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Octreotide for the treatment of chylothorax in neonates

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Authors

Animitra Das1, Prakeshkumar S Shah2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Pediatrics, Waterford Regional Hospital, Waterford, Ireland [top]
2Department of Paediatrics and Department of Health Policy, Management and Evaluation, Rm 775A, University of Toronto, Toronto, Canada [top]

Citation example: 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.

Contact person

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

E-mail: pshah@mtsinai.on.ca

Dates

Assessed as Up-to-date: 06 July 2010
Date of Search: 07 March 2010
Next Stage Expected: 06 July 2012
Protocol First Published: Issue 1, 2007
Review First Published: Issue 9, 2010
Last Citation Issue: Issue 9, 2010

What's new

Date / Event Description

History

Date / Event Description

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.

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.

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.

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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).

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).

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.

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;
  3. congenital or acquired chylothorax;
  4. timing of introduction of octreotide (< 7 days or greater than/or equal to 7 days of diagnosis).

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Methods

Criteria for considering studies for this review

Types of studies

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

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
  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:
    1. number of days of mechanical ventilation,
    2. number of days of continuous positive airway pressure (CPAP),
    3. number of days of oxygen therapy.
  3. Duration of hospital stay (days).
  4. Mortality before 28 days of age.
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:
    1. thoracoscopic pleurodesis,
    2. pleuroperitoneal pump,
    3. ligation of the thoracic duct,
    4. 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:
    1. abnormal glucose homeostasis (serum glucose of < 2.6 mmol/L or > 7 mmol/L),
    2. diarrhoea,
    3. elevated liver enzymes (aspartate transaminase (AST)/alanine aminotransferase (ALT) > 40 IU/ml),
    4. 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).

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. 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/ 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)
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, 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.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. (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 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 (ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy). 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 to outcomes. We planned to assess methods as: adequate (< 20% missing data); inadequate (greater than/or equal to 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 data-dependent 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.

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.

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.

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;
  3. congenital and acquired causes of chylothorax;
  4. timing of introduction of octreotide (< 7 days or greater than/or equal to 7 days after diagnosis if data are available).

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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.

Risk of bias in included studies

We did not assess risk of bias as no studies were eligible for inclusion.

Effects of interventions

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.

Discussion

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.

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

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

  • None noted.

Characteristics of excluded studies

  • None noted.

Characteristics of studies awaiting classification

  • None noted.

Characteristics of ongoing studies

  • None noted.

Additional tables

1 Case reports of use of octreotide in neonatal chylothorax

Author Year

Diagnosis

Birth weight (G); Gestational age (wk); Sex

Route, dose, frequency and duration

Age at start of treatment

Pleural drainage prior to treatment

Outcomes

Length of stay

Side effects

Response

Altuncu 2007

Congenital chylothorax

3020; 36; Male

Infusion,
1-10µg/kg/h, 28 days

NA

NA

Cessation 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

106 days

Subsequent development of chronic lung disease following extubation resulting in persistent drainage; octreotide treatment ceased

No

Au 2003

Postoperative chylothorax (repair of gastroschisis)

NA; 36; Male

Infusion, 3.5 µg/kg/h,
8 days

Day 33

100-150 ml/d per side

Significant decrease to 40ml on the right side and 55 ml on the left side

55 days

None reported

Yes

Bulbul 2009

Congenital chylothorax

3770; term; Male

Infusion 3.5 µg/kg/h increased daily by 1 µg/kg/h to 10 µg/kg/h

Day 11

200-250 ml/day

Significant decrease in pleural fluid drainage after 10 µg/kg/h dose was reached and the dose was tapered over next 7 days

14 days

None reported

Yes

Coulter 2004

Spontaneous chylothorax (2 months after ligation of patent ductus arteriosus)

960; 26; Female

IV infusion,
4-24 µg/kg/d, 14 days

Day 109

300 ml/d

Drainage 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

148 days

Recurrence of effusion one day later required 21 more days of octreotide infusion with complete resolution on day 148

Yes

Goto 2003

Chylothorax (Left)

467; 24; Male

IV infusion, 0.3 µg/kg/h,
5 days

Day 36

60 ml/d

Chest drainage stopped on the second day; chest tube removed on day 47

NA

None reported

Yes

Goyal 2003

Chylothorax (Left)

3560; 41; Male

Subcutaneous,
10 µg/kg/h,
6 days

Day 10 after drain insertion

> 100ml/d

Chest drainage decreased dramatically in the first 24 hrs to < 50mL/d and fell to < 10 mL/d within 6 days of treatment

NA

None reported

Yes

Lauterbach 2005

Spontaneous chylothorax

690; 24; Male

IV infusion,
0.3 µg/kg/h,
4 days

Day 5 after diagnosis

50 ml/d

Chest drainage ceased after 24 hr of therapy; chest tube removed on the third day of treatment

127 days

None reported

Yes

Maayan-Metzaer 2005

Congenital chylothorax

2500; 34; NA

IV infusion, 60 µg/kg/d,
10 days

Day 33

40/60 ml (Left/Right)

Resolution within 48 hrs after initiation of octreotide

57 days

Transient hypothyroidism

Yes

Matsukuma 2009

Congenital chylothorax

2482; 33 + 6 days; Female

IV infusion,
0.5-10 µg/kg/h,
5 days

Day 23

20-150 ml/d

No significant decrease in chest tube drainage; octreotide treatment failed and OK-432 treatment was used instead

80 days

Not specified

No

Congenital chylothorax

2324; 33 + 6 days; Male

IV infusion,
10 µg/kg/h

Day 28 (earlier but specific date not specified)

> 150 ml/d

No significant decrease in chest tube drainage; octreotide treatment failed and OK-432 treatment was used instead

78 days

Not specified

No

Mohseni-Bod 2004

Postoperative chylothorax (coarctation repair)

2600; NA; Male

IV infusion, 2-4 µg/kg/h, 3 days

Day 14

NA

Failure to reduce drainage in the first 48 hrs

60 days

Developed necrotizing enterocolitis 3 days after start of infusion

No

Ochiai 2006

Congenital chylothorax in a patient with trisomy 21

1836; 29; Male

IV infusion 1-10 µg/kg/h, 22 days

Day 180

NA

Octreotide was started after failure of OK-432

22 days

No change, patient died at 400 days of age due to sepsis and multiorgan failure

No

Paget-Brown 2006

Chylothorax with Turner’s syndrome

3685; 40; Female

IV infusion, 10 µg/kg/h, 11 days

Day 13

100-400 ml/d (combined chest tube drainage)

Significant decrease in chest tube drainage; near total end of drainage by 8th day (5th day of 10 µg/kg/hr dosage)

30 days

None reported

Yes

Rasiah 2004

Congenital chylothorax

2500; 34; Female

IV infusion, 10 µg/kg/h, 10 days

Day 32

600 ml/day from both chest drains (bilateral intercostals drains)

Decreased chyle loss over a 10 day period; Chest drains removed 12 days later

50 days

Mildly distended abdomen on the 2nd day but subsided without alteration of treatment

Yes

Roehr 2006

Congenital chylothorax

NA; 34; Male

Subcutaneous, 40 µg/kg/d, 21 days

Day 53

NA

Resolution of chylothorax

NA

  • None noted.

Yes

Sahin 2005

Congenital chylothorax

2350; 33; Female

IV infusion, 0.5-10 µg/kg/h, 10 days

Day 15

200 ml/d

Prompt respiratory improvement; weaned to room air on 7th day of treatment; chest drains removed on 12th day

NA

Mild distension on the 3rd day but subsided without alteration of treatment

Yes

Siu 2006

Spontaneous neonatal chylothorax

3280; 37 + 5 days; Male

Route not specified, 3 µg/kg/h, 4 days

Day 19

42 ml on day 10

Significant decrease in chest drainage after the first 24 hr; complete cessation of drainage by 72 hr

NA

Yellowish 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

Yes

Sivasli 2004

Spontaneous neonatal chylothorax (Left)

2070; 24; Male

IV infusion, 3.5 µg/kg/h, 9 days

Day 22

6 ml/d

Pleural drainage ceased; chest tube was removed

45 days

None reported

Yes

Tibbals 2004

Postoperative chylothorax (cardiac surgery - Right)

2100; 36; NA

IV infusion,
3-5 µg/kg/h, 3 days

Day 10

110-130ml/d

Drainage ceased within 16 hrs; fluid re accumulated in the right pleural cavity on day 13 (octreotide was not recommenced)

NA

None reported

Can not tell

Young 2004

Congenital chylothorax

3700; 40 weeks and 2 days; Female

Subcutaneous via octreotide port, 40-70 µg/kg/d, 16 days

Day 2

NA

Resolution of chylothorax and discharge on day 21

NA

None reported

Yes

Footnotes

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).

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References to studies

Included studies

  • None noted.

References to excluded studies

  • None noted.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Altuncu 2007

Altuncu E, Akman I, Kiyan G, Ersu R, Yurdakul Z, Bilgen H, Ozdogan T, Ozek E. Report of three cases: congenital chylothorax and treatment modalities. Turkish Journal of 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 Surgery 2003;38(2):251-3.

Au 2003

Au M, Weber TR, Fleming RE. Successful use of somatostatin in a case of neonatal chylothorax. Journal of Pediatric Surgery 2003;38(7):1106-7.

Brissaud 2003

Brissaud O, Desfrere L, Mohsen R, Fayon M, Demarquez JL. Congenital idiopathic chylothorax in neonates: chemical pleurodesis with povidone iodine (Betadine). Archives of Disease in Childhood Fetal and Neonatal Edition 2003;88(6):F531-3.

Buck 2004

Buck M. Octreotide for management of chylothorax in infants and children. Paediatric Pharmacotherapy 2004;10(10):www.medscape.com/viewarticle/494653.

Bulbul 2009

Bulbul A, Okan F, Nuhoglu A. Idiopathic congenital chylothorax presented with severe hydrops and treated with octreotide in term newborn. Journal of Maternal Fetal and Neonatal Medicine 2009;22(12):1197-200.

Buttiker 1999

Buttiker V, Fanconi S, Burger R. Chylothorax in children: guidelines for diagnosis and management. Chest 1999;116(3):682-7.

Coulter 2004

Coulter DM. Successful treatment with octreotide of spontaneous chylothorax in a premature infant. Journal of Perinatology 2004;24(3):194-5.

Glaser 1993

Glaser B, Hirsch HJ. Persistent hyperinsulinemic hypoglycemia of infancy: long term octreotide treatment without pancreatectomy. Journal of Pediatrics 1993;123(4):644-50.

Gonzalez 2005

Gonzalez SM, Tarazona Fargueta JL, Munoz AP, Mira NJ, Jimenez CB. Use of somatostatin in five neonates with chylothorax. Anales de Pediatria 2005;63(3):244-8.

Goto 2003

Goto M, Kawamata K, Kitano M, Watanabe K, Chiba Y. Treatment of chylothorax in a premature infant using somatostatin. Journal of Perinatology 2003;23(7):563-4.

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.

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 Surgery 2008;43(6):1209-10.

Rennie 1999

Rennie JM, Roberton NRC. Textbook of Neonatology. 3rd edition. Churchill Livingstone, 1999.

Rocha 2007

Rocha G, Henriques Coelho T, Correia Pinto J, Guedes MB, Guimaraes H. Octreotide for conservative management of postoperative chylothorax in the neonate. Acta Medica Portuguesa 2007;20(5):467-70.

Roehr 2006

Roehr CC, Jung A, Proquitte H, Blankenstein O, Hammer H, Lakhoo K, Wauer RR. Somatostatin or octreotide as treatment options for chylothorax in young children: a systematic review. Intensive Care Medicine 2006;32(5):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.

Sivasli 2004

Sivasli E, Dogru D, Aslan AT, Yurdakok M, Tekinalp G. Spontaneous neonatal chylothorax treated with octreotide 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.

Wasmuth 2004

Wasmuth-Pietzuch A, Hansmann M, Bartmann P, Heep A. Congenital chylothorax: lymphopenia and high risk of infections. Acta Paediatrica 2004;93(2):220-4.

Young 2004

Young S, Dalgleish S, Eccleston A, Akierman A, McMillan D. Severe congenital chylothorax treated with octreotide. Journal of Perinatology 2004;24(3):200-2.

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Data and analyses

  • None noted.

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Sources of support

Internal sources

  • Department of Paediatrics, Mount Sinai Hospital, Toronto, Canada

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 9, 2010 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.