safety and efficacy of octreotide in the treatment of chylothorax
in neonates. Such a trial should have neonates with idiopathic
chylothorax diagnosed antenatally or postnatally as population,
failure to spontaneous resolution by seven days as entry criteria,
must receive octreotide via subcutaneous or intravenous route,
and have improvement in the amount of chylous drainage by at
least 50% within three days of attaining pre-determined maximum
dose and improvement in respiratory status (significant reduction
in the need for respiratory support by seven days of initiation of
treatment) as primary outcomes and side effects and mortality as
secondary outcomes.
ACKNOWLEDGEMENTS
We thank Ms Elizabeth Uleryk, Chief Librarian at the Hospital for
Sick Children Toronto for her help in developing and executing
the search strategy. We also thank Ms Jamie Zao for her help in
preparation of this review.
The Cochrane Neonatal Review Group has been funded in part
with Federal funds from the Eunice Kennedy Shriver National
Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services,
USA, under Contract No. HHSN267200603418C.
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
7
REFERENCES
Additional references
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Pediatrics 2007;49(4):418–21.
Andreou 2005
Andreou A, Papouli M, Papavasiliou V, Badouraki
M. Postoperative chylous ascites in a neonate treated
successfully with octreotide: bile sludge and cholestasis.
American Journal of Perinatology 2005;22(8):401–4.
Arevalo 2003
Arevalo RP, Bullabh P, Krauss AN, Auld PA, Spigland
N. Octreotide-induced hypoxaemia and pulmonary
hypertension in premature neonates. Journal of Pediatric
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Au M, Weber TR, Fleming RE. Successful use of
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Brissaud O, Desfrere L, Mohsen R, Fayon M, Demarquez
JL. Congenital idiopathic chylothorax in neonates: chemical
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Buck M. Octreotide for management of chylothorax in
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Bulbul A, Okan F, Nuhoglu A. Idiopathic congenital
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Glaser 1993
Glaser B, Hirsch HJ. Persistent hyperinsulinemic
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Gonzalez 2005
Gonzalez SM, Tarazona Fargueta JL, Munoz AP, Mira NJ,
Jimenez CB. Use of somatostatin in five neonates with
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Goto M, Kawamata K, Kitano M, Watanabe K, Chiba
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Goyal 2003
Goyal A, Smith NP, Jesudason EC, Kerr S, Losty PD.
Octreotide for treatment of chylothorax after repair of
congenital diaphragmatic hernia. Journal of Pediatric Surgery
2003;38(8):E19–E20.
Helin 2006
Helin RD, Angeles STV, Bhat R. Octreotide therapy
for chylothorax in infants and children : a brief review.
Pediatric Critical Care Medicine 2006;7:1–5.
Higgins 2002
Higgins RD, Yan Y, Schrier BK. Somatostatin analogs
inhibit neonatal retinal neovascularization. Experimental
Eye Research 2002;74:553–9.
Lamberts 1996
Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ.
Drug therapy: Octreotide. New England Journal of Medicine
1996;334:246–54.
Lauterbach 2005
Lauterbach R, Sczaniecka B, Koziol J, Knapczyk M.
Somatostatin treatment of spontaneous chylothorax in an
extremely low birth weight infant. European Journal of
Pediatrics 2005;164(3):195–6.
Maayan-Metzaer 2005
Maayan-Metzaer A, Sack J, Mazkereth R, Vardi A, Kuint
J. Somatostatin treatment of congenital chylothorax may
induce transient hypothyroidism in newborns. Acta
Paediatrica 2005;94:785–9.
Markham 2000
Markham K, Glover J, Welsh R, Lucas R, Bendick P.
Octreotide in the treatment of thoracic duct injuries.
American Surgeon 2000;66:1165–7.
Matsukuma 2009
Matsukuma E, Aoki Y, Sakai M, Kawamoto N, Watanabe
H, Iwagaki S, et al.Treatment with OK-432 for persistent
congenital chylothorax in newborn infants resistant to
octreotide. Journal of Pediatric Surgery 2009;44(3):e37–9.
Mohseni-Bod 2004
Mohseni-Bod H, Macrae D, Slavik Z. Somatostatin analog
(octreotide) in management of neonatal postoperative
chylothorax: is it safe?. Pediatric Critical Care Medicine
2004;5(4):356–7.
Ochiai 2006
Ochiai M, Hikino M, Nakayam H, Ohga S, Taguchi T,
Hara T. Nonimmune hydrops fetalis due to generalized
lymphatic dysplasia in an infant with Robertsonian trisomy
21. American Journal Perinatology 2006;23(1):63–6.
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
8
Paget-Brown 2006
Paget-Brown A, Kattwinkel J, Rodgers BM, Michalsky
MP. The use of octreotide to treat congenital chylothorax.
Journal of Pediatric Surgery 2006;41(4):845–7.
Qu 2009
Qu Y, Zhang S, Xu X, Wang H, Li J, Zhou F, Wei F.
Octreotide inhibits choroidal neovascularization in rats.
Ophthalmic Research 2009;42(1):36–42.
Radetti 2000
Radetti G, Gentili L, Paganini C, Messner H. Cholelithiasis
in a newborn following treatment with the somatostatin
analogue octreotide. European Journal of Pediatrics 2000;
159(7):550.
Rasiah 2004
Rasiah SV, Oei J, Lui K. Octreotide in the treatment of
congenital chylothorax. Journal of Paediatrics and Child
Health 2004;40(9-10):585–8.
Reck-Burneo 2008
Reck-Burneo CA, Parekh A, Velcek FT. Is octreotide a risk
factor in necrotizing enterocolitis?. Journal of Pediatric
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Roehr 2006
Roehr CC, Jung A, Proquitte H, Blankenstein O, Hammer
H, Lakhoo K, Wauer RR. Somatostatin or octreotide as
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650–7.
Sahin 2005
Sahin Y, Aydin D. Congenital chylothorax treated with
octreotide. Indian Journal of Pediatrics 2005;72(10):885–8.
Siu 2006
Siu SL, Lam DS. Spontaneous neonatal chylothorax treated
with octreotide. Journal of Paediatrics and Child Health
2006;42(1-2):65–7.
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Sivasli E, Dogru D, Aslan AT, Yurdakok M, Tekinalp G.
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in Turkey: a case report. Journal of Perinatology 2004;24(4):
261–2.
Tibbals 2004
Tibballs J, Soto R, Bharucha T. Management of newborn
lymphangiectasia and chylothorax after cardiac surgery with
octreotide infusion. Annals of Thoracic Surgery 2004;77(6):
2213–5.
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Wasmuth 2004
Wasmuth-Pietzuch A, Hansmann M, Bartmann P, Heep
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Rocha 2007
Rocha G, Henriques Coelho T, Correia Pinto J, Guedes MB,
Guimaraes H. Octreotide for conservative management
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∗
Indicates the major publication for the study
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
9
DATA AND ANALYSES
This review has no analyses.
ADDITIONAL TABLES
Table 1. Case reports of use of octreotide in neonatal chylothorax
Author
Year
Diagnosis
Birth
weight
(G); Gestational age
(wk); Sex
Route,
Age
dose, fre- at start of
quency
treatment
and duration
Altuncu
2007
Congeni3020; 36; Infusion,
NA
tal
chy- Male
1-10µg/
lothorax
kg/h, 28
days
NA
Au 2003
PostoperNA;
ative chy- Male
lothorax
(repair of gastroschisis)
100Significant 55 days
150 ml/d decrease
per side
to 40ml on
the right
side and 55
ml on the
left side
36; InDay 33
fusion, 3.5
µg/kg/h,
8 days
Pleural
Outcomes Length of Side
drainage
stay
effects
prior to
treatment
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cessation 106 days
of drainage
by
28
days
of
age; when
octreotide
was lowered; on
the
4th
day of extubation,
chronic
lung
disease
developed
with
re
accumulation
of
fluid
resulting
in
intubation;
drainage
persisted
and treatment was
stopped
Response
SubseNo
quent development
of chronic
lung
disease following extubation resulting in persistent
drainage;
octreotide
treatment
ceased
None
reported
Yes
10
Table 1. Case reports of use of octreotide in neonatal chylothorax
(Continued)
Bulbul
2009
Congeni- 3770;
Infusion 3. Day 11
tal
chy- term; Male 5 µg/kg/
lothorax
h increased
daily by 1
µg/kg/h to
10 µg/kg/h
200-250
ml/day
Significant 14
decrease in
pleural
fluid
drainage
after
10 µg/kg/
h dose was
reached
and
the
dose was
tapered
over next 7
days
None
reported
Coulter
2004
Sponta960; 26;
neous chy- Female
lothorax (2
months after ligation
of patent
ductus arteriosus)
300 ml/d
Drainage
148 days
decreased
markedly
after
drug increase but
re-started
after stoppage
of
drug
which required
re-institution of
treatment
and gradual weaning;
no pleural
fluid
was visible
on x-rays
from days
120-121
RecurYes
rence of effusion one
day later
required
21 more
days of octreotide infusion
with complete resolution on
day 148
60 ml/d
Chest
NA
drainage
stopped on
the second
day; chest
tube
removed on
day 47
None
reported
Goto 2003 Chylothorax (Left)
467;
Male
IV
Day 109
infusion,
424 µg/kg/
d, 14 days
24; IV
in- Day 36
fusion, 0.3
µg/kg/h,
5 days
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Yes
Yes
11
Table 1. Case reports of use of octreotide in neonatal chylothorax
Goyal
2003
Chylothorax (Left)
Lauterbach
2005
Sponta690;
neous chy- Male
lothorax
MaayanMetzaer
2005
Congeni2500; 34; IV
in- Day 33
tal
chy- NA
fusion, 60
lothorax
µg/kg/d,
10 days
Matsukuma
2009
Congeni2482; 33 + IV
Day 23
tal
chy- 6 days; Fe- infusion,
0.5-10 µg/
lothorax
male
kg/h,
5 days
(Continued)
3560; 41; SubcutaDay 10 af- > 100ml/d
Male
neous,
ter drain
10 µg/kg/ insertion
h,
6 days
Chest
NA
drainage
decreased
dramatically in the
first 24 hrs
to < 50mL/
d and fell
to <10 mL/
d within 6
days
of
treatment
None
reported
Yes
Chest
127 days
drainage
ceased after 24 hr
of therapy;
chest tube
removed on
the third
day
of
treatment
None
reported
Yes
40/60 ml Resolu57 days
(Left/
tion within
Right)
48 hrs after initiation of octreotide
Transient
hypothyroidism
Yes
20-150
ml/d
No signifi- 80 days
cant
decrease in
chest tube
drainage;
octreotide
treatment failed
and OK432 treatment was
used
instead
Not speci- No
fied
Congeni2324; 33 + IV
Day
> 150 ml/d No signifi- 78 days
tal
chy- 6
days; infusion,
28 (earlier
cant
lothorax
Male
10 µg/kg/h but specific
decrease in
Not speci- No
fied
24; IV
Day 5 after 50 ml/d
infusion,
diagnosis
0.3 µg/kg/
h,
4 days
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
12
Table 1. Case reports of use of octreotide in neonatal chylothorax
(Continued)
date not
specified)
chest tube
drainage;
octreotide
treatment failed
and OK432 treatment was
used
instead
MohseniBod 2004
Postoper2600; NA; IV
in- Day 14
ative chy- Male
fusion, 2-4
lothorax
µg/kg/h, 3
(coarctadays
tion repair)
NA
Failure to 60 days
reduce
drainage in
the first 48
hrs
Developed No
necrotizing enterocolitis 3
days after
start of infusion
Ochiai
2006
Congeni1836; 29; IV
Day 180
tal
Male
infusion 1chylotho10 µg/kg/
rax in a pah, 22 days
tient with
trisomy 21
NA
Octreotide 22 days
was started
after failure of OK432
No
No
change,
patient
died at 400
days of age
due to sepsis
and multiorgan failure
PagetBrown
2006
Chylotho- 3685; 40;
rax with Female
Turner’s
syndrome
IV
in- Day 13
fusion, 10
µg/kg/h,
11 days
100400 ml/d
(combined
chest tube
drainage)
Significant 30 days
decrease in
chest tube
drainage;
near total
end
of drainage
by 8th day
(5th day of
10 µg/kg/
hr dosage)
None
reported
Rasiah
2004
Congeni2500; 34; IV
in- Day 32
tal
chy- Female
fusion, 10
lothorax
µg/kg/h,
10 days
600 ml/
day from
both chest
drains (bilateral intercostals
drains)
Decreased 50 days
chyle
loss over a
10 day period; Chest
drains removed 12
Mildly dis- Yes
tended abdomen on
the
2
nd day but
subsided
without al-
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Yes
13
Table 1. Case reports of use of octreotide in neonatal chylothorax
34; SubcutaDay 53
neous,
40 µg/kg/
d, 21 days
(Continued)
days later
teration of
treatment
NA
Resolution NA
of
chylothorax
None
Roehr
2006
CongeniNA;
tal
chy- Male
lothorax
Sahin
2005
Congeni2350; 33; IV infu- Day 15
tal
chy- Female
sion, 0.5lothorax
10 µg/kg/
h, 10 days
200 ml/d
Prompt
NA
respiratory
improvement;
weaned to
room
air on 7
th day of
treatment;
chest
drains removed on
12th day
Mild
Yes
distension on the
3rd day but
subsided
without alteration of
treatment
Siu 2006
Spontaneous
neonatal
chylothorax
3280; 37 + Route not Day 19
5
days; specified, 3
Male
µg/kg/h, 4
days
42 ml on Significant NA
day 10
decrease in
chest
drainage
after the
first 24 hr;
complete
cessation
of drainage
by 72 hr
Yellowish
Yes
loose stool
passed
mixed
with blood
streaks
starting on
the 2nd day
of
treatment;
bloody diarrhea persisted despite
the cessation of infusion;
poor feeding and abdominal distension developed
Sivasli
2004
Spontaneous
neonatal
2070; 24; IV
in- Day 22
Male
fusion, 3.5
µg/kg/h, 9
6 ml/d
None
reported
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Pleural
drainage
ceased;
45 days
Yes
Yes
14
Table 1. Case reports of use of octreotide in neonatal chylothorax
chylothorax (Left)
(Continued)
days
chest tube
was
removed
Tibbals
2004
Postoper2100; 36; IV
Day 10
ative chy- NA
infusion,
3-5 µg/kg/
lothorax
h, 3 days
(cardiac
surgery Right)
110130ml/d
Drainage
NA
ceased
within 16
hrs; fluid
re accumulated in the
right pleural cavity
on day 13
(octreotide
was
not recommenced)
None
reported
Can
tell
Young
2004
Congeni3700; 40 SubcuDay 2
tal
chy- weeks and taneous via
lothorax
2 days; Fe- octreotide
male
port, 4070 µg/kg/
d, 16 days
NA
ResNA
olution of
chylothorax
and
discharge
on day 21
None
reported
Yes
not
NA = Not available, SC = subcutaneous, IV = intravenous. Two reports were not included: one review was in Spanish (Gonzalez 2005)
and another case report was in Portugese (Rocha 2007).
HISTORY
Protocol first published: Issue 1, 2007
Review first published: Issue 9, 2010
CONTRIBUTIONS OF AUTHORS
A Das
Writing and editing protocol
Identifying and collecting information from searched articles
P Shah
Writing and editing protocol
Developing search
Identifying articles
Selection of articles
Writing and editing the review
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
15
DECLARATIONS OF INTEREST
None
SOURCES OF SUPPORT
Internal sources
• Department of Paediatrics, Mount Sinai Hospital, Toronto, Canada.
External sources
• No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
None
INDEX TERMS
Medical Subject Headings (MeSH)
Chylothorax [∗ drug therapy]; Infant, Newborn; Octreotide [∗ therapeutic use]
MeSH check words
Humans
Octreotide for the treatment of chylothorax in neonates (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
16