The use of fibrin sealant during non-emergency surgery: a systematic review of evidence of benefits and harms

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Chapter 1 Background

Chapter 2 Definition of the decision problem

Chapter 3 Assessment of clinical effectiveness

Results

Quantity and quality of research available

Quantity of randomised controlled trials

A total of 2509 records were identified by searching MEDLINE, EMBASE and The Cochrane Library (Figure 1). After deduplication and screening records, 443 full-text papers were assessed for inclusion. After reviewing the full text, 257 studies were excluded for various reasons, as outlined in Figure 1 (for details of excluded studies see Appendix 3). We included 186 RCTs, which are summarised in Table 2. These RCTs were undertaken in 14 different surgical specialties (classification based on the Royal College of Surgeons of England58) or included a mix of different surgical specialties (four papers combined different surgical specialties), and are presented in Table 2.

FIGURE 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram for RCTs.

TABLE 2 - Overview of surgical specialties and number of RCTs

ENT, ear, nose and throat; GI, gastrointestinal.

Surgical area	Number of RCTs
Upper GI tract (digestive system)	33
Stomach	11
Liver	13
Gallbladder	3
Pancreas	6
Breast and lymph nodes	30
Breast and/or axillary lymph nodes	19
Inguinal and/or axillary lymph nodes	9
Pelvic and/or para-aortic lymph nodes	1
Thorax/oesophagus lymph nodes	1
Cardiothoracic	20
Lung	16
Heart	4
Orthopaedic (joints)	17
Shoulder	1
Hip	5
Knee	11
Eye	15
Hernia	14
Otolaryngology (ENT)	7
Nose	6
Tonsils	1
Vascular	13
Plastic or reconstructive	10
Skin (graft and ulcer)	5
Buttock (pilonidal disease)	2
Abdomen (lipoabdominoplasty)	2
Ischial region	1
Colorectal (anus)	5
Urology (urinary tract)	5
Kidney	3
Prostate	1
Urethra	1
Oral (mouth) and maxillofacial	7
Mixed	4
Gynaecological	4
Neurological	2
Total	186

Sample sizes ranged from seven participants in Nativ et al. 59 to 1436 participants in Tavilla et al. ,60 with a median sample size of 62 participants and most values at the lower end. RCTs were published over the past 30 years, since 1985. The main fibrin sealants used were Tisseel (n = 37)/Tissucol^® (ImmunoAG, Vienna, Austria) (n = 16), Quixil^® (Johnson & Johnson Wound Management, Somerville, NJ, USA) (n = 23), TachoSil^® (Takeda Austria GmbH, Linz, Austria) (n = 18), Beriplast^® (Behringwerke, Marburg, Germany; FSBP, Aventis Behring, Strasbourg, France) (n = 12), Vivostat^® (Vivolution A/S, Birkerød, Denmark) (n = 8) and EVICEL (n = 6).

In addition, 87 RCTs from clinicaltrials.gov were identified, of which 11 relevant trials started since January 2013 (see Appendix 4). Seven trials from controlled-trials.com were found, of which none was recent (since January 2013). A total of 26 trials from clinicaltrialsregister.eu were found, of which 4 were relevant, recent RCTs (see Appendix 4).

In the following subsections the quantity of RCTs and their characteristics for each of the 14 surgical specialties are described.

Upper gastrointestinal (digestive system) surgery

A total of 33 upper gastrointestinal (GI) tract surgery RCTs were identified:61–93 13 liver surgeries,65–75,77,250 three cholecystectomies,78–80 seven pancreatic surgeries,81–86,93 five gastric surgeries63,64,89,90,92 and five surgeries in other areas of the digestive tract61,62,87,88,91 (Table 3). Fibrin sealants had a range of indications in the RCTs reporting GI tract surgeries: improving haemostasis, reducing leakage and wound drainage, and preventing post-operative complications. A variety of different fibrin sealants were used. The sample size ranged from 1361 to 32062 participants, with a mean size of 116 participants. The follow-up duration varied from approximately 7 days in Fernandez et al. 63 to 53 months in Huang et al. ,64 but was infrequently reported.

TABLE 3 - Summary of included RCTs in upper GI tract (digestive system) surgery

Study (author, year)	Sample size	Surgery	Intervention	Control
Bektas et al., 201465	31	Liver resection	Tisseel spray	Compression
de Boer et al., 201266	45	Liver resection	Quixil/Crosseal (Johnson & Johnson Wound Management, Somerville, NJ, USA)	Standard care
Chapman et al., 200067	60	Hemihepatectomy or segmental liver resection	CoStasis Surgical Hemostat (Cohesion Technologies Inc., Palp Alto, CA, USA)	Standard care
Uetsuji et al., 199468	96	Hepatectomy	IMMUNOAG spray (IMMUNO AG, Vienna, Austria)	Liver mobilisation
Liu and Lui, 199369	118	Liver resection	Fibrin sponge/bandage	Standard care
Noun et al., 199670	137	Liver resection	Biocol glue (Bio-transfusion, Lille, France)	Standard care
Figueras et al., 200771	143	Liver and contralateral resection	Tissucol	Standard care
Fischer et al., 201172	146	Liver resection	TachoSil patch	Argon beam coagulation
Frilling et al., 200573	148	Liver resection	TachoSil	Argon beam coagulation
Kakaei et al., 201374	166	Liver resection	TachoSil patch	Surgicel (Ethicon, Somerville, NJ, USA)
Kohno et al., 199275	174	Liver resection	Beriplast	Bovine microcrystalline collagen powder
Moench et al., 201476	187	Liver resection	TachoSil patch	Collagen hemostat sangustop fleeces (B. Braun Surgical S.A., Barcelona, Spain)
Schwartz et al., 200477	207	Liver resection	Crosseal/Quixil spray	Haemostatic agents
Fu et al., 200978	60	Laparoscopic cholecystectomy	Fibrin sealant	Fibrin sealant and ropivacaine hydrochloride
Danielsen et al., 201079	51	Laparoscopic cholecystectomy	Vivostat	Human albumin
Dimo et al., 198980	80	Cholecystectomy	Beriplast spray	Standard care
Carter et al., 201381	101	Pancreatectomies	Vitagel injection (Stryker, Kalamazoo, MI, USA)	Staples or sutures
Suzuki et al., 199582	56	Distal pancreatectomy	Tisseel glue	Standard care
Lillemoe et al., 200483	124	Pancreaticoduodenectomy	Hemaseel glue (Baxter Healthcare Corp, Deerfield, MA, USA)	Standard care
Montorsi et al., 201284	275	Pancreatectomy	TachoSil patch	Standard suturing or stapling
Suc et al., 200385	182	Pancreaticoduodenectomy	Tissucol spray	Standard care
Martin and Au, 201386	57	Pancreaticoduodenectomy	Tisseel adhesive	Standard care
Hwang and Chen, 199661	13	Closure of low-output enterocutaneous fistula	Fibrin tissue glue, infused	Conservative treatment
Huang et al., 201564	42	Locally advanced gastric cancer without peritoneal metastases	Fibrin sealant spray	Cisplatin hyperthermic intraoperative chemotherapy
Fernandez Fernandez et al., 199663	86	Total gastrectomy for gastric adenocarcinoma	Tissucol fibrin glue	Standard care
Oliver et al., 201287	104	Anastomosis of the digestive tract	Tissucol Duo (1 ml)	Standard care
Musella et al., 201488	100	Laparoscopic sleeve gastrectomy	Tiseel spray	Standard care
Silecchia et al., 200862	320	Laparoscopic Roux-en-Y antecolic antegastric gastric bypass	Tissucol/Tisseel	Sutures
Pilone et al., 201289	30	Laparoscopic sleeve gastrectomy for bariatric surgery	TachoSil spray	Standard care
Sroka et al., 201590	165	Laparoscopic sleeve gastrectomy	EVICEL spray	Sutures
Fékété et al., 199291	100	Surgery requiring oesophageal anastomosis	Quick-setting fibrin glue	Standard care
Bulbuller et al., 201392	65	Gastrectomy	Tisseel	Without suture
Huang and Qian, 201493	95	Radical gastrectomy	Fibrin spray	Standard care

Breast and lymph node surgery

A total of 30 breast and lymph nodes surgery RCTs94–123 were identified: 19 in breast and/or axillary lymph nodes,95–112,123 nine in inguinal and/or axillary lymph nodes,94,113–120 one in pelvic and/or para-aortic lymph nodes121 and one in thorax/oesophagus lymph nodes122 (Table 4). Fibrin sealants were used as a wound sealant in all RCTs apart from Zhibo and Miaobo,95 when a local anaesthetic was incorporated into the fibrin sealant. A variety of different fibrin sealants were used in different forms, such as patches [TachoComb (Takeda Pharma, Apotekerstien, Denmark) and TachoSil] and sprays (Vivostat, Tisseel and Beriplast). Control-group interventions included standard closure, lidocaine only, no fibrin and no drain. The sample size ranged from 26114 to 159110 participants, with a mean size of 66 participants. Individual randomisation took place in all the RCTs. The follow-up duration varied from approximately 3 days in Moore et al. 106 to 46 months in Swan et al. ,113 but was infrequently reported.

TABLE 4 - Summary of included RCTs in breast and lymph nodes surgery

Study (author, year)	Sample size	Surgery	Intervention	Control
Zhibo and Miaobo, 200995	30	Breast: surgical augmentation	Fibrin glue and lidocaine	Lidocaine only
Ulusoy et al., 200396	54	Breast: mastectomy	Fibrin sealant, spray	Standard closure
Dinsmore et al., 200097	27	Breast: mastectomy	Autologous fibrin glue, spray	Standard closure
Nielsen et al., 1985123	38	Breast: mastectomy	Tisseel, spray	Standard care
Udén et al., 199398	68	Breast and axillary lymph nodes	Tisseel, adhesive	Standard closure
Jain et al., 200499	116	Breast and axillary lymph nodes	Tisseel spray; no drains	No fibrin, no drain
Johnson et al., 2005100	82	Breast and axillary lymph nodes	Hemaseel APR, spray	Standard closure
Llewellyn-Bennett et al., 2012101	101	Breast and axillary lymph nodes	Tisseel, spray	Standard closure
Ko et al., 2009102	95	Breast and axillary lymph nodes	Greenplast kit (Green Cross Corp., Seoul, Korea), spray	Standard closure
Miri Bonjar et al., 2012103	60	Breast and axillary lymph nodes	Hemaseel, spray	Standard closure
Mustonen et al., 2004104	40	Breast and axillary lymph nodes	Tisseel, spray	Standard closure
Segura-Castillo et al., 2005105	45	Breast and axillary lymph nodes	Quixil, spray	Standard closure
Moore et al., 1997106	63	Breast and axillary lymph nodes	Autologous fibrin sealant, spray	Standard closure
Berger et al., 2001107	60	Axillary lymph nodes	TachoComb H, patch	Standard closure
GiIlly et al., 1998108	108	Axillary lymph nodes	Tissucol, unclear application	Standard closure
Benevento et al., 2014109	60	Axillary lymph nodes	Fibrin sealant	Standard closure
Cipolla et al., 2010110	159	Axillary lymph nodes	Fibrin sealant, spray	Standard closure
Moore et al., 2001111	80	Axillary lymph nodes	Fibrin sealant VI Guard spray (V.I. Technologies, Inc. Vitex, Watertown, MA, USA) 4/8/16 ml	Standard closure
Vaxman et al., 1995112	40	Axillary lymph nodes	Tisseel, spray	Standard closure
Swan et al., 2011113	74	Axillary or inguinal lymph nodes	Tisseel, spray	Standard closure
Siim et al., 1994114	26	Axillary or inguinal lymph nodes	Tisseel, unclear application	Standard closure
Gilly et al., 1994115	40	Axillary or inguinal lymph nodes	Tissucol, spray	Standard closure
Furrer et al., 1993116	30	Axillary or inguinal lymph nodes	Tissucol, spray	Standard closure
Di Monta et al., 2012117	70	Axillary or ilioinguinal lymph nodes	TachoSil, patch	Standard closure
Neuss et al., 2009118	58	Inguinal lymph nodes	Tissucol, spray	Standard closure
Simonato et al., 2009119	60	Inguinal lymph nodes	TachoSil, patch	Standard closure
Carlson et al., 200894	137	Inguinal lymph nodes	Tisseel, spray	Standard closure
Mortenson et al., 2008120	30	Inguinofemoral lymph nodes	Tisseel, unclear application	Standard closure
Scholz et al., 2002121	93	Pelvic or pelvic and para-aortic lymph nodes	Tissucol, spray	Standard closure
Tachibana et al., 2003122	43	Thorax/oesophagus lymph nodes	Bohleal (Kaketsuken Pharmaceutical, Kumamoto, Japan), spray	Standard closure

Cardiothoracic surgery

A total of 18 cardiothoracic surgery RCTs60,124–140 were identified, of which 14 were in lung surgery124–137 and four were in heart surgery60,138–140 (Table 5). In lung surgery, fibrin sealants were used to prevent or reduce air leakage, whereas in heart surgery the indication for fibrin sealants was to stop bleeding. A variety of different fibrin sealants were used, such as patches (TachoComb and TachoSil) and sprays (Vivostat, Tisseel or Beriplast). Control-group interventions included sutures, stapling, clips, standard patches, fleece material, electrocautery or no additional procedures. The sample size ranged from 23138 to 346129 participants, with a mean size of 115 participants.

TABLE 5 - Summary of included RCTs in cardiothoracic surgery

Study (author, year)	Sample size	Surgery	Intervention	Control
Lung
Fabian et al., 2003128	100	Pulmonary resection	Fibrin glue spray	Stapling
Droghetti et al., 2008124	40	Pulmonary resection	Fibrin patch	Stapling
Lopez et al., 2013129	346	Pulmonary resection	TachoSil patch	Suturing
Rena et al., 2009127	60	Pulmonary resection	TachoSil patch	Standard treatment
Gonfiotti et al., 2011130	186	Pulmonary resection	Fibrin sealant	No additional interventions
Moser et al., 2008126	25	Pulmonary resection	Vivostat system	No additional interventions
Belcher et al., 2010131	102	Pulmonary resection	Vivostat system, spray	BioGlue (CryoLife, Kennesaw, GA, USA)
Mouritzen et al., 1993132	114	Pulmonary resection (pneumonectomies, lobectomies, bilobectomies, segmental resections, subsegmental resections or decortications)	Beriplast P spray	Not specified
Belboul et al., 2004133	40	Pulmonary resection (lobectomy)	Vivostat system	No additional interventions
Lang et al., 2004134	186	Pulmonary resection (lobectomy)	TachoComb, fleece-bound sealant	Sutures
Anegg et al., 2007125	152	Pulmonary resection (lobectomy, segmentectomy)	TachoSil, fleece-bound sealant patch	Sutures with absorbable patches or staples
Marta et al., 2010135	299	Pulmonary resection (lobectomy)	TachoSil, surgical patch	Resuturing, stapling or no treatment
Filosso et al., 2013136	24	Pulmonary resection (thoracotomy, lobectomy)	TachoSil, patch	Stapling/suturing
Czerny et al., 2004137	80	Lobectomy and mediastinal lymph node dissection	TachoComb, bandage/patch	Conventional surgical haemostasis
Heart
Kjaergard and Trumbull, 1998138	23	Primary coronary artery bypass surgery/grafting	Vivostat system	Sutures, clips and electrocautery
Kjaergard and Trumbull, 2000139	60	Median sternotomy	Vivostat system	No additional interventions
Maisano et al., 2009140	119	Elective surgery on the heart, ascending aorta or arch requiring a cardiopulmonary bypass procedure	TachoSil, patch	Standard haemostatic fleece material

Orthopaedic (joint) surgery

A total of 17 RCTs14,141–156 in orthopaedic surgery were identified (Table 6). Eleven reported fibrin usage for knee arthroplasty,14,142–151 whereas five reported on hip arthroplasty141,152–154,156 and one on shoulder surgery. 155 In knee and hip arthroplasty, fibrin was used as a haemostatic agent. The most commonly reported sealant used was Quixil spray, which was used in eight RCTs. 14,144–148,154,156 The remaining RCTs reported using EVICEL,149–151 Vivostat141 and Omrixil^® spray (Omrix Biopharmaceuticals, Tel Hashomer, Israel),153 whereas two RCTs did not specify the product that was used. 152,155 Control groups mostly constituted patients receiving standard care. The sample size ranged from 24145 to 198142 participants, with a mean size of 81 participants. Within-patient randomisation took place in Kjaergard and Trumbull139 and individual randomisation was undertaken in the remaining RCTs. Duration of follow-up ranged from 7 days in Randelli et al. 149 to 3 years in Mawatari et al. 152

TABLE 6 - Summary of included RCTs in orthopaedic (joint) surgery

Study (author, year)	Sample size	Surgery	Intervention	Control
Knee
Aguilera et al., 2013143	166	Total knee arthroplasty	Fibrin glue, Tissucol	None
Levy et al., 199914	58	Total knee arthroplasty	Quixil, spray	Standard care
Wang et al., 2001144	46	Knee arthroplasty	Quixil, spray	Standard care
Kluba et al., 2012145	24	Total knee arthroplasty	Quixil, spray	Anaesthesia and fluid regimen
McConnell et al., 2012146	65	Knee arthroplasty	Quixil, spray	Tranexamic acid
Molloy et al., 2007147	150	Total knee arthroplasty	Quixil, spray	Tranexamic acid
Sabatini et al., 2012148	70	Total knee, cement-less arthroplasty	Quixil	Dideco blood recovery device (Liva Nova, London, UK)
Randelli et al., 2014149	62	Total knee arthroplasty	EVICEL, spray	Electrocautery
Skovgaard et al., 2013150	48	Total knee arthroplasty	EVICEL, spray	Saline
Choufani et al., 2015151	60	Total knee arthroplasty	EVICEL, spray	Standard care
Heyse et al., 2014142	198	Total knee arthroplasty	Fibrin, spray	Standard care
Hip
Mawatari et al., 2006152	100	Total hip arthroplasty	Autologous fibrin tissue adhesive, spray	Standard care
Wang et al., 2003153	81	Total hip arthroplasty	Omrixil, spray	Standard care
Lassen et al., 2006141	58	Hip arthroplasty	Vivostat, spray	Standard care
Falez et al., 2013154	95	Hip arthroplasty	Quixil, spray	Bipolar sealer (Medtronic, Minneapolis, MN, USA)
McConnell et al., 2011156	66	Hip arthroplasty	Quixil, spray	Tranexamic acid
Shoulder
Antuña et al., 2013155	28	Arthroscopic massive rotator cuff tears repair	Platelet-rich fibrin	Standard care

Eye surgery

A total of 15 eye surgery RCTs157–171 were identified, of which 13 were on pterygium surgeries,157–163,165–169,171 one was a cataract surgery170 and one a corneal perforation surgery164 (Table 7). In pterygium surgery, fibrin adhesives were used to attach conjunctival autografts. For cataracts and perforation, fibrin sealants were used for wound closure and perforation closure, respectively. The most commonly reported sealant used within the RCTs was Tisseel (used in seven RCTs157,160–163,167,171). Quixil159,166,169 and Beriplast158,168 were also used, whereas the product was not specified in three RCTs. 164,165,170 Control group interventions were sutures in all the RCTs except for one in which cyanoacrylate tissue adhesive was used (Sharma et al. 164). The sample size ranged from 22168 to 116165 participants, with a mean size of 63 participants.

TABLE 7 - Summary of included RCTs in eye surgery

Study (author, year)	Sample size	Surgery	Intervention	Control
Ocular surface
Kucukerdonmez et al., 2010157	70	Pterygium surgery with autograft	Tisseel VH, glue	Sutures
Eye
Yüksel et al., 2010158	58	Pterygium surgery with autograft	Beriplast P/Combi-set (Aventis Hehring GmbH, Marburg, Germany)	Sutures
Bahar et al., 2006159	65	Pterygium surgery	Quixil	Sutures
Rubin et al., 2011166	42	Pterygium surgery with autograft	Quixil, glue	Sutures
Conjunctiva
Hall et al., 2009160	50	Pterygium surgery with autograft	Tisseel, glue	Sutures
Karalezli et al., 2008161	50	Pterygium surgery with autograft	Tisseel, glue	Sutures
Koranyi et al., 2005162	43	Pterygium surgery with autograft	Tisseel, glue	Sutures
Sati et al., 2014163	90	Pterygium surgery with autograft	Tisseel, spray	Sutures
Ratnalingam et al., 2010165	137	Pterygium surgery with autograft	Fibrin, glue	Sutures
Srinivasan et al., 2009167	40	Pterygium surgery with autograft	Tisseel	Sutures
Uy et al., 2005168	22	Pterygium surgery with autograft	Beriplast P, glue	Sutures
Mellin and Kondler, 1989170	100	Cataract surgery	Fibrin, glue	Sutures
Malik and Kumar, 2010171	50	Pterygium surgery with autograft	Tisseel Duo Quick	Sutures
Cornea
Sharma et al., 2003164	40	Corneal perforation	Fibrin, glue	Cyanoacrylate tissue adhesive
Bahar et al., 2007169	81	Pterygium surgery with autograft	Quixil	Sutures

Hernia surgery

A total of 14 hernia surgery RCTs172–185 were identified (Table 8). Fibrin sealants were used mostly for prosthetic mesh fixation (12 RCTs172–176,178,181–186). The most commonly reported sealant used was Tisseel/Tissucol (10 RCTs172,176–178,180–185). Quixil (two RCTs174,179) and Vivostat (one RCT173) were also used, whereas one RCT did not report which fibrin product was used. 175 Three papers reported using fibrin sealant in spray form176,177,179 and three reported using laparoscopic applicators. 172,178,180 One paper reported using a needle applicator,174 another reported using a manual application catheter183 and the remaining six papers did not specify how it was applied. 173,175,181,182,184,185 Fibrin was compared with a range of interventions across the RCTs including sutures, staples, tacks and self-gripping mesh. The sample size ranged from 22173 to 600185 participants, with a mean size of 172 participants. Within-patient randomisation took place in Boldo173 and individual randomisation was undertaken in the remaining RCTs. The follow-up duration varied from approximately 3 months in Cambal et al. 175 to 26 months in Olmi et al. 185

TABLE 8 - Summary of included RCTs in hernia surgery

Study (author, year)	Sample size	Surgery	Intervention	Control
Inguinal canal
Lau, 2005172	93	Endoscopic totally extraperitoneal inguinal hernioplasty	Tisseel VH	Staples
Boldo, 2008173	22	Laparoscopic hernioplasty	Vivostat	Staples
Bracale et al., 2014174	102	Hernioplasty	Quixil	Sutures
Cambal et al., 2012175	100	Laparoscopic hernioplasty	Fibrin glue	Self-gripping (or self-anchoring) mesh
Campanelli et al., 2012176	316	Hernioplasty	Tissucol/Tisseel	Sutures
Canonico et al., 1999177	50	Hernioplasty	Tissucol	Standard care
Chan et al., 2014178	129	Total extraperitoneal hernioplasty	Tisseel spray	Staples
Lionetti et al., 2012179	148	Hernioplasty	Quixil spray	Sutures
Wong et al., 2011182	56	Hernioplasty	Tisseel glue	Sutures
Damiano et al., 2014184	468	Herniorrhaphy	Tissucol	Sutures
Olmi et al., 2007185	600	Laparoscopic transabdominal pre-peritoneal hernia repair	Tissucol/Tisseel	Staples
Inguinal and femoral canals
Lovisetto et al., 2007180	197	Hernioplasty	Tissucol/Tisseel	Staples
Tolver et al., 2013181	100	Laparoscopic groin hernia	Tisseel spray	Tacks
Umbilicus
Eriksen et al., 2013183	34	Laparoscopic ventral hernia repair	Tisseel Duo Quick	Tacks

Ear, nose and throat surgery

Seven RCTs186–192 were identified in ear, nose and throat (ENT) surgery: six nasal surgeries186–191 and one tonsillectomy192 (Table 9). Fibrin adhesives were mostly used to aid haemostasis (five RCTs188–192) and to improve healing. The most commonly reported sealant used was Quixil (spray/glue) and was used in four RCTs,188,189,191,192 whereas Beriplast187 and EVICEL186 were also used. Control-group interventions included packing, compression, sutures and standard care. The sample size ranged from 10186 to 513191 participants, with a mean size of 133 participants. Within-patient randomisation took place in two RCTs,186,190 whereas individual randomisation was undertaken in the remaining RCTs. The follow-up duration varied from approximately 21 days in Pryor et al. 186 to 1 year in Prado et al. 187

TABLE 9 - Summary of included RCTs in ENT surgery

Study (author, year)	Sample size	Surgery	Intervention	Control
Nose
Prado et al., 2006187	22	Rhinoplasty	Beriplast	Standard care
Pryor et al., 2008186	10	Rhinoplasty	EVICEL	Compression
Vaiman et al., 2005189	64	Endoscopic sinus surgery	Quixil/Crosseal (Johnson & Johnson Wound Management, Somerville, NJ, USA) spray	Nasal packing
Yu et al., 2014190	41	Rhinosinusitis refractory	Fibrin spray	Sponge packing
Vaiman et al., 2005191	513	Endonasal surgery	Quixil glue	Nasal packing
Nose and septum
Vaiman et al., 2002188	204	Septoplasty and conchotomy	Quixil aerosol glue	Quixil aerosol glue and trans-septal suturing
Tonsils
Vaiman et al., 2006192	80	Tonsillectomy	Quixil spray	Electrocautery

Vascular surgery

A total of 13 vascular surgery RCTs193–205 were identified (Table 10). Fibrin sealant was used in all cases to control suture hole bleeding from placing the graft for vascular access or vascular reconstruction surgery. In Bajardi et al. 194 Poly(ethyl benzene-1,4-dicarboxylate) [Dacron^® (Ethicon Inc., Somerville, NJ, USA)] grafts were used, whereas in all other RCTs193,195–204 polytetrafluoroethylene grafts were used. These materials are frequently used for vascular replacement or bypass when no autologous venae are available. All RCTs used different fibrin sealants apart from the Joseph et al. 200 and Czerny et al. 205 RCTs that used TachoComb patches. Control group interventions were manual compression194,196–198,200,204,205 or use of thrombin,196 thrombin-soaked materials,196,199 Surgicel195,196 or Kalkostat. 202 The sample size ranged from 24200 to 199199 participants, with a mean size of 66 participants. Individual randomisation was undertaken in all RCTs. Follow-up duration varied from approximately 30 days in Sintler et al. 202 to 6 months in Schenk et al. ,195 but was infrequently reported.

TABLE 10 - Summary of included RCTs in vascular surgery

PTFE, poly(1,1,2,2-tetrafluoroethylene).

Study (author, year)	Sample size	Surgical area	Surgery	Intervention	Control
Schenk et al., 2003195	48	Upper extremity; artery and vein in the upper arm or forearm	Vascular access surgery using PTFE graft placement (dialysis required for end-stage renal failure)	Bioplasma (ZLB, Bioplasma AG, Bern, Switzerland) glue	Surgicel (Johnson & Johnson, Somerville, NJ, USA)
Schenk et al., 2002196	28	Upper extremity; artery and vein in the upper arm or forearm	Vascular access surgery using PTFE graft placement	Hemaseel spray (Haemacure Corp., Sarasota, FL, USA)	Thrombin (n = 8); pressure (n = 6); thrombin-soaked Gelfoam (Pfizer Inc., New York City, NY, USA) (n = 2); Surgicel (n = 2)
Saha et al., 2012197	140	Upper and lower extremity: axillofemoral, iliofemoral, femorofemoral, iliopopliteal, proximal femoropopliteal, distal femoropopliteal and femorotibial vessel bypass	Arterio-arterial bypasses and arteriovenous shunting for dialysis access with expanded PTFE graft placement	Fibrin sealant	Compression
Chalmers et al., 2010198	147	Femoral or upper extremity arteries	PTFE grafts	EVICEL	Compression
Taylor et al., 2003199	199	Femoral artery	PTFE grafts	Beriplast P gel	Thrombin-soaked gelatin sponge
Joseph et al., 2004200	24	Femoral or carotid artery	Femoral anastomosis and femoral or carotid patch angioplasty with PTFE grafts	TachoComb patch	Compression
Jackson et al., 1999193	47	Carotid artery	Elective carotid endarterectomy with expanded PTFE patch angioplasty (atherosclerotic occlusive diseases)	Investigational new drug number 4353, human fibrin sealant	Gelfoam
Milne et al., 1995201	17	Carotid artery	Endarterectomy with a PTFE patch	Fibrin spray	No treatment
Sintler et al., 2005202	20	Carotid artery	Endarterectomy with an expanded PTFE patch	Quixil	Kaltostat (ConvaTec, Flintshire, UK)
Milne et al., 1996203	39	Artery or aorta	Arterial bypass surgery with a PTFE bypass graft and aortic aneurysm repair with a woven Dacron graft	Fibrin injection	No treatment
Saha et al., 2011204	73	Anastomoses (junction) of arterio-arterial bypasses and arteriovenous shunts	Bypass vessel PTFE grafts	Tisseel	Compression
Czerny et al., 2000205	60	Aortofemoral, femoropopliteal and crossover bypasses, femoral artery, arteria carotis interna	Vascular reconstruction; anastomoses or patch angioplasties with PTFE prostheses	TachoComb H patch	Compression
Bajardi et al., 2009194	20	Infrarenal abdominal aorta	Elective infrarenal abdominal aortic aneurysm replacement with a Dacron graft	TachoSil patch	Compression

Plastic or reconstructive surgery

Ten RCTs206–215 in plastic/reconstructive surgery in various body sites were found (Table 11). Fibrin sealant had different indications within plastic/reconstructive surgery: haemostasis (four RCTs207,208,211,212), reduction of seroma formation (two RCTs213,214), reduction of drainage (two RCTs210,215) and wound healing (two RCTs206,209). Various types of fibrin sealants were used across the RCTs: sprays (Tisseel,210,211 Cryoseal,206,212 Quixil213 and autologous sealant using a spraypen207) and a Bioseed fibrin net. 208 Control-group interventions included standard care,206,210,212,214,215 pressure,208,209 thrombogen kit,207 fabric dressing211 and suction drains. 213 The sample size ranged from 10210 to 225208 participants, with a mean size of 58 participants. Individual randomisation was undertaken in all RCTs except Drake and Wong,207 which reported within-patient randomisation. The follow-up duration varied from 1 week207 to 12 months210 and was not reported in Oliver et al. 215

TABLE 11 - Summary of included RCTs in plastic or reconstructive surgery

Study (author, year)	Sample size	Surgical area	Surgery	Intervention	Control
Drake and Wong, 2003207	34	Skin	Skin graft	Vivolution spraypen (Vivolution A/S, Birkerød, Denmark)	Thrombogen Kit (Johnson & Johnson Wound Management, Somerville, NJ, USA)
Vanscheidt et al., 2007208	225	Lower legs	Treatment of recalcitrant venous leg ulcers	BioSeed fibrin net (BioTissue Technologies GmbH, Freiburg, Germany)	Pressure dressing pad
Danielsen et al., 2008209	39/40	Legs	Treatment of leg ulcers	Vivolution	Gauze and pressure
Erba et al., 2010210	10	Ischial region	Seal fasciocutaneous flaps to cover ischial pressure sore	Tisseel spray	Standard care
Healy et al., 2013211	40	Thigh	Treat split skin graft donor sites	Tisseel spray	Mefix self-adhesive fabric dressing (MoInlycke Healthcare, Lancashire, UK)
Altinli et al., 2007206	32	Buttock	Limberg flap procedure in pilonidal disease	CryoSeal spray (Thermogenesis, Rancho Cordova, CA, USA)	Standard care
Sözen et al., 2011212	50	Buttock	Karydakis flap operation for pilonidal sinus	CryoSeal spray	Standard care
Bercial et al., 2012213	43	Abdomen	Abdominoplasty	Quixil spray	Suction drains
Mabrouk et al., 2013214	60	Abdomen	Lipoabdominoplasty	Fibrin glue	Standard care
Oliver et al., 2002215	44	Axilla, groin, back and abdomen	Axillary dissection, groin dissection, latissimus dorsi flaps and abdominoplasty	Beriplast spray	Standard care

Colorectal surgery

Five RCTs were found in colorectal surgery216–220 (Table 12). Fibrin sealant was used mainly to minimise recurrence and prevent incontinence after anal fistula surgery. Three RCTs216,217,219 reported the use of Tisseel/Tissucol in the fibrin group, whereas Beriplast was used in one RCT218 and the remaining RCT220 did not specify the product used. The sample size ranged from 28219 to 62217 participants and the mean number of patients was 44. Individual randomisation was undertaken in all RCTs. The follow-up duration varied from approximately 1 year217 to 60 months. 220

TABLE 12 - Summary of included RCTs in colorectal surgery (anal fistula)

Study (author, year)	Sample size	Surgery	Intervention	Control
Ellis and Clark, 2006216	57	Mucosal or anodermal advancement flap for surgical management of anal fistulas	Tisseel injection	Flap repair
Altomare et al., 2011217	62	Treatment of trans-sphincteric anal fistulas	Tissucol	Seton treatment
Lindsey et al., 2002218	42	Treatment of anal fistulas	Beriplast glue	Fistulotomy or loose seton insertion
Hammond et al., 2011219	28	Treatment of idiopathic anal fistula	Tisseel glue	Permacol (Covidien, Dublin, Ireland)
van der Hagen et al., 2011220	30	Treatment of complex perianal fistulas	Fibrin sealant glue	Seton drainage

Urology (urinary tract)

Five RCTs59,221–224 were found in urological surgery (Table 13). Fibrin sealant was used for haemostasis in all the RCTs except for Schultz and Christiansen224 in which it was used to reduce the post-operative drainage period. Various fibrin sealants were used across the RCTs: Siemer et al. 221 and Cormio et al. 222 used a TachoSil patch, Nativ et al. 59 used an Ethicon pad, Luke et al. 223 used Beriplast and Schultz and Christiansen224 used Tisseel. Control groups received standard care in all the RCTs. The sample size ranged from 759 to 185221 participants, and the mean number of patients was 67. Individual randomisation was undertaken in all RCTs. The follow-up duration varied from 159,221 to 3 months223 but was not reported for Cormio et al. 222 and Schultz and Christiansen. 224 Randomisation was carried out at an individual level in all RCTs.

TABLE 13 - Summary of included RCTs in urology (urinary tract) surgery

Study (author, year)	Sample size	Surgery	Intervention	Control
Kidney
Nativ et al., 201259	7	Open partial nephrectomy	Ethicon pad (Johnson & Johnson Wound Management, Somerville, NJ, USA)	Standard care
Siemer et al., 2007221	185	Resection of small, superficial kidney tumours not extending into the collecting duct system; nephron-sparing surgery	TachoSil patch	Standard suturing
Cormio et al., 2012222	96	Percutaneous nephrolithotomy	TachoSil patch	Nephrostomy tube
Prostate
Luke et al., 1986223	30	Transurethral resection of the prostate	Beriplast glue	Standard care
Urethra
Schultz and Christiansen, 1985224	16	Closure of the ureterotomy after ureteral stone surgery	Tisseel adhesive	Dexon sutures (Syneture, Mansfield, MA, USA)

Oral and maxillofacial surgery

Seven RCTs225–231 were found in oral and maxillofacial surgery (Table 14). Fibrin sealant was used mostly to reduce post-operative wound drainage in different types of procedures. A variety of fibrin sealants were used across RCTs: Tisseel,225,226,230 Crosseal,227 Beriplast spray,228 autologous fibrin glue229 and Artiss. 231 Control-group interventions included ‘no sealant’,225,228,231 tranexamic acid229 and sutures. 230 The sample size ranged from 9227 to 75231 participants, with a mean size of 41 participants. Within-patient randomisation was carried out in four RCTs,226–228,231 whereas the remaining three reported individual-level randomisation. 225,229,230 The follow-up duration varied from 24 hours in Oliver et al. 228 to 3 weeks in Maharaj et al. 230

TABLE 14 - Summary of included RCTs in oral and maxillofacial surgery

Study (author, year)	Sample size	Surgery	Intervention	Control
Face
Marchac and Greensmith, 2005226	29	Rhytidectomy	Tisseel spray	Rhytidectomy using the vertical U incision technique without glue
Oliver et al., 2001228	20	Rhytidectomy	Beriplast spray	No sealant
Face and neck
Lee et al., 2009227	9	Rhytidectomy	Crosseal	No Crosseal treatment
Hester et al., 2013231	75	Rhytidectomy	Artiss	No application of fibrin sealant
Thyroid gland
Uwiera et al., 2005225	56	Hemithyroidectomy and total thyroidectomy	Tisseel	No sealant
Tooth socket
Carter et al., 2003229	49	Dental extraction	Autologous fibrin glue	Active 4.8% tranexamic acid solution
Parotid glands
Maharaj et al., 2006230	50	Superficial and total parotidectomy	Tisseel fibrin glue	Vicryl and Monocryl sutures (Johnson & Johnson Wound Management, Somerville, NJ, USA)

Gynaecological surgery

Four RCTs232–235 were found in gynaecological surgery (Table 15). Fibrin sealant was indicated for the following: the prevention of post-operative adhesions,232,234 haemostasis around myomectomy suture sites233 and prevention of a vesicovaginal fistula. 235 A variety of fibrin sealants were used across RCTs and control group patients received ‘no sealant’ procedures. The sample size ranged from 16232 to 91 participants,234 with a mean size of 54 participants. Follow-up duration was 3 months235 to 1 year,233 but not reported in Diamond et al. 232 and Takeuchi et al. 234

TABLE 15 - Summary of included RCTs in gynaecological surgery

Study (author, year)	Sample size	Surgical area	Surgery	Intervention	Control
Diamond et al., 2011232	16	Ovaries	Bilateral ovarian surgery	Adhexil spray/drip (Johnson & Johnson Wound Management, Somerville, NJ, USA)	Standard care
Maggiore et al., 2011233	70	Uterus/endometrium	Laparoscopic removal of myomas (neoplasm)	TachoSil sponge	Standard care
Takeuchi et al., 2005234	91	Uterus/abdomen	Laparoscopic myomectomy	Beriplast spray	TachoComb sheet
Safan et al., 2009235	38	Vesicovaginal region	Treatment of vesicovaginal fistula	Fibrin adhesive	Standard care

Neurosurgery

Two RCTs236,237 reporting on fibrin sealant for prevention of cerebrospinal fluid leakage were found in neurosurgery (Table 16). Beriplast adhesive was compared with autologous fibrin sealant in Nakamura et al. ,236 whereas collagen sponge was compared with standard care in Hutter et al. 237 Nakamura et al. 236 reported a sample size of 30 participants, whereas the sample size in Hutter et al. 237 was 229 participants, giving a mean sample size of 134 participants. Individual randomisation was undertaken in both RCTs. The follow-up duration was 32 days in Hutter et al. 237 and 8 weeks in Nakamura et al. 236

TABLE 16 - Summary of included RCTs in neurosurgery

Study (author, year)	Sample size	Surgical area	Surgery	Intervention	Control
Nakamura et al., 2005236	39	Dura layer of spinal cord	Spinal cord tumours and related illnesses	Beriplast adhesive	Autologous fibrin sealant
Hutter et al., 2014237	229	Dura mater of the brain	Elective cranial surgery involving a dural incision	Collagen sponge	Standard care

Mixed surgery

Four RCTs238–241 across more than one surgical area were found (Table 17): Bochicchio et al. 239 and Verhoef et al. 240 were in spinal and vascular surgery, hepatic resection and soft tissue dissection; Hanks et al. 238 was cardiothoracic, general, obstetric and gynaecological and vascular surgery; and Fischer et al. 241 was in abdominal, retroperitoneal, pelvic and non-cardiac thoracic surgeries. Fibrin sealant was used for haemostasis in all the RCTs and different products were used across them. Raplixa fibrocaps powder was used in Bochiccio et al. 239 and Verhoef et al. 240 In Hanks et al. 238 autologous fibrin sealant derived from patients’ blood was used, whereas in Fischer et al. 241 fibrin pads were used. The sample size ranged from 69238 to 719239 participants, with a mean size of 263 participants. Individual randomisation was undertaken in all RCTs. The follow-up duration was around 1 month in Bochicchio et al. 239 and Fischer et al. ,241 but was not reported in the other two RCTs.

TABLE 17 - Summary of included RCTs in mixed surgery

Study (author, year)	Sample size	Surgical specialties	Surgery	Interventions	Control
Bochicchio et al., 2015239	719	Spine, liver, arteries, soft tissues	Spinal procedures; vascular procedures with suture hole bleeding; hepatic resection; soft tissue dissection	Raplixa fibrocaps powder (ProFibrix BV – The Medicines Company, Leiden, The Netherlands)	Gelatin sponge
Verhoef et al., 2015240	122	Spine, liver, arteries, soft tissues	Hepatic resections (46%), spinal procedures (30%), vascular procedures (24%) and soft tissue dissection (1%)	Raplixa fibrocaps powder	Pressure dressing pad
Hanks et al., 2003238	69	Cardiothoracic, general, obstetric and gynaecological, and vascular	Not reported	Vivostat system	Dry surgical sponge
Fischer et al., 2013241	90/141	Abdomen, retroperitoneum, pelvis and non-cardiothoracic surgery	Surgical operations in the abdomen, retroperitoneum, pelvis and non-cardiothoracics	Fibrin pad	Surgicel

Quality of randomised controlled trials

A risk-of-bias table for RCTs can be found in Appendix 5. Overall, 154 studies were assessed as having an ‘unclear risk of bias’, eight RCTs as having a ‘high risk of bias’ and 24 RCTs as having a ‘low risk of bias’ (see Table 37). The risk-of-bias table (see Table 37) shows a high level of uncertainty about the validity of data collected across all parameters, especially regarding the blind collection of patient outcomes. Owing to the nature of the intervention, surgeons could not be blinded to the intervention, as they had to apply the fibrin sealant; however, patients and outcome assessors who could be blinded to the intervention were frequently not blinded either.

Most of the funnel plots did not show publication bias (see Appendix 6); however, the funnel plot for development of haematoma meta-analysis [Egger bias –0.63, 95% confidence interval (CI) –1.20 to –0.06; p = 0.03] (see Figure 43) and duration of drainage for breast surgery meta-analysis (Egger bias –3.34, 95% CI –6.75 to –0.05; p = 0.05) (see Figure 47) showed a skewed figure of publications, which indicated the presence of small study effects.

Quantity of observational studies and regulatory body reports

The search of electronic databases identified 4714 potentially relevant articles about harms related to the use of fibrin sealants, of which 3709 references were excluded and 1005 full-text papers assessed (Figure 2 and Appendix 7). There were an additional 93 reports, reviews or notifications about harms from the use of these products from the MHRA, EMA and FDA websites.

FIGURE 2.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of observational studies and regulatory body reports.

After screening and applying the eligibility criteria, eight observational studies were included242–249 (Table 18). Three observational studies were in eye surgery,242–244 three in upper GI tract surgery,245–247 one in plastic/reconstructive surgery248 and one in vascular surgery. 249 There were three cohort studies,243,245,249 three comparative studies242,244,247 and two reviews of patient records. 246,248 The following fibrin sealants were used: unspecified fibrin glue in eye surgery,242–244 Tiseel,245 Beriplast,247 aerosolised fibrin glue248 and platelet-enriched fibrin glue sealant. 249 Comparator interventions were standard care245–249 or sutures in eye surgery. 242–244 Sample sizes ranged from 40243 to 529246 participants.

TABLE 18 - Overview of observational studies

Study (author, year)	Sample size	Type of comparative study	Surgery	Intervention	Control
Eye surgery
Cagatay et al., 2014242	103	Comparative study (consecutive sample)	Conjunctival autografting for pterygium surgery	Fibrin glue	Sutures
Jiang et al., 2008243	40	Cohort study	Conjunctival autografting for pterygium surgery	Fibrin glue	Sutures
Choi et al., 2010244	126	Comparative study	Pars plana vitrectomy (eye)	Fibrin glue	Sutures
Upper GI tract surgery
Efthimiou et al., 2010245	474	Cohort (consecutive sample supplemented with clinical observations and chart reviews)	Laparoscopic Roux-en-Y gastric bypass	Tisseel	Standard care
Ibele et al., 2014246	529	Review of patient records (consecutive sample)	Laparoscopic Roux-en-Y gastric bypass	Autologous fibrin sealant	Standard care
Nanashima et al., 2012247	341	Comparative study (consecutive sample)	Hepatobiliary pancreas surgery; hepatectomy and pancreatectomy	Beriplast fibrin glue spray	Standard care
Plastic/reconstructive surgery
Marchac and Sándor, 1994248	200	Review of patient records (consecutive sample)	Rhytidectomy	Aerosolised fibrin glue	Standard care
Vascular surgery
Sakic et al., 2013249	418	Cohort study (consecutive sample)	Bilateral internal thoracic artery grafting	Platelet-enriched fibrin glue sealant	Standard care

Five reports from the regulatory body websites that reported on harms related to the use of fibrin sealants were included (see Table 43).

Quality of observational studies

The validity of the eight observational studies was compromised owing to a general failure to report whether or not adverse events were assessed independently and whether or not blinding to the assigned was performed (Table 19). Cagatay et al. 242 reported that harms were assessed independently. Five studies described measurement instruments,243,245,246,248,249 but only three studies reported timing and duration of follow-up. 243,246,249 Only Sakic et al. 249 appeared to have used objective measures. All eight studies, except that by Jiang et al. ,243 attributed the harms to the use of fibrin sealants and seven studies explained terms used to identify harms. 242–246,248,249 No studies reported to have blinded the collection of outcomes to the treatment assignment.

TABLE 19 - Quality of observational studies

AE, adverse event; N, no; NA, not applicable; UC, unclear; Y, yes.

Study (author, year)	AEs assessed independently?	Measurement instruments described?	Timing and duration of follow-up reported?	Standard or validated measurement instrument used?	Objective measures?	AEs attributed to the intervention?	Collection of outcomes blinded to assigned treatment?	Terms used to identify AEs clearly explained?	All AEs from the population reported?
Cagatay et al., 2014242	Y	N	N	N	N	Y	N	Y	Y
Jiang et al., 2008243	N	Y	Y	Y	UC	N	NA	Y	Y
Choi et al., 2010244	N	N	N	N	N	Y	N	Y	Y
Efthimiou et al., 2010245	N	Y	N	UC	UC	Y	UC	Y	Y
Ibele et al., 2014246	N	Y	Y	Y	UC	Y	N	Y	Y
Nanashima et al., 2012247	N	N	N	N	UC	Y	N	N	N
Marchac and Sándor, 1994248	N	Y	N	N	N	Y	N	Y	Y
Sakic et al., 2013249	Y	Y	Y	Y	Y	Y	N	Y	Y

Assessment of benefits

The following sections present the analyses of benefits for the primary and secondary outcomes (Table 20). Fixed-effects model results are presented in the text and random-effects model results in Appendix 8. Data on primary and secondary outcomes used in the meta-analysis for all RCTs are presented in Appendix 9.

TABLE 20 - Overview of outcomes and analysis

Outcomes	Variables
Primary outcomes (dichotomous)
Seroma development	Number of patients who developed seroma
Haematoma development	Number of patients who developed haematoma and a post hoc analysis in which the development of seroma and haematoma are combined
Secondary outcomes (dichotomous)
Haemorrhage (blood loss)	Number of patients with bleeding
Reoperation	Number of patients with reoperation
Infections	Number of patients with wound infection
Use of analgesics	Number of patients (no meta-analysis as the data from RCTs were too heterogeneous)
Complications arising from the use of drains	Number of patients with complications (no data in RCTs reported)
Secondary outcomes (continuous)
Duration of operation	Mean duration in minutes
Length of hospital stay	Mean duration in days
Use of drains	Mean duration of drainage in days
Pain levels	Mean level of pain (no meta-analysis as the data from RCTs were too heterogeneous)
Health-related quality of life	Mean health-related quality-of-life value (no data in RCTs reported)

Primary outcomes

Seroma development

Development of seroma was reported in 37 RCTs, of which 33 (n = 3472) were included in the meta-analysis (Figure 3). The remaining four RCTs were excluded for the following reasons: Cipolla et al. 110 as all participants in the fibrin and control groups developed seroma; Erba et al. 210 and Uwiera et al. 225 because no patients developed seroma; and Siim et al. 114 because seroma development was not reported separately but combined with other complications reported as ‘post-operative complications’. The included RCTs were across different surgical specialties: breast and axillary/inguinal (19 RCTs94,96–105,107–109,111,113,115,118,120), hernia (8 RCTs172–174,178,181,182,184,185), plastic, hepatic and otolayrngology. 202,204,227

FIGURE 3.

Seroma development in all surgical specialties: fibrin sealant vs. standard care.

Patients receiving fibrin sealants rather than the control had a statistically non-significant reduced risk of developing seroma (OR 0.84, 95% CI 0.68 to 1.04; p = 0.13; I² = 12.7%, fixed-effects model). The random-effects model showed a similar result (see Appendix 8). Two of the 32 RCTs with an unclear risk of bias showed a statistically significant difference in seroma development: Mabrouk et al. 214 reported a significant benefit of fibrin sealant, whereas Lau172 reported more seroma development in patients receiving fibrin sealants.

There were some differences in how seroma was defined and at which time point it was reported; the data used in the meta-analysis were the first point at which seroma was reported for the hernia RCTs. 144,172–174,178,181,184,185 Jain et al. 99 had two control groups: (1) no drain and no fibrin, and (2) drain and no fibrin. The first was deemed to be most appropriate for analysis as the only difference from the intervention group was the addition of fibrin. In Moore et al. 111 three intervention groups were reported in which different amounts of fibrin were used; therefore, the control group was divided into three and compared accordingly. Olmi et al. 185 reported one intervention group and three control groups which were different types of fixation, and so the fibrin group was divided into three and compared with each control group. In cases where seroma development was reported at different time points, only the development at the first time point was included in the analysis.

Subgroup analysis was conducted for two surgical specialties that were deemed comparable: breast surgery RCTs (Figure 4) and hernia RCTs (Figure 5). In breast RCTs, patients (n = 1277) receiving fibrin sealants had a statistically non-significantly reduced risk of developing seroma than control group patients (OR 0.84, 95% CI 0.64 to 1.11; p = 0.26; I² = 0.0%, fixed-effects model). In hernia RCTs, patients (n = 1592) receiving fibrin sealants had no difference in risk of developing seroma than control group patients (OR 0.98, 95% CI 0.66 to 1.46; p = 1.00; I² = 0.0%, fixed-effects model). The random-effects models showed similar results for these subgroups (see Appendix 8). These results are broadly consistent with the primary analysis that showed an apparent trend of a decrease in the risk of seroma development in patients receiving fibrin sealants.

FIGURE 4.

Seroma development in breast surgery: fibrin sealant vs. standard care.

FIGURE 5.

Seroma development in hernia surgery: fibrin sealant vs. standard care.

Haematoma development

Development of haematoma was reported in 26 RCTs, of which 24 were included in the meta-analysis (Figure 6). Two RCTs were excluded from the primary analysis for following reasons: Prado et al. 187 reported only median, quartiles and ranges across a 12-month period and Lovisetto et al. 180 reported haematoma and seroma combined and not separately. The 24 included RCTs65,70,90,100,101,103,110,111,113,118,141,143,144,148,173,177,181,185,188,221,222,227,228,231 (n = 2665) were within the following surgical specialties: breast and axillary/inguinal lymph nodes, hernia, plastic, orthopaedic, upper GI tract, oral and otolaryngology. Patients receiving fibrin sealant had a statistically significant lower risk of developing haematomas than control patients (n = 2403, OR 0.62, 95% CI 0.44 to 0.86; p = 0.01; I² = 0%, fixed-effects model). The random-effects model showed a similar result (see Appendix 8).

FIGURE 6.

Haematoma development in all surgical specialties: fibrin sealant vs. standard care.

Overall haematoma development was calculated by combining groin and axillary haematomas in Swan et al. ,113 and by combining hepatic and post procedural haematomas in Bektas et al. 65 Reviewers checked that different haematomas did not occur in the same person and, therefore, that data were not double-counted. Data from multiple intervention and control groups in Olmi et al. 185 and Moore et al. 111 were dealt with in the same manner as in the seroma analysis. As two different fibrin groups and two controls were reported in Aguilera et al. 143 it was decided for analysis purposes to compare fibrin glue to control and Tissucol to tranexamic acid.

Subgroup analyses were conducted for the following areas: breast (Figure 7), hernia (Figure 8), orthopaedics (Figure 9) and upper GI tract (Figure 10). A statistically significant reduction in the risk of haematoma formation due to fibrin use occurred only in a meta-analysis of four hernia surgery RCTs173,177,181,185 (n = 794, OR 0.22, 95% CI 0.06 to 0.74; p = 0.01; I² = 0%, fixed-effects model). There was a trend of a decreased risk of haematoma when using fibrin sealants within the remaining surgical specialties, but these reductions were not statistically significant: p = 0.87 (seven breast RCTs,100,101,103,110,111,113,118 n = 588), p = 0.20 (four orthopaedic RCTs,141,143,144,148 n = 347) and p = 0.88 (three upper GI tract RCTs,65,70,90 n = 243). The random-effects models showed similar results (see Appendix 8).

FIGURE 7.

Haematoma development in hernia surgery: fibrin sealant vs. standard care.

FIGURE 8.

Haematoma development in breast surgery: fibrin sealant vs. standard care.

FIGURE 9.

Haematoma development in orthopaedic surgery: fibrin sealant vs. standard care.

FIGURE 10.

Haematoma development in upper GI tract surgery: fibrin sealant vs. standard care.

A post hoc analysis including 48 RCTs65,70,90,94,96–105,107–111,113,115,118,120,141,143,144,148,172–174,177,178,180–182,184,185,188,206,212,214,221,222,227,228,230,231,250 (n = 4876) was carried out to explore impact of combining seroma and haematoma as an outcome (Figure 11). The study by Lovisetto et al. ,180 who reported only combined haematoma and seroma rates (and, therefore, was excluded from the haematoma analysis), was included in the combined analysis. This meta-analysis demonstrated a statistically significant reduction in the risk of developing seroma or haematoma with fibrin sealant compared with control (OR 0.77, 95% CI 0.64 to 0.92; p = 0.01; I² = 6.7%, fixed-effects model). The random-effects model showed a similar result (see Appendix 8).

FIGURE 11.

Seroma and haematoma development combined in all surgical specialties: fibrin sealant vs. standard care.

Secondary dichotomous outcomes

The following sections present the five dichotomous outcomes: haemorrhage (bleeding), reoperation, infections, use of analgesics and complications arising from the use of drains.

Haemorrhage (bleeding)

Haemorrhage was reported in 19 RCTs, of which 1759,62,74,75,84,85,99,102,134,135,158,168,177,197,199,205,250 (n = 2125) were included in the meta-analysis (Figure 12). Two RCTs (Neuss et al. 118 and Jackson et al. 193) were excluded because they reported that none of the participants experienced post-operative bleeding. The included RCTs were within several surgical specialties: cardiothoracic,134,135,205 breast and axillary/inguinal lymph nodes,99,102 hernia,177 vascular,197,199 eye,158,168 upper GI tract62,74,75,84,85,250 and urology. 59 There was statistically non-significant reduction in risk of post-operative bleeding between patients receiving fibrin sealants versus standard care (OR 0.64, 95% CI 0.40 to 1.02; p = 0.08; I² = 0%, fixed-effects model). The random-effects model showed a similar result (see Appendix 8).

FIGURE 12.

Haemorrhage (bleeding) in all surgical specialties: fibrin sealant vs. standard.

Randomised controlled trials that did not report the number of patients and only reported bleeding as total number of blood units were also excluded. In Jain et al. 99 two control groups (no drain and no fibrin; drain and no fibrin) were reported and the first group was deemed to be most appropriate for analysis as the only difference between the intervention and control group was the addition of fibrin.

Subgroup analyses were conducted for the following surgical specialties: upper GI tract (Figure 13), cardiothoracic lung (Figure 14), breast (Figure 15), vascular (Figure 16) and eye (Figure 17). There was a statistically significant reduction in risk of haemorrhage when using fibrin sealants compared with standard care within upper GI tract surgery (six RCTs,62,74,75,84,85,250 n = 995, OR 0.39, 95% CI 0.19 to 0.80; p = 0.01; I² = 0%, fixed-effects model) and no significant difference in the remaining surgical specialties: p = 0.84 (three cardiothoracic lung RCTs,134,135,205 n = 501), p = 0.69 (two breast RCTs,99,102 n = 153), p = 0.76 (two vascular RCTs,197,199 n = 339) and p = 0.61 (two eye RCTs,158,168 n = 80). The random-effects models showed similar results (see Appendix 8).

FIGURE 13.

Haemorrhage (bleeding) in upper GI tract surgery: fibrin sealant vs. standard.

FIGURE 14.

Haemorrhage (bleeding) in cardiothoracic lung surgery: fibrin sealant vs. standard care.

FIGURE 15.

Haemorrhage (bleeding) in breast surgery: fibrin sealant vs. standard care.

FIGURE 16.

Haemorrhage (bleeding) in vascular surgery: fibrin sealant vs. standard care.

FIGURE 17.

Haemorrhage (bleeding) in eye surgery: fibrin sealant vs. standard care.

Reoperation

A total of 20 RCTs reported reoperation as an outcome, of which 1560,77,85,86,93,101,107,116,125,135,138,140,143,237,239 were included in the meta-analysis (Figure 18). Five RCTs were excluded for the following reasons: Droghetti et al. ,124 Milne et al. 201 and Dimo et al. 80 reported that none of the trial patients had a reoperation; Bulbuller et al. 92 reported that the only patients who had a reoperation were in an additional intervention arm and not in the fibrin or standard care arms; and Moser et al. 126 did not report any data for the fibrin group.

FIGURE 18.

Reoperation in all surgical specialties: fibrin sealant vs. standard care.

The RCTs included in the meta-analysis reported fibrin use within four surgical specialties: cardiothoracic lung and heart, breast and axillary/inguinal lymph nodes, orthopaedics and neurosurgery. Patients receiving fibrin sealants had a statistically significant lower risk of reoperation than those in the control group (15 RCTs,60,77,85,86,93,101,107,116,125,135,138,140,143,237,239 n = 3789, OR 0.65, 95% CI 0.48 to 0.87; p ≤ 0.01; I² = 0%, fixed-effects model). The random-effects model showed a similar result (see Appendix 8).

A subgroup analysis was conducted for the following surgical specialties: upper GI tract (Figure 19), cardiothoracic lung (Figure 20), cardiothoracic heart (Figure 21) and breast (Figure 22). The decrease in reoperations associated with using fibrin sealants was only statistically significant in upper GI tract (four RCTs,77,85,86,93 n = 455, OR 0.43, 95% CI 0.27 to 0.70; p = 0.0009; I² = 51.4%, fixed-effects model). There was a statistically non-significant decrease in the risk of reoperation in cardiothoracic heart surgery (three RCTs,60,138,140 n = 1578; OR 0.71, 95% CI 0.43 to 1.19; p = 0.24; I² = 0%, fixed-effects model), whereas in cardiothoracic lung surgery (two RCTs,125,135 n = 451; OR 1.38, 95% CI 0.47 to 4.04; p = 0.76; no I², fixed-effects model) and breast surgery (three RCTs,101,107,116 n = 191; OR 1.21, 95% CI 0.51 to 2.90; p = 0.83; I² = 0%, fixed-effects model) there was a non-significant increase in risk of reoperation for fibrin sealant compared with standard care.

FIGURE 19.

Reoperation in upper GI tract surgery: fibrin sealant vs. standard care.

FIGURE 20.

Reoperation in cardiothoracic lung surgery: fibrin sealant vs. standard care.

FIGURE 21.

Reoperation in cardiothoracic heart surgery: fibrin sealant vs. standard care.

FIGURE 22.

Reoperation in breast surgery: fibrin sealant vs. standard care.

Infection

Wound infections were reported by 30 RCTs, of which 2514,59,60,64,72,73,75,83,84,86,96,99,102,111,118,120,122,130,135,143,170,178,198,230,250 were included in meta-analysis (Figure 23). The RCTs included in the meta-analysis reported fibrin use within four surgical specialties: upper GI tract (eight RCTs),64,72,73,75,83,84,86,250 breast (seven RCTs),96,99,102,111,118,120,122 cardiothoracic lung (two RCTs)130,135 and heart (one RCT),60 orthopaedic knee (two RCTs),14,143 vascular (one RCT),198 eye (one RCT),170 urology (one RCT),59 oral (one RCT)230 and hernia (one RCT). 178 The following five RCTs were excluded because they reported no wound infections in the fibrin sealant and standard care group: Udén et al. ,98 Sabatini et al. ,148 Danielsen et al. ,79 Lovisetto et al. 180 and Lau. 172 Patients receiving fibrin sealants did not have a statistically significant lower risk of wound infection than control patients (25 RCTs, n = 3902, OR 0.76, 95% CI 0.54 to 1.06; p = 0.12; I² = 0%, fixed-effects model). The random-effects model showed a similar result (see Appendix 8).

FIGURE 23.

Infections in all surgeries: fibrin sealant vs. standard care.

A subgroup analysis was conducted for the following surgical specialties: upper GI tract (Figure 24), breast (Figure 25), cardiothoracic lung (Figure 26) and orthopaedic knee (Figure 27). The risk of wound infection appeared not to be statistically significantly different in upper GI tract surgery (n = 917, OR 1.15, 95% CI 0.59 to 2.27; p = 0.81; I² = 0%, fixed-effects model), cardiothoracic lung surgery (n = 484, OR 0.34, 95% CI 0.05 to 2.16; p = 0.43; I² = 0%, fixed-effects model), breast surgery (n = 418, OR 0.95, 95% CI 0.50 to 1.81; p = 0.99; I² = 0%, fixed-effects model) or orthopaedic surgery (n = 224, OR 1.00, 95% CI 0.22 to 4.51; p = 0.70; I² = 0%, fixed-effects model).

FIGURE 24.

Infections in upper GI tract surgery: fibrin sealant vs. standard care.

FIGURE 25.

Infections in breast surgery: fibrin sealant vs. standard care.

FIGURE 26.

Infections in cardiothoracic lung surgery: fibrin sealant vs. standard care.

FIGURE 27.

Infections in orthopaedic knee surgery: fibrin sealant vs. standard care.

Use of analgesics

Three RCTs133,217,222 reported on use of analgesics, but the data were too heterogeneously reported for meta-analysis. Belboul et al. 133 (cardiothoracic lung) reported on the number of days of post-operative thoracic epidural analgesia, which was 2 days in the fibrin group and 3 days in the standard care group. Altomare et al. 217 (colorectal) reported that no patients were on analgesics in the fibrin group and almost all patients in the standard care group received analgesics. Cormio et al. 222 (kidney) reported on the number of doses of analgesic required during the first 24 hours post operation, which was 1.2 [standard deviation (SD) 1.69] in the fibrin group and 1.17 (SD 1.56) in the control group.

Complications arising from the use of drains

No RCTs reported on complications arising from the use of drains.

Continuous secondary outcomes

Continuous outcomes were analysed separately for each surgical area for RCTs with similar interventions and comparators as the type of intervention (e.g. staples vs. stitches). The following continuous outcomes are reported below: duration of operation, length of hospital stay, duration of drainage, pain levels and health-related quality of life.

Duration of operation (minutes)

Duration of operation was reported in the following surgical specialties: upper GI tract (gastric and liver), eye and hernia.

Upper gastrointestinal surgery

Gastric surgery

Mean duration of operation was reported in five gastric surgery RCTs,62,88–90,92 of which two were included in the meta-analysis88,90 (Figure 28). As operation time was expected to be dictated by the type of surgery and interventions, only Sroka et al. 90 and Musella et al. ,88 who reported on use of fibrin in laparoscopic sleeve gastrectomies, were comparable. Sroka et al. 90 compared sealant application with both sutures and not applying sealant and Musella et al. 88 compared fibrin sealant with no sealant. A non-significantly shorter mean time of –2.03 minutes (95% CI –4.12 to 0.14 minutes; p = 0.07) was found for fibrin sealant versus no sealant (n = 198).

FIGURE 28.

Mean duration of gastric surgery in minutes: fibrin sealant vs. no sealant.

Three RCTs were excluded from the meta-analysis: Pilone et al. 89 compared fibrin sealant with no sealant, Silecchia et al. 62 compared sealant application with sutures and Bulbuller et al. 92 compared sealant application with both sutures and not applying sealant. SDs were reported only by Silecchia et al.,62 who investigated the use of fibrin in laparoscopic gastric bypass and reported no statistically significant difference in operative time. Challenges faced in interpreting these data are that duration of operation was not explicitly defined in the papers and the type of sealant applied may have an effect on the time taken.

Liver surgery

Mean duration of surgery was reported by four RCTs68–71 using fibrin in hepatic resection surgery: Liu and Liu69 and Noun et al. 70 seemed comparable as hepatic resection was carried out without liver mobilisation (Figure 29). Without liver mobilisation, the MD of the duration of surgery for fibrin sealant compared with standard care is a decrease of 14 minutes (two RCTs,69,70 n = 117, 95% CI –54.2 to 24.3 minutes; p = 0.46), but this is not statistically significant.

FIGURE 29.

Mean duration of hepatic resection without liver mobilisation in minutes: fibrin sealant vs. standard care.

In Figueras et al. ,71 liver mobilisation was carried out in both intervention and comparator groups. Uetsuji et al. 68 had three groups: (1) liver mobilisation and no sealant, (2) liver mobilisation with sealant and (3) no liver mobilisation or sealant. Figueras et al. 71 and the ‘liver mobilisation’ groups were combined in a separate meta-analysis. In liver with mobilisation, the MD increased by 19.07 minutes (two RCTs,68,71 n = 364, 95% CI 2.75 to 35.38 minutes; p = 0.02) for fibrin sealant compared with standard care (Figure 30). This result indicates a statistically significant increase in surgery time associated with the use of fibrin sealants compared with standard care in hepatic resection with liver mobilisation.

FIGURE 30.

Mean duration of hepatic resection with liver mobilisation in minutes: fibrin sealant vs. standard care.

Eye surgery

Duration of surgery was reported in 12 RCTs157–163,165,166,168,169,171 that all compared fibrin sealant with sutures and eight RCTs were included in the meta-analysis (Figure 31). Three RCTs159,160,169 did not report variability around the means and, thus, were excluded from the analysis.

FIGURE 31.

Duration of eye surgery in minutes: fibrin sealant vs. sutures.

The mean duration was statistically significant shorter in the fibrin group than the sutures group, with a MD of –12.13 minutes (95% CI –12.59 to –11.67 minutes; p < 0.01; I² = 99.1%, fixed-effects model, eight RCTs,157,158,161,163,165,166,168,171 n = 519). The high level of heterogeneity was explored by sequentially excluding individual RCTs to identify if the potential cause of the heterogeneity was caused by any individual RCT. This was found not to be the case as I² always remained > 90%. The random-effects model showed a MD of –17.19 minutes (95% CI –23.35 to –12.50 minutes; p < 0.0001; I² = 99.1%, see Appendix 8). Furthermore, the RCTs excluded from the meta-analysis also reported a shorter mean duration of surgery in the fibrin group than the sutures group: Hall et al. 160 (12.04 vs. 26.04 minutes, respectively), Bahar et al. 159 (16 vs. 20 minutes, respectively) and Bahar et al. 169 (16 vs. 28 minutes, respectively).

Hernia surgery

Five RCTs175,176,178,180,184 reported mean duration of surgery, of which four176,178,180,184 reported means and SDs and were included in two separate meta-analyses. Campanelli et al. 176 and Damiano et al. 184 compared fibrin sealant with sutures (Figure 32). Surgery time was statistically significantly shorter for fibrin sealant than sutures in the meta-analysis (n = 784), with a MD of –2.56 minutes (95% CI –3.57 to –1.56 minutes; p < 0.01). Lovisetto et al. 180 and Chan et al. 178 compared fibrin with staples (Figure 33). Surgery time was statistically significantly longer with fibrin than with staples (n = 326), with a MD in surgery time of 13.22 minutes (95% CI 11.59 to 15.26 minutes; p < 0.01). The excluded RCT175 reported on a using self-gripping mesh instead of fibrin and, therefore, could not be compared with either intervention.

FIGURE 32.

Duration of hernia surgery in minutes: fibrin sealant vs. sutures.

FIGURE 33.

Duration of hernia surgery in minutes: fibrin sealant vs. staples.

Length of hospital stay (days)

Length of hospital stay was reported in the following surgical specialties: upper GI tract (pancreas, gastric and bowel), cardiothoracic (lung and heart), breast and joint (knee).

Upper gastrointestinal surgery

Pancreatic surgery

Three RCTs81,83,86 reported mean length of hospital stay for pancreatic surgery when using fibrin sealant and two83,86 were included in the meta-analysis (Figure 34). The study by Carter et al. 81 was excluded because the authors did not report variability around the mean. Fibrin sealants statistically significantly decreased hospital stay for fibrin sealant compared with standard care in a meta-analysis (n = 181), with a MD of –1.40 days (95% CI –1.72 to –1.09 days; p < 0.01). Carter et al. 81 reported that mean hospital stay was shorter in the fibrin sealant group (6.4 days) than in the control group (7.3 days), which is consistent with the results of the meta-analysis.

FIGURE 34.

Length of hospital stay in days in pancreatic surgery: fibrin sealant vs. standard care.

Gastric and bowel surgery

Three RCTs62,88,89 reported mean length of hospital stay: two for surgery around the gastric region88,89 and one for stay after bowel surgery,62 utilising fibrin sealant. The three RCTs were considered sufficiently similar to be analysed together; however, Pilone et al. 89 did not report variability around the mean and was therefore excluded. Silecchia et al. 62 and Musella et al. 88 were combined in meta-analysis (Figure 35). There was not a statistically significant increase in hospital stay for fibrin sealant compared with standard care in the meta-analysis (n = 420), which had a MD of 0.04 days (95% CI –0.34 to 0.42 days; p = 0.82). Pilone et al. 89 reported a mean hospital stay of 6.5 days and 7 days for the fibrin sealant and control groups, respectively.

FIGURE 35.

Length of hospital stay in days in pancreatic surgery: fibrin sealant vs. standard care.

Cardiothoracic surgery

Lung surgery

Six RCTs124,125,127,128,130,136 reported mean hospital stay for lung surgery and were considered similar enough to be included in a meta-analysis. However, only three RCTs127,130,136 reported variability around the mean and were analysed (Figure 36). Mean length of hospital stay was statistically significantly reduced for fibrin sealant compared with standard care in the meta-analysis (n = 269), with a MD of –1.37 days (95% CI –1.93 to –0.81 days; p < 0.01; I² = 91.9%). However, there is a high level of heterogeneity between the RCTs, and the significant result becomes non-significant in a random-effects meta-analysis (MD –1.20 days, 95% CI –3.22 to 0.81 days; p = 0.24). The studies excluded from the meta-analysis reported a lower mean hospital stay for the fibrin group than the control group: Fabian et al. 128 reported 4.6 versus 4.9 days, respectively; Droghetti et al. 124 reported 11 versus 14.3 days, respectively; and Anegg et al. 125 reported 6.2 versus 7.7 days, respectively.

FIGURE 36.

Length of hospital stay in days in cardiothoracic lung surgery: fibrin sealant vs. standard care.

Heart surgery

Tavilla et al. 60 (n = 1436) reported a mean length of hospital stay of 5.99 days (SD 3.95 days) and 6.07 days (SD 4.21 days) between fibrin and control groups, respectively, and p-value of 0.71 indicating no statistically significant difference.

Breast surgery

Ten RCTs reported mean hospital stay following breast surgery using fibrin sealants, of which eight104,106–109,112,115,116 were included in the meta-analysis (Figure 37). Two RCTs were excluded for the following reasons: Udén et al. 98 did not report variability around the mean and Jain et al. 99 did not report mean duration separately for two of the groups. Mean length of hospital stay was statistically significantly reduced in the meta-analysis (n = 440), with a MD of –0.73 days (95% CI –0.95 to –0.50 days; p < 0.01; I² = 88.7%). The high level of heterogeneity was explored by sequentially excluding individual RCTs to identify if the potential cause of the heterogeneity was caused by any individual RCT. This was found not to be the case as I² always remained > 80%. However, the statistically significant result became non-significant in a random-effects meta-analysis (MD –0.87 days, 95% CI –1.75 to 0.01 days; p = 0.05).

FIGURE 37.

Length of hospital stay in days in breast surgery: fibrin sealant vs. standard care.

Joint surgery (knee)

Four RCTs reported mean hospital stay following knee surgery using fibrin sealants, of which three143,145,149 were included in the meta-analysis (Figure 38). Molloy et al. 147 was excluded from the meta-analysis because they did not report variability around the mean. There was no significant effect on the mean duration of hospitalisation for knee surgery for fibrin sealant compared with standard care in the meta-analysis (n = 251), giving a MD of 0.07 days (95% CI –0.74 to 0.88 days; p = 0.87; I² = 0%, fixed-effects model).

FIGURE 38.

Length of hospital stay in days for knee surgery: fibrin sealant vs. standard care.

Duration of drainage

Duration of drainage was reported in the following surgical specialties: breast and axillary lymph nodes, liver and lung surgery.

Breast and axillary lymph nodes

A total of 15 RCTs reported mean duration of drainage, of which 1396,102,104–107,109,110,112,115–117,251 were included in the meta-analysis (Figure 39). Two RCTs did not report variability around the means97,123 and were excluded from the meta-analysis. In the meta-analysis (n = 953), there was a statistically significantly lower mean number of days of drainage of –0.50 days (95% CI –0.68 to –0.33 days; p < 0.01; I² = 90.6%, fixed-effects model) when fibrin sealant was used than standard care. The high level of heterogeneity was explored by sequentially excluding individual RCTs to identify if the potential cause of the heterogeneity was caused by any individual RCT. This was found not to be the case as I² always remained > 90%. However, the random-effects model showed an increased MD of –1.06 days (95% CI –1.69 to –0.42 days; p = 0.01; see Appendix 8).

FIGURE 39.

Duration of drainage in days in breast and axillary lymph nodes surgery: fibrin sealant vs. standard care.

Liver surgery

Mean duration of drainage after liver surgery was reported by four RCTs65,69,74,75 and combined in a meta-analysis (Figure 40). In the meta-analysis (n = 202) there was a not a statistically significant difference in the number of drainage days for fibrin sealant compared with standard care, with a MD of –0.27 days (95% CI –0.82 to 0.27 days; p = 0.33; I² = 0%, fixed-effects model).

FIGURE 40.

Duration of drainage in days for liver surgery: fibrin sealant vs. standard care.

Lung surgery

Mean duration of drainage after lung surgery was reported by five RCTs126,127,130,136,137 that were combined in a meta-analysis (Figure 41). In the meta-analysis (n = 399) there was a statistically significant lower number of drainage days for fibrin sealant than standard care, with a MD of –0.46 days (95% CI –0.53 to –0.39 days; p < 0.01; I² = 91%, fixed-effects model). The high level of heterogeneity was explored by sequentially excluding individual RCTs to identify if the potential cause of the heterogeneity was caused by any individual RCT. This was found not to be the case as I² always remained > 80%. The random-effects model also showed a statistically significant MD of –2.10 days (95% CI –3.65 to –0.56 days; p = 0.01; see Appendix 8).

FIGURE 41.

Duration of drainage in days for lung surgery: fibrin sealant vs. standard care.

Pain levels

Pain was reported by 20 RCTs in six surgical specialties: breast,95,99,101 joint,142,147,150 ENT,187,190,192 plastic and reconstructive,209,211 eye157,159,161,165,166,168,169,171 and urology. 222 The large differences in the different scales used, time points at which assessments took place and lack of variability data did not permit a meta-analysis. When RCTs measured pain at different time intervals, pain is reported for the first mentioned measurement point after surgery (Table 21).

TABLE 21 - Pain levels in included RCTs

NR, not reported.

The patient received the intervention and control on different body areas. Therefore, different body parts were randomised to receive either the intervention or control.

Absolute values not reported.

Study (author, year)	Fibrin sealant and standard care group description	Number of patients	Pain score and variability description	Pain score	Variability around score
Breast
Jain et al., 200499	Fibrin sealant (Tisseel), no drain	29	Mean post-operative pain at 24 hours (not reported separately for Tisseel, no drain and no glue, no drain groups)	3.2	SD 0.9
	No glue, no drain	29		3.2	SD 0.9
	No glue, drain	58		4.5	SD 1.5
Llewellyn-Bennett et al., 2012101	Fibrin sealant (Tisseel)	48	Donor-site pain visual analogue scale score over 15 days	27	Range: 0–89
	Standard closure	53		34	Range: 7–79
Zhibo and Miaobo, 200995	Fibrin sealant and lidocaine	10	Post-operative pain during first week post operation (day 1); self-reported pain recorded on a scale of 0–3, where 0 = no pain, 1 = light pain, 3 = worst pain	1	NR
	Standard care (lidocaine only)	10		9	NR
	Fibrin sealant only	10		10	NR
Joint (knee)
Skovgaard et al., 2013150	Fibrin sealant (EVICEL), spray	24	Visual analogue scale score for rest and flexion at day 1 post surgery	Rest: 22; flexion: 45	Rest: range 8.5–58; flexion: range 22–71
	Standard care (saline)	24		Rest: 26; flexion: 44	Rest: range 12–51; flexion: range 29–67
Molloy et al., 2007147	Fibrin sealant (Quixil)	50	Pain scores at 6 hours using a 100-mm visual analogue scale, in which 0 represented no pain and 100 the most severe pain	17.6	15.9
	Tranexamic acid	50		19.4	17.9
	Standard care	50		20.03	20.4
Heyse et al., 2014142	Fibrin sealant spray	98	Pain (on visual analogue scale) at 6 weeks	4.3	NR
	Standard care	100		3.9	NR
ENT (nose)
Vaiman et al., 2006192	Fibrin sealant (Quixil)	40	Visual analogue scale pain scores at peak for saliva swallow, normal swallow, drinking and dysphagia severity score	Approximately 6.5–7.0	NR
	Standard care (electrocautery)	40		Approximately 6.8–7.6	NR
Prado et al., 2006187	Fibrin sealant (Beriplast)	11	Pain (10-cm visual analogue scale)	4	25% quartile: 3; 75% quartile: 4
	Standard care	11		4	25% quartile: 3; 75% quartile: 5
Yu et al., 2014190	Fibrin sealant spray	41	Pain during packing; pain on removal of packing	4.2; 4.5	1.4; 1.0
	Standard care (sponge packing)	Within patienta		3.1; 8.3	0.9; 1.1
Plastic and reconstructive
Danielsen et al., 2008209	Fibrin sealant (Vivolution)	20/19	Pain score on day 5 post surgery	3	Range: 2.0–5.0
	Standard care (gauze and pressure)	20		4	Range: 3.0–5.0
Healy et al., 2013211	Fibrin sealant (Tisseel)	20	Mean daily pain score at 14 days post surgery	0.42	95% CI 0.19 to 0.65
	Mefix self-adhesive fabric dressing	20		1.6	95% CI 1.11 to 2.08
Eye
Rubin et al., 2011166	Fibrin sealant	21	Overall mean post-operative pain as recorded on visual analogue scale	5.1	SD 1.26
	Standard care (sutures)	26		4.77	SD 1.21
Uy et al., 2005168	Fibrin sealant (Beriplast)	11	Pain on day 1; using a five-point scale adapted from Lim-Bon-Siong et al.:252 0 = none, no pain; 1 = very mild, presence of pain but easily tolerated; 2 = mild, pain causing some discomfort; 3 = moderate, pain that partially interferes with usual activity or sleep; 4 = severe, pain that completely interferes with usual activity or sleepb	≈2.2	NR
	Standard care (sutures)	11		≈3.1	NR
Bahar et al., 2007169	Fibrin sealant (Quixil)	42	Mean pain score on day 1 post surgery; grading symptoms and signs on a scale of 0–4a	≈37	NR
	Standard care (sutures)	39		≈66	NR
Malik and Kumar, 2010171	Fibrin sealant (Tisseel duo-quick)	25	Pain score, based on Wong Baker FACES® Pain Rating Scale253	0.44	SD 0.583
	Standard care (sutures)	25		3.32	SD 0.802
Kucukerdonmez et al., 2010157	Fibrin sealant	32	Five-point scale assessment of degree of paina	≈2.4	≈1
	Standard care (Vicryl sutures)	38		≈3.6	≈1
Bahar et al., 2006159	Fibrin sealant (Quixil)	39	Mean pain score on day 2 post surgery; grading symptoms and signs on a scale of 0–4a	≈48	NR
	Standard care (sutures)	26		≈22	NR
Karalezli et al., 2008161	Fibrin sealant (Tisseel)	25	Pain on day 1 post surgery using a five-point scale, adapted from Lim-Bon-Siong et al.252: 0 = none, no pain; 1 = very mild, presence of pain but easily tolerated; 2 = mild, pain causing some discomfort; 3 = moderate, pain that partially interferes with usual activity or sleep; 4 = severe, pain that completely interferes with usual activity or sleepb	≈2.5	NR
	Standard care (sutures)	25		≈3.1	NR
Ratnalingam et al., 2010165	Fibrin sealant	68	Median pain score day 1 post surgery	1	NR
	Standard care (sutures)	69		2	NR
Urology
Cormio et al., 2012222	Fibrin sealant (TachoSil patch)	49	Visual analogue scale pain score at day 1 post operation	4.24	SD 2.32
	Standard care (nephrostomy tube)	47		4.77	SD 2.28

No data on pain assessments could be reported for five RCTs for the following reasons: Antuña et al. 155 reported values only for the entire group; Mabrouk et al. 214 reported only that ‘all of the patients suffered from pain, ecchymosis, and oedema postoperatively, but to varying degrees’; Diamond et al. 232 reported only that ‘the most common adverse event reported was abdominal pain’; Hall et al. 160 did not report values; and Pryor et al. 186 reported only ‘no significance difference for overall rate of pain or recovery (p = 0.06)’. Furthermore, eight RCTs78,107,108,151,153,221,239,250 only reported the number of patients with pain.

Health-related quality of life

No RCTs reported on health-related quality of life.

Assessment of harms

Randomised controlled trials

Ten RCTs in various surgical specialties (liver, two RCTs;73,77 kidney, two RCTs;59,221 mixed, one RCT;241 oral and maxillofacial, one RCT;231 hernia, one RCT;176 plastic and reconstructive, one RCT;208 vascular, one RCT;204 and orthopaedic, one RCT143) reported adverse events that were thought to be related to the use of fibrin sealants (Table 22). Sample sizes varied from 759 to 316176 participants. Only Fischer et al. 241 reported a death as possibly related to fibrin sealant application in upper GI tract surgery caused by a large bleed, but bleeding did not occur at the target bleeding site and no further information was provided. Other RCTs reported on various non-severe adverse events: mild cellulitis and mild seroma,231 anaemia,73 extravasation of urine,221 incision site complications204 and mild generalised skin rash. 143 Severity was unclear for the following: excessive pain, scar pain and testicular pain hydrocele in Campanelli et al. ,176 post-procedural haemorrhage in Nativ et al. 59 and antibodies to hepatitis B in Schwartz et al. 77 It was not reported how adverse events were related to the application of fibrin sealant or how severity was determined. The time when adverse events occurred after surgery was immediately in Aguilera et al. ,143 2 hours later in Nativ et al. ,59 1 and 14 days later in Hester et al. 231 and 32 days later in Saha et al. ,204 but was not reported in Fischer et al. ,241 Campanelli et al. ,176 Schwartz et al. ,77 Frilling et al. 73 and Siemer et al. 221 Furthermore, another 21 RCTs explicitly reported that there were no complications or adverse events related to fibrin. 14,62,65,67,88,94,124–127,141,142,193–195,206,207,225,227,232,238

TABLE 22 - Fibrin-related adverse events reported in RCTs

AE, adverse event; FS, fibrin sealant; SAE, serious adverse event; VH S/D 4 s-apr, ARTISS sealant.

Study (author, year)	Sample size	Surgery	Adverse event
Fischer et al., 2013241	90/141	Mixed	Of the patients who received fibrin pads, 2.7% (3/11) experienced a related or possibly related AE, compared with 6.7% (2/30) of patients who received absorbable haemostat. These events include operative haemorrhage, ascites and suspected pulmonary embolism. There was no confirmation to rule out relatedness, therefore these AEs were attributed as related to the assigned treatment Seven serious AEs resulted in death: six (5.4%) in the fibrin group and one (3.3%) in the absorbable haemostat group. One of the deaths in the fibrin pad group was considered possibly related to treatment (massive intraluminal GI bleed, although bleeding did not occur at the target bleeding site)
Hester et al., 2013231	75	Oral and maxillofacial	Two of the non-SAE were considered related to treatment: 1 patient had mild cellulitis on the side of the face treated with FS VH S/D 4 s-apr (14 days postoperatively), and 1 patient had mild seroma on postoperative day 1
Campanelli et al., 2012176	316	Hernia	Adverse events were attributed to study product in three patients in the fibrin sealant group (1.9%: one excessive pain; one scar pain; one testicular pain hydrocele)
Schwartz et al., 200477	207	Liver	One patient developed antibodies to hepatitis B after being treated with Crosseal. The patient had also received 16 units of allogeneic blood and, in view of the recognised effectiveness against hepatitis B virus of the viral inactivation techniques used in the manufacture of Crosseal, this event was considered unlikely to be related to the fibrin sealant. No further information was available regarding blood donors
Frilling et al., 200573	148	Liver	Four adverse events were considered to be possibly related to the test treatment. Three of them were considered to be serious: postoperative haemorrhage (TachoSil), abscess and pleural effusion (argon beamer), while one was considered not to be serious: anaemia (TachoSil)
Siemer et al., 2007221	185	Kidney	Two severe adverse events were related to treatments in the trial. In a subject who received TachoSil extravasation of urine, a non-serious event was reported. One patient who received standard treatment reported subileus, a serious event. The patient was treated successfully with analgesics, laxatives, and diet. Both patients recovered fully
Nativ et al., 201259	7	Kidney	One case was haemodynamically instable and post-procedural haemorrhage was observed in the drain 2 hours after surgery. This required the patient to be reoperated, and the source of bleeding was the resection area beneath the fibrin pad. The fibrin pad was removed and haemostasis was achieved using a standard surgical technique. A total of 10 units of blood were administered in the post-operative period and the patient was discharged from the hospital without sequelae
Vanscheidt et al., 2007208	225	Plastic or reconstructive	One patient was found to have a ‘certain’ adverse event (application site disorders) related to the study treatment; this was in the Bio Seed-Ss group. Two AEs (general disorders, n = 1; skin and appendages, n = 1) reported in the BioSeeds treatment group were ‘probably’ related to treatment. Six AEs (general disorders, n = 2; skin and appendages, n = 2; secondary terms, n = 2) were ‘possibly’ related
Saha et al., 2011204	73	Vascular	One non-serious AE that was considered possibly related to FS was incision site complications. The complication occurred 32 days after application of FS and raised concerns of possible graft occlusion. An angiogram indicated venous stenosis in the area of the anastomosis. The investigator stated that a causal relationship to FS was unlikely but could not be completely ruled out
Aguilera et al., 2013143	166	Orthopaedic (joint)	A 67-year-old man who received Tissucol developed a mild generalized skin rash in the immediate postoperative period. This rash resolved after the administration of an oral antihistamine and topical corticosteroid treatment

Observational studies

Eight included observational studies reported adverse events that appear to be fibrin related (Table 23). There were no reports of death or serious adverse events from the observational studies included in the systematic review. Cagatay et al. 242 and Choi et al. 244 thought that the application of too much fibrin sealant caused discomfort for patients undergoing eye surgery, but this was expected to be solved by surgeons gaining more expertise with fibrin sealant application. Jiang et al. 243 reported a slighter higher proportion of patients with graft oedema in eyes treated with fibrin sealant. In upper GI tract surgery statistically significantly more events were seen in patients treated with fibrin sealants (i.e. inflammation,245 strictures requiring dilatation246 and uncontrolled ascites247). In Marchac et al. 248 trapped pockets of air were only found in the fibrin group and Sakic et al. 249 reported more superficial sternal infections in patients treated with fibrin sealant.

TABLE 23 - Fibrin-related adverse events reported in observational studies

Study (author, year)	Sample size	Surgery	Adverse event
Cagatay et al., 2014242	103	Conjunctival autografting for pterygium surgery (eye)	One patient experienced serious discomfort post operatively as a result of excess glue. The excess was removed from the ocular surface using scissors to trim it under slit lamp biomicroscopy The development of Tenon’s cyst was not higher in patients in the fibrin group (5/53) than in the control group (3/53) in a statistically significant manner (p = 0.71)
Jiang et al., 2008243	40	Conjunctival autografting for pterygium surgery (eye)	A yellowish graft edema was observed in some eyes in the first few days post operatively, which resolved gradually and spontaneously. There were more cases of edema in the fibrin sealant group than in the sutures group (8/20 vs. 3/20, respectively). However, the difference between the two groups in graft edema development was not statistically significant (p = 0.077)
Choi et al., 2010244	126	Pars plana vitrectomy (eye)	Three patients reported discomfort, possibly caused by the application of too much glue, and two cases showed wound dehiscence, probably caused by too little solution. However, such problems can be overcome with further experience
Efthimiou et al., 2010245	474	Laparoscopic Roux-en-Y gastric bypass (upper GI tract)	Patients had an increased inflammatory response with the application of fibrin sealant, indicated by statistically significant higher temperature, white blood count and heart rate in the fibrin group compared to the two control groups (p = 0.001). There was an increased rate of fever (six patients in fibrin group vs. none in the control group) and abdominal collection (two patients in fibrin group vs. none in the control groups)
Ibele et al., 2014246	529	Laparoscopic Roux-en-Y gastric bypass (upper GI tract)	The rate of stricture requiring dilation was a significantly increased in the sealant group (11.3%, compared with 4.8% stricture rate in patients who did not receive sealant; p = 0.04) Patients in the fibrin sealant group showed a notable stricture delay with strictures occurring an average of 4.1 weeks following surgery without sealant and 9.2 weeks after surgery (p = 0.3), suggesting that the mechanism of stricture formation may have differed between the two groups
Nanashima et al., 2012247	341	Hepatobiliary pancreas surgery; hepatectomy and pancreatectomy (upper GI tract)	In the hepatectomy group, uncontrolled ascites were more frequent in the fibrin glue group (145/228) than in the non-fibrin glue group (6/94) (p < 0.05)
Marchac et al., 1994248	200	Rhytidectomy (plastic)	One complication unique to the fibrin glue treated group was the postoperative finding of trapped pockets of air. These had the appearance of small haematomas and yielded 3–5 cc of air on aspiration
Sakic et al., 2013249	418	Bilateral internal thoracic artery grafting (vascular)	The use of platelet-enriched-fibrin glue (PRF) sealant, however, was associated with more superficial sternal infections (OR: 3.7, 95% CI: 1.3 to 10.5, p = 0.02)

Regulatory body reports

Five reports from the MHRA (one report), EMA (one report) and FDA (three reports) websites reported on deaths associated with the use of fibrin sealants, as either case series or single case reports (Table 24).

TABLE 24 - Serious adverse events (deaths) reported by the MHRA, EMA and FDA

Regulatory body	Fibrin sealant name	Date	Subject	Findings	Source
MHRA254	EVICEL, Tisseel and Artiss	February 2013	Drug safety update	The MHRA notes the findings from the EMA	www.gov.uk/drug-safety-update/sprayable-fibrin-sealants-evicel-tisseel-and-artiss-updated-guidance (accessed 11 November 2015)
EMA255	Artiss, Beriplast P, EVICEL, Tisseel, Tissucol spray applications	15 March 2013	Questions and answers	Risk of air or gas embolism; recommendations for surgeons	www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Fibrinogen-containing_solutions_for_sealant_authorised_for_administration_by_spray_application/human_referral_000332.jsp&mid=WC0b01ac05805c516f (accessed 11 November 2015)
FDA256	Artiss and Tisseel	5 October 2009	Important drug warning: fatality reported	Risk of life-threatening air or gas embolism with the use of spray devices employing pressure regulator to administer fibrin sealants	www.fda.gov/biologicsbloodvaccines/safetyavailability/ucm209778.htm (accessed 11 November 2015)
FDA257	Tisseel	2014	Fatalities reported	Three deaths thought to have occurred as a result of the use of Tisseel fibrin sealant	www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/pediatricadvisorycommittee/ucm386895.doc (accessed 11 November 2015)
FDA258	Tisseel	February 2015	Medical device report analysis	An analysis of nine reports of adverse events involving one death	www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/pediatricadvisorycommittee/ucm388149.pdf (accessed 11 November 2015)

Medicines and Healthcare products Regulatory Agency

The MHRA notes the findings from the EMA, namely the number of life-threatening or fatal air embolisms. A total of six reports of such events have been reported worldwide according to the EMA – EVICEL (five reports), Tisseel (four reports), Quixil (four reports)254 – although Quixil is no longer available in the UK. In 2013, the MHRA provided updated guidance for the use of sprayable fibrin sealants. Four sprayable fibrin sealants are authorised for use in the UK:254

1. EVICEL

2. Tisseel Lyo

3. Tisseel Ready to use

4. Artiss solution for sealant, deep frozen.

European Medicines Agency

In 2012, the EMA completed a review of the safety and effectiveness of four fibrin sealants (Tisseel, Tissucol, Artiss and Beriplast P) used in spray formation. 254 The agency’s CHMP considered the evidence for the development of gas embolisms and concluded that the benefits outweigh the risks. The CHMP recommended that the wording on product information be strengthened; the manufacturers of the products should ensure that they are used with pressure regulators that do not exceed the maximum pressure necessary for the delivery of the fibrin sealant; and labelling with the recommended pressure and distance. Furthermore, the EMA report suggests that the product information should include a warning that the risk of gas embolism appears to be higher when sprayed with air than with carbon dioxide (CO₂)_. The report also recommends patients to be closely monitored for signs of possible gas embolism (heart rate, blood pressure, oxygen and CO₂ levels in blood) during procedures using sprayable fibrin sealants.

Food and Drug Administration

The FDA website contained reports of five fatalities arising from the use of fibrin sealants.

Artiss and Tisseel, 2009256

The FDA reported:

Air or gas embolism has occurred with the use of spray devices employing pressure regulator to administer fibrin sealants. This event appears to be related to the use of the spray device at higher than recommended pressures and in close proximity to the tissue surface. When applying fibrin sealants using a spray device, be sure to use the pressure within the pressure range recommended by the spray device manufacturer. In the absence of a specific recommendation avoid using pressure above 20–25 psi. Do not spray closer than the distance recommended by the spray device manufacturer. In the absence of a specific recommendation avoid spraying closer than 10–15 cm from the surface of the tissue. When spraying the fibrin sealant, changes in blood pressure, pulse, oxygen saturation and end tidal CO₂ should be monitored because of the possibility of occurrence of air or gas embolism.

Recommendations for surgeons are similar those previously mentioned for the EMA:

Specifically, the safety update includes the following instructions for sealant application using a spray device to help prevent air or gas embolism:

1. utilize spray pressure that is within the recommended guidelines by the device manufacturer

2. ensure that distance between the spray head and the application bed is within the recommended guidelines of the device manufacturer;

3. monitor patients for air or gas embolism.

EVICEL, 2010257

The FDA reported a fatal air embolism after the use of an EVICEL spray device. EVICEL was being used to arrest a haemorrhage using a spray device (wall unit) at a higher than recommended pressure. Additionally, the spray head was held at a distance from the bleeding area that was closer than the recommended guidelines suggest. The website also advises the use of fibrin sealant spray at pressures of < 20–25 pounds/inch².

Tisseel, 2014258

A safety review for Tiseel/Tissucol by the Centre for Biologics Evaluation and Research of the FDA identified three adult deaths considered likely to be associated with the use of the fibrin sealant. In one case (reference 9283933) from Columbia, a fatal thrombosis and colon necrosis was observed in a male aged 60 years. Tissucol was sprayed after a right hepatectomy. After the operation the patient underwent a repeat laparotomy and a mesenteric thrombosis was found; after a hepatectomy the patient died. Underlying liver disease is a risk factor for development of mesenteric thrombosis. In a second case (reference 9540751), from Germany (in 1990), a male experienced a fatal air embolism after gastropic sealing for the closure of a fistula. It is reported that:

. . . seconds after the Tissucol immune gas flow, the patient lost consciousness and had a cardiac arrest. Autopsy showed the right ventricle filled with air and death was assumed to be due to air embolism.

The third death associated with Tissucol (case 8815161) was of a male aged 37 years from the UK who suffered a fatal cardiac arrest during revision laminectomy. The device was held closer than the recommended distance to the tissue, with the tip of the applicator being located within the wound.

Furthermore, the FDA Manufacturer and User Safety Device Experience database reports one death of a patient who lost consciousness and experienced a cardiac arrest:

Autopsy showed the right ventricle was filled with air, and death was assumed to be due to an air embolism.

However, the source is reported to be published literature from 1990 and, as the wording is similar to that of case reference 9540751 from the safety review, the researchers of this report consider it highly likely to be a duplicate report.

Chapter 4 Discussion

Chapter 5 Conclusions

Acknowledgements

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Appendix 1 Literature search strategies

Appendix 2 Tables of study characteristics and data tables