Banding ligation versus beta-blockers for primary prophylaxis of oesophageal variceal bleeding in children

  • Protocol
  • Intervention

Authors

  • Juan Cristóbal Gana,

    Corresponding author
    1. Division of Paediatrics, Escuela de Medicina, Pontificia Universidad Católica de Chile, Gastroenterology, Hepatology, and Nutrition Unit, Santiago, Region Metropolitana, Chile
    • Juan Cristóbal Gana, Gastroenterology, Hepatology, and Nutrition Unit, Division of Paediatrics, Escuela de Medicina, Pontificia Universidad Católica de Chile, 85 Lira, Santiago, Region Metropolitana, 8330074, Chile. jcgana@gmail.com.

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  • Lorena I Cifuentes,

    1. Escuela de Medicina, Pontificia Universidad Católica de Chile, Division of Paediatrics, Evidence-based Health Care Programme, Santiago, Metroplitana, Chile
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  • Jaime Cerda,

    1. Faculty of Medicine, Pontificia Universidad Católica de Chile, Department of Public Health, Santiago, Chile
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  • Luis A Villarroel del Pino,

    1. Faculty of Medicine, Pontificia Universidad Católica de Chile, Department of Public Health, Santiago, Chile
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  • Alfredo Peña,

    1. Escuela de Medicina, Pontificia Universidad Católica de Chile, Department of Paediatrics, Division of Paediatrics, Santiago, Chile
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  • Marcela Rivera Cornejo

    1. Pontificia Universidad Católica de Chile, Biblioteca Biomedica, Sistema de Bibliotecas, Santiago, Región Metropolitana, Chile
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the benefits and harms of banding ligation compared to any type of beta-blocker for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.

Background

Oesophageal varices in portal hypertension

Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including haemorrhage from oesophageal and gastrointestinal varices. The prevalence of cirrhosis among adults in developed countries ranges between 0.4% and 1.1% (Bellentani 1994; Quinn 1997). Up to two thirds of people will develop gastroesophageal varices (Garceau 1963; Jensen 2002). The prevalence of gastroesophageal varices in patients with cirrhosis increases by nearly 5% per year (Merli 2003).

As varices grow larger they become more likely to rupture and bleed (Lebrec 1980; NIEC 1988). Haemorrhage from ruptured oesophageal varices is one of the most common causes of gastrointestinal bleeding and the most common cause of death in patients with cirrhosis (D'Amico 2006; Garcia-Tsao 2007). Studies by the Northern Italian Endoscopic Club have shown that the frequency of bleeding from large varices is 50% to 53% over two years, compared to 5% to 18% from small varices (NIEC 1988; Zoli 1996). Up to 30% of the initial bleeding episodes are fatal, and bleeding reoccurs in 70% of the survivors (Graham 1981; NIEC 1988; Sharara 2001; D'Amico 2003; Bambha 2008). Primary prophylaxis with non-selective beta-blockers or endoscopic variceal banding lowers the incidence of first variceal haemorrhage, especially of medium to large varices (Garcia-Tsao 2007; Garcia-Tsao 2008).

Description of the condition

Variceal haemorrhage also commonly occurs in children with chronic liver disease or portal vein obstruction (Mitra 1978; Webb 1979; Kobayashi 1984; Toyosaka 1993; Lykavieris 2000; Miga 2001; van Heurn 2004). In children with biliary atresia, the incidence of variceal haemorrhage ranges from 17% to 29% over a five to 10 year period (Kobayashi 1984; Miga 2001; van Heurn 2004) and is 50% in children who survive more than 10 years without liver transplantation (Toyosaka 1993). Recently, a report of 125 children with biliary atresia with signs of portal hypertension or previous history of gastrointestinal bleeding were evaluated under oesophagogastroduodenoscopy. Eighty-eight patients (70%) were identified with oesophageal varices (Duche 2010). Among 50 children with oesophageal varices, primarily due to cirrhosis, who were prospectively followed and not offered active treatment to prevent variceal bleeding, 42% suffered upper gastrointestinal haemorrhage during a median 4.5 year follow-up period (Goncalves 2000). For children with portal vein thrombosis, the available studies suggest that up to 50% suffer a major variceal haemorrhage by 16 years of age (Lykavieris 2000). A mortality rate of 19% has been reported within 35 days of variceal bleeding episodes among North American children with liver disease of various aetiologies (Eroglu 2004). Two other studies showed that 5% and 15% of children with biliary atresia and variceal haemorrhage will die (Stringer 1989; van Heurn 2004). On the other hand, variceal haemorrhage seems to carry a very low risk of death in children with portal vein thrombosis and no parenchymal liver disease (Lykavieris 2000).

Description of the intervention

Primary prophylaxis of variceal haemorrhage in adults is the established standard of care following numerous randomised clinical trials demonstrating the efficacy of non-selective beta-blockers and endoscopic variceal ligation in decreasing the incidence of variceal haemorrhage (Garcia-Tsao 2007; Garcia-Tsao 2008). There are no evidence-based recommendations for the prophylactic management of children at risk of variceal haemorrhage due to the lack of appropriate good quality randomised clinical trials. In a previous survey of 30 paediatric gastroenterologists in the United States, approaches to the management of children with portal hypertension to screening endoscopy and primary prophylaxis of variceal bleeding varied considerably among the respondents. In this survey, 63% perform surveillance of oesophageal varices and 84% offered primary prophylaxis of variceal bleeding in children (Shneider 2004). In a recent survey in Canada, the majority of paediatric gastroenterologists (70%) reported that they would consider screening for oesophageal varices in children with liver disease and evidence of cirrhosis or portal hypertension (such as splenomegaly, thrombocytopenia, or portosystemic collaterals on sonography); however, only 58% of respondents who would screen for varices would provide primary prophylactic treatment (Gana 2011). This suggests that many paediatric specialists apply to children the guidelines for management of adults with portal hypertension; however, there is an important variation of care provided by physicians probably secondary to the lack of good quality studies. There are several differences in the pathophysiology of portal hypertension between adults and children, so precautions must be taken before extrapolating the results between the groups. Children are more dependent upon chronotropy for maintenance of systemic blood pressure during hypovolaemia in contrast to adults who depend mainly on vasoconstriction. The main concern is that by limiting tachycardia in children, the use of a non-selective beta-blocker may impair tolerance of hypovolaemia and worsen the outcome from variceal haemorrhage. Secondly, the efficacy, pharmacokinetics, and adverse event profiles of the drugs may differ significantly between children and adults. Finally, the principal aetiologies of liver disease and portal hypertension are different in these populations. In children, the main causes of portal hypertension are biliary atresia and portal vein thrombosis, while in adults these are hepatitis C and alcohol-related cirrhosis.

Although the use of banding ligation is frequently used in children, there is a limitation in infants. The currently available equipment for banding ligation is too large to be introduced into the oesophagus of infants smaller than 12 to 15 kg body weight.

How the intervention might work

Endoscopic variceal ligation and beta-blockers have been shown to be the best treatment modalities in adults (Garcia-Tsao 2007; Garcia-Tsao 2008). A meta-analysis by Imperiale 2001 has shown that endoscopic variceal ligation for primary prophylaxis of oesophageal varices in cirrhotic adults reduces the incidence of variceal haemorrhage and mortality by 64% compared with no therapy. Different meta-analyses in adult population have shown that nonselective beta-blockers reduce the incidence of variceal haemorrhage by 50% in adults with cirrhosis (D'Amico 1995; Hayes 1990). The mechanisms of action include reduction of cardiac output, reduction of portal venous flow, and antagonism of the norepinephrine-induced constriction of intrahepatic myofibroblasts, activated stellate cells, and vascular smooth muscle cells. These interventions are deemed reasonable to be considered as prophylaxis options in children with oesophageal varices. We will therefore perform a systematic review on banding ligation versus beta-blockers for primary prevention of oesophageal varices bleeding in children.

Why it is important to do this review

Variceal haemorrhage commonly occurs in children with oesophageal varices secondary to chronic liver disease or portal vein obstruction, and has been associated with mortality. Prevention is therefore important.There is no systematic review on this topic at present.

Different treatments have been proposed for the primary prophylaxis of oesophageal varices bleeding. This systematic review is one of six reviews that will examine the utility of these treatments modalities (Gana 2013a; Gana 2013b; Gana 2013c; Gana 2013d; Gana 2013e).

Objectives

To determine the benefits and harms of banding ligation compared to any type of beta-blocker for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised clinical trials for assessment of benefits and harms.

Non-randomised studies that may be retrieved with the searches will be included for data on harm only.

Types of participants

Participants will include paediatric patients (up to 18 years old) with chronic liver disease or portal vein thrombosis, irrespective of the aetiology, severity of disease, and duration of illness, in whom the presence of oesophageal varices was confirmed by oesophagogastroduodenoscopy. The review will focus on therapy questions related to children who have not yet suffered gastrointestinal bleeding from oesophageal varices (primary prophylaxis).

Children with a previous surgical portal-systemic shunt procedure or insertion of a transjugular intrahepatic portal-systemic shunt (TIPS), previous sclerotherapy of oesophageal varices, or previous history of upper gastrointestinal bleeding are a distinct group in whom the diagnosis or natural history of oesophageal varices has been modified. These children will not be the focus of this review, hence studies that include such children will be excluded unless data are presented in such a way as to allow this patient group to be isolated from other included children.

Types of interventions

Endoscopic variceal ligation versus beta-blockers as primary prophylaxis of variceal bleeding in children.

Types of outcome measures

Primary outcomes

We will consider patient-oriented outcomes.

1. All-cause mortality.
2. Bleeding-related mortality.
3. Serious adverse events. A serious adverse event, defined according to the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (ICH-GCP 1997), is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. All other adverse events will be considered non-serious adverse events.
4. Quality of life.

Secondary outcomes

1. Oesophageal bleeding.
2. Overall gastrointestinal bleeding.
3. Non-serious adverse events.

Search methods for identification of studies

Electronic searches

Searches will be conducted in the Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2013), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (Royle 2003). No language or document type restrictions will be applied. Search strategies with the time spans of the searches are listed in Appendix 1.

Searching other resources

Additional references will be identified by manually searching the references of articles from the computerised databases and relevant review articles. Unpublished studies will be sought by contacting experts in the field and pharmaceutical companies to inquire about additional trials.

Data collection and analysis

We will follow the available guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2013). The analyses will be performed using Review Manager 5 (RevMan 2012).

Selection of studies

Publications will be retrieved if they are potentially eligible for inclusion based on an abstract review, or if they are relevant review articles for a manual reference search. The publications will be reviewed independently for eligibility by JC and AP. To be eligible, each publication will be assessed to determine if participants meet the inclusion criteria detailed above. Abstracts will only be included if sufficient data are provided for analysis. Any disagreements will be resolved by consensus between JC, AP, and JCG.

Data extraction and management

Two authors (JC and AP) will independently complete a data extraction form on all included studies. The following data will be retrieved.

  1. General information: title, journal, year, publication status, and study design.

  2. Sample size: number of participants meeting the criteria and total number screened.

  3. Baseline characteristics: baseline diagnosis, age, sex, race, disease severity, and concurrent medications used. Severity of liver disease of the studied population may be considered using the Child Pugh score (Pugh 1973), the paediatric end-stage liver disease (PELD) scores for ages less than 12 years (McDiarmid 2002), and model for end-stage liver disease (MELD) for ages 12 and older (Kamath 2001).

  4. Oesophageal bleeding, all-cause mortality, bleeding-related mortality, and non-variceal bleeding of the upper gastrointestinal tract.

  5. Adverse events: serious and non-serious.

Missing data

Primary authors of the trial publications will be contacted for missing data.

Assessment of risk of bias in included studies

Two review authors will independently assess the risk of bias of each included trial according to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), the Cochrane Hepato-Biliary Group Module (Gluud 2013), and methodological studies (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovic 2012; Savovic 2012a). We will use the following definitions in the assessment of risk of bias.

Allocation sequence generation

- Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice are adequate if performed by an independent person not otherwise involved in the trial.
- Uncertain risk of bias: the method of sequence generation was not specified.
- High risk of bias: the sequence generation method was not random.

Allocation concealment

- Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (for example, if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).
- Uncertain risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.
- High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.

Blinding of participants, personnel, and outcome assessors

- Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.
- Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to induce bias on the results.
- High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes was likely to be influenced by lack of blinding.

Incomplete outcome data

- Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, have been employed to handle missing data.
- Uncertain risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.
- High risk of bias: the results were likely to be biased due to missing data.

Selective outcome reporting

- Low risk of bias: all outcomes were pre-defined and reported, or all clinically relevant and reasonably expected outcomes were reported.
- Uncertain risk of bias: it is unclear whether all pre-defined and clinically relevant and reasonably expected outcomes were reported.
- High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.

For a trial to be assessed with low risk of bias in the selective outcome reporting domain, the trial should have been registered either on the www.clinicaltrials.gov web site or a similar register, or there should be a protocol, for example published in a paper journal. In the case where the trial was run and published in the years when trial registration was not required, we will carefully scrutinise all publications reporting on the trial to identify the trial objectives and outcomes. If usable data on all outcomes specified in the trial objectives are provided in the publication's results section, then the trial can be considered low risk of bias in the 'Selective outcome reporting' domain.

For-profit bias

- Low risk of bias: the trial appears to be free of industry sponsorship or other kind of for-profit support that may result in manipulation of the trial design, conduct, or results of the trial.
- Uncertain risk of bias: the trial may or may not be free of for-profit bias as no information on clinical trial support or sponsorship is provided.
- High risk of bias: the trial is sponsored by industry or has received other kinds of for-profit support.

Other biases

- Low risk of bias: the trial appears to be free of other sources of bias.
- Uncertain risk of bias: there is insufficient information to assess whether other sources of bias are present.
- High risk of bias: it is likely that potential sources of bias related to the specific trial design used or other bias risks are present.

We expect a lack of blinding of participants in the trials in view of the different treatment modalities (endoscopic versus oral), and this could lead to a bias that will need to be analysed.

Trials assessed as having 'low risk of bias' in all of the specified domains will be considered 'trials with low risk of bias'. Trials assessed as having 'uncertain risk of bias' or 'high risk of bias' in one or more of the above domains will be considered trials with 'high risk of bias'.

A 'Risk of bias' graph and 'Risk of bias' summary will be generated to show a summary of this assessment.

Measures of treatment effect

The effect measures will be relative risks (RR) with 95% confidence intervals (CI).

Unit of analysis issues

The number of observations in the analysis is the number of patients that were randomised. Participants are individually randomised to two or more intervention groups, and a single measurement for each outcome from each participant is collected and analysed.

Dealing with missing data

We will only analyse available data. We will also address the potential impact of missing data on the findings using intention-to-treat analyses.

Regarding the primary outcomes, we will include patients with incomplete or missing data in the sensitivity analyses by imputing them according to the following scenarios.

- Poor outcome analysis: assuming that dropouts and participants lost from both the experimental and the control arms experienced the outcome; all randomised participants will be included in the denominator.
- Good outcome analysis: assuming that none of the dropouts and participants lost from the experimental and the control arms experienced the outcome; all randomised participants will be included in the denominator.
- Extreme case analysis favouring the experimental intervention ('best-worse' case scenario): none of the dropouts or participants lost from the experimental arm, but all of the dropouts and participants lost from the control group experienced the outcome; including all randomised participants in the denominator.
- Extreme case analysis favouring the control ('worst-best' case scenario): all dropouts or participants lost from the experimental arm, but none from the control arm experienced the outcome; including all randomised participants in the denominator.

Assessment of heterogeneity

Heterogeneity will be addressed in both clinical and statistical ways. First, depending on the number of eligible trials, we plan to add co-variates that may explain heterogeneity to the regression model, such as severity of the underlying liver disease.

The primary meta-analyses will be performed using random-effects models stratified by severity of liver disease (Child Pugh A, B, or C and PELD or MELD).

To assess heterogeneity between the trials, we will use the Chi2 heterogeneity statistic, and we will present the heterogeneity statistic I2.

Assessment of reporting biases

Reporting biases will be assessed with funnel plots of the relative risk estimates from the individual trials (plotted on a logarithmic scale) against trial size or precision (variance) or the estimators. Funnel plots will be constructed if there are at least 10 included trials.

Data synthesis

Meta-analyses

The analyses will be performed in Review Manager 5.2 (RevMan 2012) and R Program 2.15 (RDCT 2012).

We will apply both fixed-effect model and random-effects model meta-analyses. In the case of statistically significant discrepancies in the results (for example one giving a significant intervention effect and the other no significant intervention effect), we will report both; otherwise we will report the results with the random-effects model.

The results of dichotomous outcomes of individual studies will be presented as relative risk (RR) with 95% CI, and continuous outcomes as mean difference ± SD, combining trials using Mantel-Haenszel or DerSimonian-Lair methods, or both.

The results of individual trials will be presented as RR with 95% CI, and heterogeneity with the I2 statistic. The main results of the individual trials and meta-analyses will be illustrated in the form of forest plots.

Trial sequential analysis

Trial sequential analysis (TSA) is a tool for quantifying the statistical reliability of the data in a cumulative meta-analysis (CTU 2011; Thorlund 2011), controlling alpha and beta values for sparse data and repetitive testing on accumulating data (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009, Wetterslev 2009; Thorlund 2010; Thorlund 2011a). TSA is a methodology that combines a required information size calculation (cumulated sample sizes of trials to prove or disprove a certain intervention effect) with the threshold of statistical significance. In order to control for the risks of random errors due to sparse data and multiplicity, we will perform TSA for the dichotomous outcomes (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009, Wetterslev 2009; Thorlund 2010; Thorlund 2011a). We will base our calculations on the diversity-adjusted required information size on the proportion of patients with the outcome in the conventional group, a relative risk reduction of 20%, an alpha (type I error) of 5%, a beta (type II error) of 20% (power 80%), and the diversity of the meta-analysis (Wetterslev 2009). We may perform sensitivity analyses choosing other variables.

Subgroup analysis and investigation of heterogeneity

We aim to perform subgroup analyses and, therefore, we will perform separate meta-analyses for trials according to their bias risk (comparing trials with low (or lower) risk of bias to trials with high risk of bias, primary prophylaxis of small varices compared to only medium or large varices, and for trials in patients with chronic liver disease and extrahepatic portal vein obstruction.

Sources of heterogeneity that we will attempt to investigate will include chronic liver disease compared to portal vein thrombosis, severity of liver disease, different aetiologies of liver disease (for example viral cirrhosis compared to alcoholic cirrhosis, cholestatic compared to non-cholestatic liver disease), and co-morbidities.

Sensitivity analysis

In addition to the sensitivity analyses specified under 'Dealing with missing data', in order to assess the robustness of the eligibility criteria, we will undertake sensitivity analyses that may explain our findings as well as any observed heterogeneity. The publications will be reviewed independently by JC and AP for the sensitivity analysis. Any disagreements will be resolved by consensus with JCG.

Summary of findings tables

'Summary of findings' tables provide information about quality of evidence, magnitude of effects of the interventions, and summarise data on outcomes. They are created using GRADEpro (http://ims.cochrane.org/revman/other-resources/gradepro). We plan to create such tables presenting all review outcomes.

Acknowledgements

Peer reviewers: Lorenzo D’Antiga, Italy; Maja Thiele, Denmark.
Contact editors: Goran Bjelakovic, Serbia; Christian Gluud, Denmark.

Appendices

Appendix 1. Search strategies

DatabaseTime spanSearch strategy
Cochrane Hepato-Biliary Group Controlled Trials RegisterDate will be given at review stage.(adrenergic and beta and (antagonist* or block* or receptor*)) AND ((ligat* and (endoscop* or band* or rubber*)) OR (EBL or EVL EBD)) AND (child* or P*ediat* or infant* or bab* or pre*school or lactant* or neonat* or adolescent* or school*child or youth* or toddler* or teen* or boy* or girl* or student* or juvenile* or minor* or pubescen* or young* or newborn)
Cochrane Central Register of Controlled Trials in The Cochrane LibraryLatest issue.

#1    MeSH descriptor: [Adrenergic beta-Antagonists] explode all trees

#2    ((beta Antagonist* or beta-Antagonists or beta-Blocker* or beta Blocker* or beta-Receptor) Adrenergic) in Trials

#3    (beta-Adrenergic or beta Adrenergic or Adrenergic or Adrenergic beta Receptor or Adrenergic beta-Receptor (Blockaders or Blockers or Blocking or Blockaders)) in Trials

#4    Receptor Blockaders, beta-Adrenergic in Trials

#5    #1 or #2 or #3 or #4

#6    MeSH descriptor: [Ligation] explode all trees

#7    ((Endoscop* or band* or Rubber) ligat*) in Trials

#8    (EBL or EVL or EBD or ligat*) in Trials

#9    #6 or #7 or #8 in Trials

#10   MeSH descriptor: [Child, Preschool] explode all trees

#11   MeSH descriptor: [Child] explode all trees

#12   MeSH descriptor: [Adolescent] explode all trees

#13   MeSH descriptor: [Infant, Newborn] explode all trees

#14   MeSH descriptor: [Infant] explode all trees

#15   child* or pediat* or paediat* in Trials

#16   infant* or baby or pre-school in Trials

#17   lactant* or neonate* or adolescent* in Trials

#18   school-child or youth or toddler* or teen* in Trials

#19   boy* or girl* or preschool* or student* in Trials

#20   juvenile or minor or pubescen* in Trials

#21   young* or babies or newborn* in Trials

#22   #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21

#23   #5 and #9 and #22 in Trials

PubMed1809 to the date of search.

#1 "Adrenergic beta-Antagonists"[Mesh]

#2 ((beta Antagonists OR beta-Antagonists OR  beta-Blockers OR beta Blockers OR beta-Receptor) Adrenergic)

#3 (beta-Adrenergic OR  beta Adrenergic OR Adrenergic OR Adrenergic beta Receptor OR Adrenergic beta-Receptor (Blockaders OR Blockers OR  Blocking OR Blockaders))

#4 Receptor Blockaders, beta-Adrenergic

#5 #1 OR #2 OR #3 OR #4

#6 "Ligation"[Mesh]

#7 ((Endoscop* OR band* OR Rubber) ligat*)

#8 (EBL OR EVL OR EBD OR ligat*)

#9 #6 OR #7 OR #8

#10 "Child, Preschool"[Mesh]

#11 "Child"[Mesh]

#12  "Adolescent"[Mesh]

#13 "Infant, Newborn"[Mesh]

#14 "Infant"[Mesh]

#15 child* OR pediat* OR paediat*

#16 infant* OR baby OR pre-school

#17 lactant* OR neonate* OR adolescent*

#18 school-child OR youth OR toddler* OR teen*

#19 boy* OR girl* OR preschool* OR student*

#20  juvenile OR minor OR pubescen*

#21 young* OR babies OR newborn*

#22 #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21

#23 #5 AND #9 AND #22

EMBASE1974 to the date of search.

1. exp beta adrenergic receptor blocking agent/

2. (adrenergic and beta and (antagonist* or block* or receptor*)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

3. 1 or 2

4. exp ligation/

5. (ligat* and (endoscop* or band* or rubber*)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

6. (EBL or EVL EBD).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

7. 4 or 5 or 6

8. exp child/

9. exp adolescent/

10. exp newborn/

11. (child* or P*ediat* or infant* or bab* or pre*school or lactant* or neonat* or adolescent* or school*child or youth* or toddler* or teen* or boy* or girl* or student* or juvenile* or minor* or pubescen* or young* or newborn).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

12. 8 or 9 or 10 or 11

13. 3 and 7 and 12

Science Citation Index Expanded1900 to the date of search.

#1 TS=(adrenergic and beta and (antagonist* or block* or receptor*))

#2 TS=(ligat* and (endoscop* or band* or rubber*))
#3 TS=(EBL or EVL EBD)
#4 #2 OR #3

#5 (child* or P*ediat* or infant* or bab* or pre*school or lactant* or neonat* or adolescent* or school*child or youth* or toddler* or teen* or boy* or girl* or student* or juvenile* or minor* or pubescen* or young* or newborn)
#6 #1 AND #4 AND #5

What's new

DateEventDescription
13 June 2013AmendedAlfredo Peña was inadvertently omitted from the author byline. The byline should read as shown now.

Contributions of authors

JCG - formulated the research question and drafted the protocol.
LC - provided methodological expert opinion and reviewed the protocol.
JC - reviewed the protocol.
LV - provided statistical expert opinion and reviewed the protocol.
AP - provided methodological expert opinion and reviewed the protocol.
MR - provided the search strategies and reviewed the protocol.
All authors agreed on the publication of the protocol in its present form.

Declarations of interest

None known.

Sources of support

Internal sources

  • Research award from the Division of Paediatrics, Pontificia Universidad Católica de Chile, Chile.

External sources

  • No sources of support supplied

Ancillary