Use of Floseal Hemostatic Matrix for Control of Hemostasis During Laparoscopic Cholecystectomy for Acute Cholecystitis: A Multicenter Historical Control Group Comparison (The GLA Study Gelatin Matrix for Acute Cholecystitis)

Abstract

Background:

In patients with acute cholecystitis undergoing laparoscopic cholecystectomy, bleeding is a common complication that can reduce procedural visibility and worsen outcome. Insufficient hemostasis can also lead to postoperative bleeding that can, in rare cases, be fatal. Topical hemostatic agents are used to ensure adequate hemostasis during laparoscopic cholecystectomy.

Subjects and Methods:

This prospective, open-label, nonrandomized, historical control group study investigated the use of Floseal^® (Baxter International, Inc., Deerfield, IL) hemostatic matrix as an adjunct to surgical techniques to achieve hemostasis of the resected areas in patients undergoing laparoscopic cholecystectomy for acute cholecystitis. The primary end point was the rate of complete hemostasis 10 minutes after laparoscopic application of Floseal to the gallbladder bed. Secondary end points included complete hemostasis rates at 2, 4, and 6 minutes, surgery time, laparoscopic procedure to open laparotomy conversion rate, postoperative bleeding rate, and mortality and safety outcomes over the entire follow-up period.

Results:

From April to November 2011, 101 consecutive patients were enrolled (51 men; mean age, 61.5±6.2 years). The historical control group of 100 age- and gender-matched patients with acute cholecystitis had undergone laparoscopic cholecystectomy without hemostatic agent. In the Floseal group, bleeding ceased within 10 minutes after laparoscopic application of the hemostatic agent to the gallbladder bed in all patients. The conversion rate was significantly lower in the Floseal group than in the control group (4 versus 12 patients, P<.05).

Conclusions:

Floseal in acute cholecystitis is safe, is effective in controlling bleeding, and results in a lower conversion rate compared with cholecystectomy without hemostatic agents.

Introduction

The benefits of laparoscopic cholecystectomy over conventional open cholecystectomy have been established over the last two decades,^1,2 and, although the optimal surgical approach for acute cholecystitis has been debated over recent years, early laparoscopic cholecystectomy is today considered the standard surgical approach for the treatment of acute cholecystitis.^3–6 The advantages of laparoscopic cholecystectomy include better cosmesis, less postoperative pain, smaller surgical wounds, faster recovery time, improved patient satisfaction, and excellent visibility of fine detail.^1,7,8 In addition, meta-analyses have established that there are no significant differences between early and delayed-interval laparoscopic cholecystectomy in terms of operation time, conversion rate (proportion of patients requiring conversion from laparoscopic procedure to open laparotomy), overall complication rate, incidence of bile leakage, and intraabdominal collection.^3–5 Early laparoscopic cholecystectomy reduces the length of total hospital stay^3–5,9 and reduces the risk of hospital readmissions as a consequence of recurrent acute cholecystitis,⁴ providing a more cost-effective approach for the management of acute cholecystitis.⁴

Acute cholecystitis does, however, pose certain challenges to the surgeon that can lead to complications for patients. One of the difficulties may be increased risk of intraoperative bleeding greater than 500 mL, which has been reported in up to 8% of all procedures during laparoscopic cholecystectomy.¹⁰ There may also be an increased risk of postoperative bleeding after laparoscopic cholecystectomy, which has been reported to be around 0.7%–3% in patients with acute cholecystitis.^11–15 Although very rare, fatal outcome from postoperative bleeding after laparoscopic cholecystectomy has been reported.¹⁶

The sources of bleeding are typically side branches of arteries and, in nearly all cases, oozing from the gallbladder bed where the gallbladder wall is resected into the liver parenchyma.^16,17 As the gallbladder bed is a relatively large uneven surface, oozing bleeding may at times be troublesome and difficult to stop using surgical techniques for hemostasis, such as the use of ligatures, clips, staples, electrocoagulation, and argon beam coagulation.¹⁸ These mechanical or thermal approaches carry a risk, albeit small, of damaging surrounding structures such as vascular structures and, especially, bile duct injuries, which is a significant complication for the patient.⁸

An ideal hemostatic approach would be to minimize the use of mechanical and thermal surgical hemostasis by using a laparoscopically applied topical hemostatic agent. Such a product should be easy to apply, be able to adhere to an oozing surface, be moldable to an uneven surface, be fast acting, and have a good safety profile. Floseal^® hemostatic matrix (Baxter International, Inc., Deerfield, IL) is one of the most interesting hemostatic sealants marketed in recent years. It has been designed for use in actively bleeding fields and is indicated for use in surgical procedures as an adjunct to hemostasis when control of bleeding by ligature or conventional procedures is ineffective or impractical.

Floseal is a gelatin-thrombin topical hemostatic matrix that works on wet, actively bleeding tissue and conforms to irregular wound surfaces. It has been proven to control bleeding from oozing to pulsatile flow.¹⁹ Floseal has been shown to provide more rapid and effective hemostasis than another commonly used gelatin-based hemostatic agent, Gelfoam^® (Pfizer, New York, NY), especially at sites of heavy bleeding.^20,21 Following its first clinical use over a decade ago, the spectrum of applications for which Floseal has been utilized has expanded across different surgical disciplines. Unlike other commonly available hemostatic agents that are presented as solids, powders, or liquid formulations, Floseal is a highly viscous topical gel, delivered using a tipped syringe applicator or gun.²² Floseal is composed of human-derived thrombin and a proprietary gelatin matrix manufactured by extracting collagen from bovine corneal tissue.²² Both components work independently and synergistically to promote clot formation at the bleeding site. While the thrombin converts fibrinogen into fibrin monomers that polymerize to form a fibrin clot, the gelatin matrix seals the wound,²³ resulting in a hemostatic plug that conforms to the shape of the lesion.

Although a broad indication exists for the use of Floseal in multiple surgical settings, including hepatic resection,²⁴ no previous clinical trials have described its specific use in laparoscopic cholecystectomy. This trial was designed to evaluate the effect and safety of Floseal hemostatic matrix in patients undergoing laparoscopic cholecystectomy for acute cholecystitis.

Subjects and Methods

Study design

The Gelatin matrix in Laparoscopic cholecystectomy for Acute cholecystitis (GLA) Study was a multicenter, prospective, open-label, nonrandomized, historical control-group comparison study of the use of Floseal hemostatic matrix as an adjunct to surgical techniques to achieve hemostasis of the resected areas when electrocoagulation was ineffective in patients undergoing laparoscopic cholecystectomy for acute cholecystitis. As with other approved hemostatic agents, Floseal was available in the operating theaters of all hospitals in the study. The historical-control group (control group) consisted of 100 age- and gender-matched patients enrolled in our study of laparoscopic cholecystectomy for acute cholecystitis, in which a hemostatic agent was not used, and followed up for 6 months.²⁵ The research was carried out in accordance with the ethical principles of the Declaration of Helsinki.

Criteria for inclusion

Inclusion criteria were the following:

• Patients 18–65 years of age

• Evidence of cholecystitis according to clinical (pain, temperature of >37.5°C, white blood cell count of >10,000/μL) and ultrasound criteria

• Surgical indication for laparoscopic cholecystectomy

• American Society of Anesthesiologists class I–III

• Informed consent

• Onset of symptoms within 72 hours

Criteria for exclusion

Exclusion criteria were the following:

• Refusal of informed consent

• Choledocholithiasis

• Presurgical generalized peritonitis on clinical evaluation

• American Society of Anesthesiologists class >III

• Active or past history of malignant systemic disease

• Pregnant or lactating females

• Known allergy to components of Floseal

• Known drug or alcohol abuse

• Patients with known diabetes, chronic renal disease, or other metabolic disease

• Patients receiving chronic steroid treatment

• Patients receiving chronic platelet inhibitors such as aspirin, clopidogrel, nonsteroidal anti-inflammatory drugs, etc.

Study end points

Before surgical treatment, subjects were evaluated using a detailed history, physical examination, standard blood chemical analyses, and abdominal ultrasound.

The primary end point was the proportion of patients with complete hemostasis 10 minutes after laparoscopic application of the hemostatic agent (Floseal) to the gallbladder bed. Secondary end points were the proportion of patients with complete hemostasis evaluated at 2, 4, and 6 minutes, time from onset of symptoms to surgery, surgery time, the proportion of patients requiring conversion from laparoscopic procedure to open laparotomy (conversion rate), the proportion of patients developing postoperative bleeding leading to re-operation or blood transfusion, time to drain removal, mortality, length of stay in hospital, and safety evaluated as the number of patients with adverse events and serious adverse events from surgery to the end of the study. Mortality and safety were assessed over the entire follow-up period in the Floseal group and compared with historical 6-month control group data. Patient morbidity was assessed at 30 days.

Statistical methods

Data are expressed as absolute numbers, percentages (%), and mean (standard deviation) values. The results of the two groups in comparison were analyzed using the Pearson's chi-squared test and Fisher's exact test, as appropriate, for proportions in the case of discrete data. Fisher's exact test was used when the data were very unequally distributed among the cells of the table or the expected frequency of any cell was less than 5 or the total N was less than 50.

For means, in case of continuous numerical data, the independent-samples t test and the Mann–Whitney U test were used, respectively, for data that were normally and non-normally distributed. The data were previously tested for normality by the Kolmogorov–Smirnov test. A P value of<.05 was considered to be statistically significant.

Procedures

Floseal was used as an adjunct to surgical hemostasis to obtain hemostasis of the resected areas in the gallbladder bed when electrocoagulation dissection was ineffective to secure hemostasis. When the gallbladder was dissected away from the gallbladder bed, Floseal gelatin matrix was prepared and applied guided by vision following the manufacturer's instructions for use.²²

When the source of bleeding at the tissue surface was identified, Floseal matrix was applied using the laparoscopic applicator, and immediately a gauze sponge was positioned against the bleeding surface, conforming Floseal to the lesion. After approximately 2 minutes, the gauze sponge was removed, and the wound site was inspected. If bleeding had ceased, excess Floseal (not incorporated in the hemostatic clot) was removed by gentle irrigation. In cases of persistent bleeding, indicated by saturation and bleeding through the granules, Floseal was re-applied. The surgeon was able to repeat re-application if necessary and evaluated the effect at 2, 4, 6, and 10 minutes. Once bleeding had ceased, excess Floseal material not incorporated in the hemostatic clot was removed by gentle irrigation.

During the surgical procedure, the standard four-trocar operative technique for laparoscopic cholecystectomy for acute cholecystitis was used. When the gallbladder was distended, its fluid content was initially aspirated. To allow a good grip on the gallbladder, larger graspers were inserted through a 5-mm right lower port. The cystic artery and duct were clip-ligated. The gallbladder and intraperitoneally “dropped” stones were collected in an endoscopic retrieval bag and extracted through the umbilical port site, which could be extended if necessary. A closed system suction drain was left intraabdominally. Fascial closure was attempted only at the umbilical port site. The skin at all the port sites was closed with staples. Conversion to laparotomy, if necessary, was decided by the operating surgeon, and each conversion was recorded and justified.

Results

From April 2011 to November 2011, 101 patients undergoing laparoscopic cholecystectomy for acute cholecystitis were enrolled. In total, 50 women and 51 men were included in the study. The mean patient age was 61.5±6.2 years. The 100 patients in the control group had a similar age and gender ratio (52 men; mean age, 64.3±7.1 years). Patient characteristics and demographic data are shown in Table 1.

Table 1.

Patient Characteristics and Demographic Data

Parameter	Floseal group (n=101)	Controls (n=100)
Age (years)	61.5±6.2	64.3±7.1
Male/female (n)	51/50	52/48
ASA physical status class	2.9±1.1	25±1.2
Mean follow-up period (months)	16.4	6.1

Data are absolute number (n) or mean±standard deviation values. There were no significant differences between groups.

ASA, American Society of Anesthesiologists.

The mean time from the onset of symptoms to surgery was 61.2±8.1 hours in the Floseal group and 67.3±9.8 hours in the control group. The operating time was lower in the Floseal group than in the control group, although the difference did not reach significance (71.9±11.5 versus 87.4±10.8 minutes) (Table 1). In all patients (100%) of the Floseal group, bleeding ceased within 10 minutes after laparoscopic application of the hemostatic agent to the gallbladder bed.

Other results are presented in Tables 2 and 3. Intraoperative complications were lower in the Floseal group than in the control group (4 versus 7 patients, difference not significant). However, the conversion rate was significantly lower in the Floseal group than in the control group: only 4 patients in the Floseal group required conversion from the laparoscopic procedure to open laparotomy, compared with 12 in the control group (P<.05).

Table 2.

Results

Parameter	Floseal group (n=101)	Controls (n=100)
Intraoperative complications (n)	4	7
Conversion rate (%)	4	12^a
Time (hours) from onset of symptoms to surgery	61.2±8.1	67.3±9.8
Operating time (minutes)	71.9±11.5	87.4±10.8
LMWH required (n)	88	91
30-day morbidity (n)	7	9
Mortality (n)	0	1
Drain removal (days)	2.9±0.8	3.1±0.6
Hospital stay (days)	3.9±0.9	4.1±1.1

Data are absolute number (n), percentage (%), or mean±standard deviation values as indicated.

P<.05 versus the corresponding Floseal group.

Conversion, conversion from laparoscopic procedure to open laparotomy; LMWH, low-molecular-weight heparin.

Table 3.

Reasons for Conversion from Laparoscopic Procedure to Open Laparotomy

Parameter	Floseal group (n=101)	Controls (n=100)
Overall conversion rate (%)	4	12^a
Anatomy (n)	1	6
Bleeding (n)	2	4
Operative time >2 hours (n)	1	2

P<.05 versus Floseal group.

There were nonsignificant differences in the time of drain removal (Floseal group, 2.9±0.8 days; control group, 3.1±0.6 days) and length of hospital stay (Floseal group, 3.9±0.9 days; control group, 4.1±1.1 days). One patient in the control group died during the 6-month observation. There were no deaths in the Floseal group during the entire 16.4-month prospective follow-up period.

In the 30 days after laparoscopic cholecystectomy, there were seven cases of morbidity in the Floseal group and nine cases of morbidity in the control group (Table 4).

Table 4.

Morbidity in the 30 Days After Laparoscopic Cholecystectomy

Parameter (n)	Floseal group (n=101)	Controls (n=100)
Bile leaks	1	2
Adverse events	0	NA
Others (medical)	6	7

Data are absolute numbers.

NA, not applicable.

Discussion

The early laparoscopic approach to remove the gallbladder in patients with acute cholecystitis is today accepted as the gold standard.^3–6 In some cases, the laparoscopic procedure needs to be converted to an open procedure in order to secure the safe completion of the surgical intervention for the patient. In the presence of acute inflammation of the gallbladder, the surrounding tissue may become edematous and fragile, leading to a potentially higher risk of hemorrhage during the dissection and increasing the likelihood of conversion becoming necessary.¹⁵ When the gallbladder has been resected, there is a risk of oozing bleeding from the gallbladder bed.¹⁷ It is a goal of laparoscopic cholecystectomy of acute cholecystitis to minimize bleeding at all times during surgery and to secure a dry surgical field upon closure to reduce the risk of adverse outcomes for the patient and to maintain adequate visibility during the surgical procedure.¹⁷ To reduce the potentially fatal complications of postoperative bleeding related to insufficient hemostasis, it therefore makes sound sense to include the use of topical hemostatic agents in association with surgical techniques to secure hemostasis during laparoscopic cholecystectomy in patients with acute cholecystitis.

To our knowledge, this is the first study to have specifically investigated the use of Floseal hemostatic matrix in patients undergoing laparoscopic cholecystectomy for acute cholecystitis. We found that the Floseal hemostatic matrix could be applied laparoscopically and under vision directly to the area of bleeding to stop the bleeding quickly and without injuring anatomical structures in the vicinity, with an overall excellent safety profile for the patient. Bleeding ceased in all patients within 10 minutes of laparoscopic application of Floseal, and there was a trend toward lower operating time and lower intraoperative complications compared with a historical control group undergoing laparoscopic cholecystectomy without the use of Floseal. It is important that the conversion rate was significantly lower in the Floseal group, with a two-thirds reduction in the proportion of patients requiring conversion from the laparoscopic procedure to open laparotomy, compared with the historical controls. In addition, the hemostatic matrix was conformable to the uneven and wet liver surface of the gallbladder bed presented after resection.

The main limitation of this study is that it was not a randomized controlled trial. However, we used an appropriate historical control group for comparison, and the primary study end point—complete hemostasis within 10 minutes—is an accepted and unambiguous clinical end point. The difference in the duration of follow-up between the control group and the Floseal group is due to the fact that the control group was a “historical control group” that was followed up for 6 months only. The Floseal group was prospectively followed up, and doctors had the chance to follow up patients for more than 6 months. Despite this difference in follow-up duration, drug effects and/or adverse reactions associated with Floseal are expected to be seen over a short period; therefore, the differences in follow-up between the two groups should not affect our data.

Conclusions

Floseal gelatin matrix is composed of a self-expandable gelatin-based matrix and purified human thrombin solution that is biodegradable, attachable to wet surfaces, and capable of hemostatic action on oozing as well as more active bleeding. As Floseal gelatin matrix is moldable and fast acting and can be applied laparoscopically, it appears to be a relevant hemostatic agent to be used in the context of laparoscopic cholecystectomy. The GLA Study data showed that the use of Floseal in acute cholecystitis is safe, is effective in controlling bleeding, and reduces the conversion rate from a laparoscopic procedure to open laparotomy.

Our findings suggest that Floseal may be a useful tool to secure hemostasis when electrocoagulation dissection is ineffective and may reduce hemostasis-related complications. However, before Floseal can be recommended for routine use in this setting, further studies are required to compare the additional cost of this treatment with the total cost of possible complications with standard thermal and surgical hemostatic procedures.

Footnotes

Acknowledgments

The authors thank Ray Hill, an independent medical writer, for English language editing assistance and journal styling prior to submission on behalf of inScience Communications, Springer Healthcare. This assistance was funded by Baxter, Italy.

Disclosure Statement

No competing financial interests exist.

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