Key messages
• The studies investigating fibrin-based agents for reducing blood loss in adult liver surgery have many design flaws, so their results are very uncertain.
• Based on the available evidence, we cannot recommend or advise against the routine use of fibrin-based agents.
What is topic of this review?
People who undergo liver surgery for tumours are at risk of significant blood loss, complications after surgery, and even death. Several techniques have been developed to reduce blood loss in liver surgery; one such method is the application of a fibrin-based agent (fibrin is the end 'scab' protein formed during blood clotting) to the cut liver surface. Non-fibrin-based agents are also available. It is unclear whether fibrin-based agents are effective for reducing blood loss and improving other outcomes compared with no treatment/placebo (dummy treatment) or non-fibrin-based agents/devices.
What did we want to find out?
We wanted to find out if fibrin-based agents are more effective than no treatment/placebo or non-fibrin base agents/devices for reducing:
• risk of death during and after surgery;
• risk of serious complications;
• time needed to stop bleeding;
• risk of needing a blood transfusion after surgery;
• risk of needing another surgery to stop the bleeding; and
• risk of the liver leaking bile after surgery.
What did we do?
We performed a rigorous search for randomised studies that compared fibrin-based agents with no intervention/placebo or non-fibrin-based agents/devices. Randomised studies normally provide the most robust evidence because they allocate participants to one or another treatment at random, so that the different treatment groups are comparable in terms of characteristics that could influence results. We compared and summarised the results of the studies and rated our confidence in the evidence based on factors such as study methods and sizes.
What did we find?
We found 22 randomised studies that included a total of 2945 adults undergoing liver surgery. Six studies in 1001 adults compared fibrin-based agents with no intervention, and 16 studies in 1944 adults compared fibrin-based agents with non-fibrin-based agents/devices.
It is unclear if fibrin-based agents compared with no treatment have an effect on risk of death within 30 days of surgery, risk of complications, blood transfusion, need for further surgery, or risk of bile leaking from the liver after surgery.
Similarly, it is unclear if fibrin-based agents compared with non-fibrin-based agents have an effect on risk of death within 30 days of surgery, risk of needing a blood transfusion after surgery, or risk of bile leaking after surgery. Fibrin-based agents may reduce the risk of needing another surgery, but we are very uncertain about the results. Fibrin-based agents may have little or no effect on the risk of serious complications compared to non-fibrin-based agents.
What are the limitations of the evidence?
We have very little confidence in the evidence because many studies had design flaws, many studies were small, and most results indicated that the treatment could benefit or harm the person receiving it, or have no effect. Based on current evidence, we cannot recommend or advise against routine use of fibrin-based agents to reduce blood loss in liver surgery. Future research should focus on use of fibrin-based agents in people who are at particularly high risk of bleeding.
Funding
Twelve trials reported commercial funding, one trial reported no financial support, and nine trials provided no information on funding.
How up to date is this evidence
The evidence is current to 20 January 2023.
The evidence for the outcomes in both comparisons (FBHAs versus no intervention and FBHAs versus non-FBHAs) was of very low certainty (or low certainty in one instance) and cannot justify the routine use of FBHAs to reduce blood loss in adult liver resection. While the meta-analysis showed a reduced risk of reoperation with FBHAs compared with non-FBHAs, the analysis was confounded by the small number of trials reporting the event and the risk of bias in all these trials.
Future trials should focus on the use of FBHAs in people undergoing liver resection who are at particularly high risk of bleeding. Investigators should evaluate clinically meaningful and patient-important outcomes and follow the SPIRIT and CONSORT statements.
Liver resection is the optimal treatment for selected benign and malignant liver tumours, but it can be associated with significant blood loss. Numerous anaesthetic and surgical techniques have been developed to reduce blood loss and improve perioperative outcomes. One such technique is the application of topical fibrin-based haemostatic agents (FBHAs) to the resection surface. There is no standard practice for FBHA use, and a variety of commercial agents and devices are available, as well as non-FBHAs (e.g. collagen-based agents). The literature is inconclusive on the effectiveness of these methods and on the clinical benefits of their routine use.
To evaluate the benefits and harms of fibrin-based haemostatic agents in reducing intraoperative blood loss in adults undergoing liver resection.
We searched the Cochrane Hepato-Biliary Group (CHBG) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science up to 20 January 2023. We also searched online trial registries, checked the reference lists of all primary studies, and contacted the authors of included trials for additional published or unpublished trials.
We considered for inclusion all randomised clinical trials evaluating FBHAs versus no topical intervention or non-FBHAs, irrespective of publication type, publication status, language of publication, and outcomes reported. Eligible participants could have any liver pathology and be undergoing major or minor liver resections through open or laparoscopic surgery.
Two review authors independently screened the results of the literature search and used data extraction forms to collate the results. We expressed dichotomous outcome results as risk ratios (RRs) and continuous outcome results as mean differences (MDs), each with their corresponding 95% confidence interval (CI). We used a random-effects model for the main analyses. Our primary outcomes were perioperative mortality, serious adverse events, haemostatic efficacy, and health-related quality of life. Our secondary outcomes were efficacy as sealant, adverse events considered non-serious, operating time, and length of hospital stay. We assessed the certainty of the evidence with GRADE and presented results in two summary of findings tables.
We included 22 trials (2945 participants) evaluating FBHAs versus no intervention or non-FBHAs; 19 trials with 2642 participants provided data for the meta-analyses. Twelve trials reported commercial funding, one trial reported no financial support, and nine trials provided no information on funding. Below we present the most clinically relevant outcome results, also displayed in our summary of findings table.
Fibrin-based haemostatic agents versus no intervention
Six trials (1001 participants) compared FBHAs with no intervention. One trial was at low risk of bias in all five domains, and all other trials were at high or unclear risk of bias in at least one domain. Two trials were at high risk of bias related to blinding. It is unclear if FBHAs compared with no intervention have an effect on perioperative mortality (RR 2.58, 95% CI 0.89 to 7.44; 4 trials, 782 participants), serious adverse events (RR 0.96, 95% CI 0.88 to 1.05; 4 trials, 782 participants), postoperative transfusion (RR 1.04, 95% CI 0.77 to 1.40; 5 trials, 864 participants), reoperation (RR 2.92, 95% CI 0.58 to 14.61; 2 trials, 612 participants), or postoperative bile leak (RR 1.00, 95% CI 0.67 to 1.48; 4 trials, 782 participants), as the certainty of evidence was very low for all these outcomes.
Fibrin-based haemostatic agents versus non-fibrin-based haemostatic agents
Sixteen trials (1944 participants) compared FBHAs with non-FBHAs. All trials had at least one domain at high or unclear risk of bias. Twelve trials were at high risk of bias related to blinding. It is unclear if FBHAs compared with non-FBHAs have an effect on perioperative mortality (RR 1.03, 95% CI 0.62 to 1.72; 11 trials, 1436 participants), postoperative transfusion (RR 0.92, 95% CI 0.68 to 1.25; 7 trials, 599 participants), reoperation (RR 0.48, 95% CI 0.25 to 0.90; 3 trials, 358 participants), or postoperative bile leak (RR 1.15, 95% CI 0.60 to 2.21; 9 trials, 1115 participants), as the certainty of evidence was very low for all these outcomes. FBHAs compared with non-FBHAs may have little or no effect on the risk of serious adverse events (RR 0.99, 95% CI 0.95 to 1.03; 9 trials, 1176 participants; low-certainty evidence).