The role of sealants for achieving anastomotic hemostasis in vascular surgery
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy of sealants as adjuncts for achieving anastomotic site hemostasis in patients undergoing vascular surgery.
Background
Description of the condition
Vascular surgeons operate on arteries and veins throughout the body to remove or bypass blockages, stop traumatic bleeding, or resect cancerous growths that involve major blood vessels. Such interventions invariably require repair of the affected vessels in order to contain the pressurized blood within the vessel walls and prevent bleeding. During vascular techniques, it may be necessary to create connections to link arteries, veins, or synthetic grafts; and these are known as an ‘anastomosis' (Barnes 1989). Vascular anastomoses can bleed from the needle‐holes that result from the creation of the anastomoses.
The process by which surgeons employ different strategies to stop bleeding is known as ‘achieving hemostasis'. Various surgical options are available for achieving hemostasis, including reversal of anticoagulation, placing sutures to close or reinforce a vessel wall defect, applying manual pressure while awaiting the body's natural hemostatic processes to control the bleeding, and cauterizing or ligating the bleeding vessels to stop bloodflow to the area of bleeding (Levy 2010; Untch 2007). Additionally, several commercially‐available hemostatic agents, adhesives, and sealants can be applied directly onto the bleeding vessels or tissues to help achieve hemostasis (Spotnitz 2008; Vyas 2013). The focus of this Cochrane Review will be to evaluate the effectiveness of sealants in achieving hemostasis from bleeding anastomoses during vascular surgical procedures.
Description of the intervention
The two categories of sealants are fibrin and synthetic sealants, which include polyethylene glycol (PEG) polymers, albumin and glutaraldehyde, and cyanoacrylate (Spotnitz 2012). Sealants are available for use in vascular surgery as adjuncts when conventional interventions are ineffective and are applied directly by the surgeon to seal bleeding anastomoses.
Fibrin sealants are derived from animal or human blood products and are prepared by combining a freeze‐dried clotting protein and thrombin, which are delivered in separate vials that are mixed shortly before their application (Vyas 2013). Conversely, synthetic sealants are packaged either as a dry powder that requires mixing with a separately supplied fluid, or in sterile syringes that do not require any further preparation (Achneck 2010). Bleeding from the target anastomosis is temporarily controlled by clamping the blood flow proximally and distally to the anastomosis, followed by careful application of the prepared sealant onto the anastomosis without contaminating neighboring tissues. The sealant is given enough time to polymerize before the vessels are unclamped and flow is restored within the sealed anastomosis.
How the intervention might work
Fibrin sealants contain human‐ or animal‐derived blood products that allow for the formation of a fibrin clot when they are mixed together. Fibrin sealants comprise of a separately packaged clotting protein, such as fibrinogen, and thrombin. The two are mixed in a liquid solution and applied onto the vascular anastomosis to recreate the final stages of the coagulation cascade and form a fibrin clot (Vyas 2013). Conversely, synthetic sealants are composed of PEG polymers and one or more additional chemicals that are mixed to form strong adhesive bonds. When applied to the vascular anastomosis, those chemicals form a hydrogel that initiates spontaneous bonding with tissues (Vyas 2013). It is thought that sealants reinforce vascular anastomoses by plugging bleeding needle‐holes and by providing greater biomechanical support to the anastomotic suture line (Spotnitz 2012; Vyas 2013).
Why it is important to do this review
There are no publicly‐available reports on the use of fibrin sealants to achieve hemostasis by vascular surgeons. In England, for example, the National Health Service (NHS) does not collect data on the use or cost of fibrin sealants (Edwards 2016). Nonetheless, the use of sealants to control bleeding and attain hemostasis has become a common practice in vascular surgery, as evidenced by the proliferation of different sealant technologies. Despite the commercial availability of several different types of sealants, the evidence for the clinical efficacy of these hemostatic adjuncts has not been definitively established in vascular surgery patients. The aim of this Cochrane Review will be to examine the evidence for using sealants in achieving hemostasis after the creation of vascular anastomoses, and to determine whether their use is associated with improved outcomes that justify their costs to the healthcare system.
Objectives
To assess the efficacy of sealants as adjuncts for achieving anastomotic site hemostasis in patients undergoing vascular surgery.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomized controlled trials that compare the use of sealants with other interventions for achieving anastomotic‐site hemostasis in vascular surgery patients.
Types of participants
We will include participants who undergo creation of an anastomosis as part of a vascular surgery procedure. We will exclude non‐vascular surgery patients, (i.e. participants having intestinal, neurosurgical, or cardiothoracic procedures). We will include studies with a combination of participants undergoing vascular and other types of surgery for which data are not stratified by type of surgery. However, we will perform additional sensitivity analyses to assess the impact of such studies have on the overall effect estimate.
Types of interventions
We will compare the intraoperative application of fibrin or synthetic sealants with other interventions for achieving anastomotic hemostasis after vascular surgery (e.g. manual compression, reversal of anticoagulation). We intend to perform subgroup analysis by type of control intervention. We will also include studies that compare sealants with hemostatic agents and adhesives after vascular surgery. Studies that do not include the use of sealants but focus entirely on hemostatic agents or adhesives in vascular surgery patients will be excluded.
Types of outcome measures
Primary outcomes
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Time to hemostasis, defined as the time from applying an intervention to control anastomotic bleeding until bleeding from the anastomosis is controlled as judged by the operating surgeon
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Failure of hemostatic intervention, defined as a failure to control anastomotic bleeding using a sealant or other intervention after up to 30 minutes of applying the intervention
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Intraoperative blood loss
Secondary outcomes
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Operating time
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Death from bleeding complications, measured up to 30 days after the intervention
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Postoperative bleeding, measured up to 30 days after the intervention
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Unplanned return to the operating room for the management of bleeding complications, measured up to 30 days after the intervention
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Quality of life, measured by validated questionnaires
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Adverse events relating to sealants, such as hypersensitivity
Search methods for identification of studies
Electronic searches
The Cochrane Vascular Information Specialist aims to identify all relevant RCTs regardless of language or publication status (published, unpublished, in press, or in progress).
The Information Specialist will search the following databases for relevant studies:
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The Cochrane Vascular Specialised Register via the Cochrane Register of Studies (CRS‐Web)
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The Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO)
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MEDLINE (Ovid MEDLINE® Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE® Daily and Ovid MEDLINE®) (1946 onwards)
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Embase Ovid (from 1974 onwards)
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CINAHL Ebsco (from 1982 onwards)
The Information Specialist has devised a draft search strategy for RCTs for MEDLINE, which is displayed in Appendix 1. This will be used as the basis for search strategies for the other databases listed.
The Information Specialist will search the following trials registries:
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The World Health Organization International Clinical Trials Registry Platform (who.int/trialsearch)
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ClinicalTrials.gov (clinicaltrials.gov)
Searching other resources
We will search internal reports and conference proceedings and contact study authors to solicit additional information about completed or ongoing studies pertaining to the role of sealants in vascular surgery patients.
Data collection and analysis
Selection of studies
Two review authors (AK, AK) will independently select studies for inclusion in this review. A third review author (AD) will assess these studies and will determine their suitability and adjudicate any disagreements between the first two review authors. We have outlined the inclusion criteria that we will use to determine suitability in the ‘Criteria for considering studies for this review' section.
Data extraction and management
Two review authors (AK, AK) will extract relevant data from the included studies. We will collect data on patient demographics (age, gender), interventions (type of operation, type and location of anastomosis, type of sealant, control intervention), and outcomes (as specified in the ‘Criteria for considering studies for this review' section). The costs associated with the interventions, if available, will also be collected. A third review author (AD) will cross‐check data. Statistical analysis will comply with the standard methods of the Cochrane Vascular group. We will use the computer software package Review Manager 5 to perform all statistical analyses and to generate figures (Review Manager 2014).
Assessment of risk of bias in included studies
Two review authors (AK, AK) will independently carry out a thorough ‘Risk of bias' assessment of all included studies using Cochrane's ‘Risk of bias' tool (Higgins 2011). The tool assesses bias in seven different domains, with each domain receiving a score of high, low, or unclear depending on each review author’s judgement. A third review author (AD) will adjudicate disagreements. We will contact study authors if clarification is required to better assess a risk of bias.
Measures of treatment effect
We will calculate and report continuous outcome measures, such as change in time to achieve hemostasis, using the mean difference (MD). If the included studies use different scales, however, then we will calculate a standardized mean difference (SMD) instead. We will also calculate the associated 95% confidence interval (CI) between the two treatment groups. We will calculate and report dichotomous (binary) outcome measures, such as death, using the hazard ratio (HR) or risk ratio (RR) with the associated 95% CI, depending on the reported data. We will perform analyses at different time points, as reported by the studies, and will base our calculations on an intention‐to‐treat approach.
Unit of analysis issues
The unit of analysis will be the treated anastomosis for procedural outcomes such as time to hemostasis or intraoperative blood loss. The unit of analysis will be the patient for outcomes such as quality of life or death.
Dealing with missing data
We will contact study authors to inquire about any missing or incomplete data. In the event that an included study has missing characteristics or outcomes for more than 10% of study participants and attempts to contact the study investigators are unsuccessful, then we will only examine available data using an intention‐to‐treat analysis, and we will examine those studies in a sensitivity analysis to determine their effect on the meta‐analysis.
Assessment of heterogeneity
We will assess inter‐study heterogeneity by visually inspecting the forest plots (Schünemann 2011a). We will also calculate Chi2 and I2 tests to measure the amount of heterogeneity (Higgins 2003). I2 values of less than 50% indicate low heterogeneity, I2 values between 50 to 75% indicate moderate heterogeneity, and I2 values greater than 75% indicate significant heterogeneity (Deeks 2011).
Assessment of reporting biases
Where 10 or more studies are available for a particular outcome, we will construct a funnel plot to assess publication bias (Sterne 2011).
Data synthesis
We will use random‐effects or fixed‐effect models to calculate the pooled treatment effect data, depending on the degree of inter‐study heterogeneity. If the calculated degree of inter‐study heterogeneity is significant (defined as I2 statistic value of greater than 75%), then we will use the random‐effects model. Otherwise, we will use the fixed‐effect model. We will calculate 95% CIs for continuous and dichotomous outcome variables, as detailed above. We will create a forest plot for each treatment effect as per Cochrane Vascular guidelines.
Subgroup analysis and investigation of heterogeneity
Depending on available data, we plan to perform subgroup analyses by each of the following.
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Type of sealant
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Type of control intervention (e.g. manual pressure, reversal of anticoagulation)
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Type of procedure (e.g. lower extremity bypass, aortic surgery, dialysis access surgery)
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Type of vessels that are incorporated in the anastomosis (e.g. arterio‐venous, arterio‐graft, or graft‐graft anastomosis)
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Number of anastomoses
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Urgency of procedure (e.g. elective versus emergency surgery)
Furthermore, we will analyze studies of agents that have multiple applications as sealants, hemostatics, and adhesives independently.
Sensitivity analysis
We plan to check if the review conclusions are robust by excluding studies at a high risk for bias from the pooled analysis and we will perform the analysis again to assess their impact. We will consider studies at high risk of bias if we deem more than three of the seven domains in the Cochrane ‘Risk of bias' tool to be at high risk (Higgins 2011), or if they are at high risk of bias in their random sequence generation. A sensitivity analysis will then be performed by sequentially excluding studies at a high risk of bias. We will also carry out sensitivity analysis if we have concerns with missing data.
‘Summary of findings' table
We will prepare a ‘Summary of findings' table using the GRADEpro Guideline Development Tool (GRADEpro GDT), to present the main findings of the review for the time point at which the most relevant data are available from the included studies (Atkins 2004). The population will consist of patients who have undergone vascular surgery and we will compare intraoperative sealant application with an alternative treatment for the achievement of hemostasis. We will include the main outcomes listed in the ‘Types of outcome measures' section that are considered essential for decision‐making in our ‘Summary of findings' table. We will evaluate the certainty of the evidence using the GRADE approach (Schünemann 2011b). We will assign one of four levels of certainty: high, moderate, low, or very low, based on overall risk of bias, directness of the evidence, inconsistency of results, precision of the estimates, and risk of publication bias as previously described (Higgins 2011). We have included an example ‘Summary of findings' table (Table 1).
| Summary of findings: Sealants compared to standard care for achieving hemostasis in vascular surgery | ||||||
| Patient or population: vascular surgery patients who undergo creation of an anastomosis Setting: hospital Intervention: sealants Comparison: standard care | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with standard care | Risk with sealants | |||||
| Time to hemostasis (units) | The mean time to hemostasis was 0 | The mean time to hemostasis in the intervention group was 0 (0 to 0) | (RCTs) | |||
| Failure of hemostatic intervention (follow‐up) | 0 per 1000 | 0 per 1000 | (RCTs) | |||
| Intraoperative blood loss (units) | The mean intraoperative blood loss was 0 | The mean intraoperative blood loss in the intervention group was 0 (0 to 0) | (RCTs) | |||
| Operating time (units) | The mean operating time was 0 | The mean operating time in the intervention group was 0 (0 to 0) | (RCTs) | |||
| Death from bleeding complications (follow‐up) | 0 per 1000 | 0 per 1000 | (RCTs) | |||
| Postoperative bleeding (follow‐up) | 0 per 1000 | 0 per 1000 | (RCTs) | |||
| Unplanned return to the operating room (follow‐up) | 0 per 1000 | 0 per 1000 | (RCTs) | |||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Summary of findings: Sealants compared to standard care for achieving hemostasis in vascular surgery | ||||||
| Patient or population: vascular surgery patients who undergo creation of an anastomosis Setting: hospital Intervention: sealants Comparison: standard care | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with standard care | Risk with sealants | |||||
| Time to hemostasis (units) | The mean time to hemostasis was 0 | The mean time to hemostasis in the intervention group was 0 (0 to 0) | (RCTs) | |||
| Failure of hemostatic intervention (follow‐up) | 0 per 1000 | 0 per 1000 | (RCTs) | |||
| Intraoperative blood loss (units) | The mean intraoperative blood loss was 0 | The mean intraoperative blood loss in the intervention group was 0 (0 to 0) | (RCTs) | |||
| Operating time (units) | The mean operating time was 0 | The mean operating time in the intervention group was 0 (0 to 0) | (RCTs) | |||
| Death from bleeding complications (follow‐up) | 0 per 1000 | 0 per 1000 | (RCTs) | |||
| Postoperative bleeding (follow‐up) | 0 per 1000 | 0 per 1000 | (RCTs) | |||
| Unplanned return to the operating room (follow‐up) | 0 per 1000 | 0 per 1000 | (RCTs) | |||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
