Intervention Protocol

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Fibrin-based haemostatic agents for reducing blood loss in adult liver resection

  1. Aimen O Amer1,†,
  2. Colin H Wilson2,‡,*,
  3. Steven A White1,
  4. Derek M Manas2

Editorial Group: Cochrane Hepato-Biliary Group

Published Online: 12 DEC 2013

DOI: 10.1002/14651858.CD010872


How to Cite

Amer AO, Wilson CH, White SA, Manas DM. Fibrin-based haemostatic agents for reducing blood loss in adult liver resection (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD010872. DOI: 10.1002/14651858.CD010872.

Author Information

  1. 1

    Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK

  2. 2

    The Freeman Hospital, Institute of Transplantation, Newcastle upon Tyne, Tyne and Wear, UK

  1. These authors contributed equally to this work.

  2. These authors contributed equally to this work.

*Colin H Wilson, Institute of Transplantation, The Freeman Hospital, Freeman Road, High Heaton, Newcastle upon Tyne, Tyne and Wear, NE7 7DN, UK. Colin.Wilson@nuth.nhs.uk. colinwilson2206@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 12 DEC 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Description of the condition

Liver resection is the treatment of choice for many benign and malignant liver tumours (Jarnagin 2002). Despite the considerable development in surgical technique since the late nineteenth century (Langenbuch 1888; Warvi 1945) and the improved understanding of segmental liver anatomy (Couinaud 1999), liver resection can still be associated with significant intraoperative bleeding (Berrevoet 2007). The intrinsic capacity of the liver to bleed is due to both its abundant venous vascular network and its inability to vasoconstrict in response to injury (Clark 1970). In addition, this can be complicated by coagulation disorders related to the underlying disease.

Operative mortality following liver resection is reported to range from 3% in non-cirrhotic patients (Jarnagin 2002) to 25% in the presence of liver cirrhosis (Mullin 2005). Intraoperative bleeding is the major cause of morbidity and mortality in liver resection (Jarnagin 2002; Ibrahim 2006). Allogeneic blood transfusion also increases morbidity and mortality through transfusion reactions, transmission of blood-borne infective agents, and potentially through immunosuppressive effects of donor-derived leukocytes (Shinozuka 2000).

 

Description of the intervention

Various surgical, anaesthetic, and pharmacological techniques have been applied to minimise blood loss and achieve haemostasis in liver surgery ( Table 1). The evidence behind the effectiveness of various vascular occlusion techniques, parenchymal transection techniques, cardiopulmonary manoeuvres, and antifibrinolytics in reducing blood loss in liver resections has been examined in Cochrane reviews (Gurusamy 2009a; Gurusamy 2009b; Gurusamy 2009c; Gurusamy 2009d).

Fibrin-based haemostatic agents are bioabsorbable topical haemostatic agents used in liver resection to enhance haemostasis and reduce blood loss. These products contain clotting factors and act by mimicking the final stages of the coagulation cascade ending in the formation of fibrin, thus promoting the process of coagulation and wound healing. The main components of commercially available fibrin-based haemostatic agents are thrombin and fibrinogen, derived from human plasma and typically purified from cryoprecipitate.

 

How the intervention might work

The two components, thrombin and fibrinogen, are usually delivered to the site of bleeding via a dual-syringe or aerosol applicator. In some products, the clotting factors are coated on a collagen sheet and applied as a surgical patch. Non-commercial preparations of fibrin-based haemostatic agents utilise autologous or allogenic blood products as a source of fibrinogen which is then combined with topical bovine thrombin (Mintz 2001). The relative concentrations of fibrinogen and thrombin within these preparations affect the haemostatic process. Higher concentrations of thrombin tend to accelerate clot formation and increase clot adhesion, whereas higher concentrations of fibrinogen produce stronger clots. Fibrinogen concentrations are usually higher and more consistent in commercial fibrin-based haemostatic agents than non-commercial preparations (Albala 2003). Other additives, including factor XIII and antifibrinolytic agents, such as aprotinin or tranexamic acid, can also be included in these preparations in order to improve clot stability ( Table 2).

In addition to their effect on haemostasis, fibrin-based haemostatic agents are also thought to have a sealant effect, preventing the leakage of bile and reducing the incidence of other complications of liver resection such as intra-abdominal fluid collection (Berrevoet 2007).

However, the use of these products is not without its risks. Fibrin-based haemostatic agents that contain plasma-derived or bovine products carry the risk of transmitting viral and prion infections (Spotnitz 2005). Those that contain bovine thrombin, upon repeated exposure, can also lead to immunologically induced coagulopathies (Rapaport 1992; Banninger 1993) and anaphylactic reactions (Mitsuhata 1994).

 

Why it is important to do this review

Various topical haemostatic agents have been employed to reduce resection surface bleeding during liver resection. Although fibrin-based haemostatic agents have been advocated as most favourable sealants (Berrevoet 2007), two recent meta-analyses have failed to show clinical improvements in outcomes from using these products in liver surgery (Sanjay 2013; Ding 2013). Nevertheless, fibrin-based haemostatic agents are frequently used in liver surgery with the aim of reducing blood loss and biliary leakage (Boonstra 2009; Nakajima 2002). The evidence for the benefits of these agents in liver resection (and indeed their superiority over other haemostatic adjuncts) is yet to be examined in a Cochrane review. It is, therefore, important to evaluate the literature critically and systematically for the benefits and risks of using fibrin-based haemostatic agents compared with no (or other) haemostatic adjuncts in these procedures.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

To assess the benefits and harms of fibrin-based haemostatic agents in reducing intraoperative blood loss in adults undergoing liver resection.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

All randomised clinical trials regardless of publication date, publication status, language, blinding, or bias risk. We will consider quasi-randomised and observational studies only for the report on adverse events related to the use of fibrin-based haemostatic agents in liver resection.

 

Types of participants

Adults, 18 years old or above, undergoing liver resection regardless of site or extent of resection, and regardless of underlying liver pathology.

 

Types of interventions

Any commercial and non-commercial fibrin-based haemostatic agent, regardless of additive (antifibrinolytic agents or factor XIII), compared with placebo, no intervention, or other haemostatic agents.

 

Types of outcome measures

 

Primary outcomes

1. Perioperative mortality: defined as death, regardless of cause, occurring within 30 days after surgery in or out of the hospital (Jacobs 2006).
2. Serious adverse events such as infection, coagulopathy, anaphylaxis, defined according to the International Conference on Harmonization Guidelines for Good Clinical Practice (ICH-GCP 1997).
3. Haemostatic efficacy as measured in the individual trial:

  • Time to haemostasis: defined as the time between application of haemostatic aid to the resected liver margin and the complete cessation of bleeding.
  • Amount of intraoperative blood loss: measured as the volume of blood lost during liver resection.
  • Perioperative transfusion requirement: measured as the number of units of packed red blood cells, platelets, or fresh frozen plasma transfused intraoperatively and postoperatively up to the time of discharge.
  • Incidence of re-operation due to bleeding.

 

Secondary outcomes

1. Efficacy as sealant:

  • Incidence of biliary leakage/fistula formation: defined according to the International Study Group of Liver Surgery as bilirubin concentration in the drain fluid at least three times the serum bilirubin concentration on or after the third postoperative day or as the need for radiological or operative intervention resulting from biliary collections or bile peritonitis (Koch 2011).
  • Incidence of intra-abdominal collections: identified radiologically or intraoperatively.
  • Abdominal drain output: measurement of daily drain volume.
  • Time to removal of abdominal drains.

2. Quality of life (as measured in the individual trial).
3. Operating time.
4. Length of hospital stay.

 

Search methods for identification of studies

 

Electronic searches

The review authors will conduct electronic searches within The Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2013), The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, PubMed, MEDLINE, EMBASE, and Science Citation Index Expanded (Royle 2003). Preliminary search strategies with the expected time spans of the searches are outlined in Appendix 1.

 

Searching other resources

The review authors will search reference lists of relevant studies in order to identify further relevant trials. In addition, the review authors will contact pharmaceutical companies and examine product inserts of fibrin-based haemostatic agents for any reference to unpublished trials. We will apply no language or date restrictions.

 

Data collection and analysis

 

Study selection and data extraction

Two review authors (AOA and CHW) will independently identify the trials suitable for inclusion and extract relevant data from trials included in the review using a standardised form. We will resolve differences in trial assessment between the review authors by discussion in order to reach a consensus. Further referral to a third review author (SAW or DMM) may be required in order to reach an agreed decision.

 

Assessment of risk of bias in included studies

Two review authors (AOA and CHW) will assess the risk of bias in the included studies independently. We will follow the recommended instructions outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and the Cochrane Hepato-Biliary Group Module (Gluud 2013). We will assess the following domains of bias risk in each included trial (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savović 2012; Savović 2012a).

 

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 (eg, 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 were 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, were 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. These include mortality, adverse events, and haemostatic efficacy related to the use of fibrin-based haemostatic agents.
  • 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 (eg, published in a paper journal). In the case when the trial was run and published in the years when trial registration was not required, we will carefully scrutinize 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 publications results section, then the trial can be considered low risk of bias trial in the 'Selective outcome reporting' domain.

 

For-profit bias

  • Low risk of bias: the trial appears to be free of industry sponsorship or other type of for-profit support that may manipulate the trial design, conductance, 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 was provided.
  • High risk of bias: the trial was sponsored by industry or received other type of for-profit support.

 

Other bias

  • Low risk of bias: the trial appears to be free of other components that could put it at risk of bias.
  • Uncertain risk of bias: the trial may or may not be free of other components that could put it at risk of bias.
  • High risk of bias: there are other factors in the trial that could put it at risk of bias.

We will summarise the risk of bias for each included trial. We will classify a trial as trial with high risk of bias if judged with unclear or high risk of bias in any of the above domains. In the remaining cases, that is, if the trial is judged with low risk of bias, we will classify the trial as a trial with low risk of bias. Then, we will group the trials following their risk of bias. If we find very few or no trials with low risk of bias, we plan to identify a group of trials with lower risk of bias according to the bias risk domains described above. This group of trials with lower risk of bias should at least include about 6% of the trial population in order to give the comparison of trials with lower risk of bias adequate power.

 

Measures of treatment effect

If appropriate, the review authors will perform a meta-analysis of the included trials according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2013). We will use the Cochrane Review Manager 5 software package (RevMan 2012).

 

Dichotomous data

Treatment effect will be calculated using the risk ratio (RR) with 95% confidence interval (CI) if more than one trial has reported the outcome. If the outcome of interest is only reported in one trial, we will calculate the Fisher's exact test P value in order to identify any significant differences between the treatment groups.

 

Continuous data

We will calculate the treatment effect using the mean difference (MD) or standardised mean difference (SMD) with 95% CI.

 

Time-to-event (survival) data

We will calculate the treatment effect using log hazard ratio [log(HR)] and standard error (SE) using individual participant data obtained from the original investigators if possible. If unavailable, we will estimate the log(HR) using Parmar’s methods (Parmar 1998).

 

Dealing with missing data

We will perform analyses on an intention-to-treat (ITT) basis whenever possible. Otherwise, we will adopt 'available case' analysis.

We will not exclude trials if summary data are missing. In the first instance, we will contact trial investigators in order to obtain any missing data. If this approach fails, we will impute missing data depending on the type of data.

In the case of missing dichotomous outcomes, we will include participants with incomplete or missing data in the sensitivity analyses by imputing them according to the following scenarios:

  • Extreme-case analysis favouring the experimental intervention ('best-worse' case scenario): none of the drop-outs/participants lost from the experimental arm, but all of the drop-outs/participants lost from the control arm experienced the outcome, including all randomised participants in the denominator.
  • Extreme-case analysis favouring the control ('worst-best' case scenario): all drop-outs/participants lost from the experimental arm, but none from the control arm experienced the outcome, including all randomised participants in the denominator.

For continuous outcomes, we will calculate missing standard deviations using reported P values or CIs (Higgins 2011). If calculation is not possible, we will impute a standard deviation as the highest standard deviation reported in the other trials for the corresponding treatment group and outcome.

We will address the potential effect of missing data on the results in the 'Discussion' section, and dropout rates will be collected and reported in the 'Risk of bias' table.

 

Assessment of heterogeneity

We will assess heterogeneity using the Chi2 test with significance set at P value 0.10. We will quantify the degree of heterogeneity observed using the I2 statistic which will be considered significant at values above 30% (Higgins 2011). Where necessary, we will not pool the effect of the interventions but will present it in a narrative format.

 

Assessment of reporting biases

We will use funnel plots of primary outcomes to provide a visual assessment of whether treatment estimates are associated with study size. We will use two tests to assess funnel plot asymmetry: adjusted rank correlation test (Begg 1994) and regression asymmetry test (Egger 1997).

 

Data synthesis

 

Meta-analysis

If the studies are clinically and methodologically comparable, we will attempt to combine the outcomes from the individual trials in a meta-analysis to provide a pooled effect estimate for each outcome. We will use both random-effects and fixed-effect models for meta-analyses of outcomes reported by more than one trial. In case of discrepancy between the two models for any outcome, we will report the results from both models. Otherwise, we will report only the results of the fixed-effect model meta-analysis.

 

Trial sequential analysis

We will also apply trial sequential analysis (CTU 2011; Thorlund 2011) as cumulative meta-analyses are at risk of producing random errors due to sparse data and repetitive testing of the accumulating data (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010).

To minimise random errors, we will calculate the required information size (the number of participants needed in a meta-analysis to detect or reject a certain intervention effect), which will take into account the diversity present in the meta-analysis (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010). In our meta-analysis, we will base the required information size on the proportion of participants with the event in the control group; assumption of an RR reduction of 20% on the RR reduction observed in the included trials with low risk of bias; an alpha (risk of type I error) of 5%; a beta (risk of type II error) of 20%; and the assumed diversity of the meta-analysis (Wetterslev 2009). The underlying assumption of trial sequential analysis is that testing for significance may be performed each time a new trial is added to the meta-analysis. We will add the trials according to the year of publication, and, if more than one trial has been published in a year, we will add trials alphabetically according to the last name of the first author.

 

Subgroup analysis and investigation of heterogeneity

We will perform the following subgroup analyses:

  • Trials with low or lower risk of bias compared to trials with high risk of bias.
  • Resection of cirrhotic livers compared to non-cirrhotic livers.
  • Major (three or more segments) compared to minor liver resections.
  • Commercial compared to non-commercial fibrin-based haemostatic agents.
  • Commercial fibrin-based haemostatic agents manufactured with antifibrinolytic agents compared to commercial fibrin-based haemostatic agents manufactured without antifibrinolytic agents.
  • Commercial fibrin-based haemostatic agents manufactured with factor VIII compared to commercial fibrin-based haemostatic agents manufactured without factor XIII.

 

Sensitivity analysis

We will perform sensitivity analyses in order to assess the robustness of the results to arbitrary decisions and assumptions made regarding the eligibility of trials and analysis. These will include:

  • The exclusion of non-commercial fibrin-based haemostatic agents.
  • Alternative imputation strategies (extreme case analysis as described in the section 'Dealing with missing data').
  • Fixed-effect meta-analysis model compared with random-effects meta-analysis model.
  • Exclusion of any 'outlier' study.

'Summary of findings' tables
We will assess the quality of evidence at the outcome level across trials using GRADEpro. If possible, we will prepare 'Summary of findings' tables presenting all the outcomes of our review (GRADE table) (GRADEpro 2008).

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Peer reviewers: Sebastian Hinz, Germany; Janus C Jakobsen, Denmark.
Contact editor: Ronald L Koretz, USA.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. Search strategies


DatabaseTime spanSearch strategy

The Cochrane Hepato-Biliary Group Controlled Trials RegisterDate will be given at review stage((topical AND (hemostatic OR haemostatic)) OR (fibrin AND seal*) OR TachoSil OR TachoComb OR Tisseel OR Beriplast OR Biocol OR EviCel OR Crosseal OR Hemaseel OR Quixil OR Bolheal OR ViGuard) AND (((liver OR hepatic) AND (surgery OR surgical OR resect* OR segmentectomy OR sectionectomy OR trisectionectomy OR lobectomy)) OR (hepatectomy OR hepatectomies OR hemihepatectomy OR hemi-hepatectomy))

The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane LibraryLatest issue((topical AND (hemostatic OR haemostatic)) OR (fibrin AND seal*) OR TachoSil OR TachoComb OR Tisseel OR Beriplast OR Biocol OR EviCel OR Crosseal OR Hemaseel OR Quixil OR Bolheal OR ViGuard) AND (((liver OR hepatic) AND (surgery OR surgical OR resect* OR segmentectomy OR sectionectomy OR trisectionectomy OR lobectomy)) OR (hepatectomy OR hepatectomies OR hemihepatectomy OR hemi-hepatectomy))

PubMed1950 to the date of search((topical AND (hemostatic OR haemostatic)) OR (fibrin AND seal*) OR TachoSil OR TachoComb OR Tisseel OR Beriplast OR Biocol OR EviCel OR Crosseal OR Hemaseel OR Quixil OR Bolheal OR ViGuard) AND (((liver OR hepatic) AND (surgery OR surgical OR resect* OR segmentectomy OR sectionectomy OR trisectionectomy OR lobectomy)) OR (hepatectomy OR hepatectomies OR hemihepatectomy OR hemi-hepatectomy))

MEDLINE (Ovid SP)1948 to the date of search(((topical and (hemostatic or haemostatic)) or (fibrin and seal*) or TachoSil or TachoComb or Tisseel or Beriplast or Biocol or EviCel or Crosseal or Hemaseel or Quixil or Bolheal or ViGuard) and (((liver or hepatic) and (surgery or surgical or resect* or segmentectomy or sectionectomy or trisectionectomy or lobectomy)) or (hepatectomy or hepatectomies or hemihepatectomy or hemi-hepatectomy))).mp. [mp=ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, ps, rs, nm, an, ui]

EMBASE (via Ovid SP)1980 to the date of search(((topical and (hemostatic or haemostatic)) or (fibrin and seal*) or TachoSil or TachoComb or Tisseel or Beriplast or Biocol or EviCel or Crosseal or Hemaseel or Quixil or Bolheal or ViGuard) and (((liver or hepatic) and (surgery or surgical or resect* or segmentectomy or sectionectomy or trisectionectomy or lobectomy)) or (hepatectomy or hepatectomies or hemihepatectomy or hemi-hepatectomy))).mp. [mp=ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, ps, rs, nm, an, ui]

Science Citation Index Expanded (apps.isiknowledge.com)1900 to the date of searchTS=(((topical AND (hemostatic OR haemostatic)) OR (fibrin AND seal*) OR TachoSil OR TachoComb OR Tisseel OR Beriplast OR Biocol OR EviCel OR Crosseal OR Hemaseel OR Quixil OR Bolheal OR ViGuard) AND (((liver OR hepatic) AND (surgery OR surgical OR resect* OR segmentectomy OR sectionectomy OR trisectionectomy OR lobectomy)) OR (hepatectomy OR hepatectomies OR hemihepatectomy OR hemi-hepatectomy)))



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

AO Amer conceived and designed the review protocol. CH Wilson is the co-author of this review protocol. Both authors have made equal contributions to designing and writing the protocol, and the pro-formas for trial selection and data extraction. SA White and DM Manas have both provided advise on the design and writing of the protocol. All authors approved of the final protocol version.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

None declared.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • Institute of Transplantation, The Freeman Hospital, Newcastle upon Tyne, UK.

 

External sources

  • The Editorial Team Office, The Cochrane Hepato-Biliary Group, Copenhagen, Denmark.

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
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