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应用纤维蛋白密封剂预防胰腺手术后胰瘘

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Abstract

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研究背景

术后胰瘘是胰腺切除后最常见和可能危及生命的并发症之一。部分外科医生采用纤维蛋白密封剂减少术后胰瘘的发生。然而, 在胰腺手术中使用纤维蛋白密封剂是有争议的。本文是对2016年发表的Cochrane综述的一次更新。

研究目的

评估纤维蛋白密封剂在胰术后胰瘘预防的安全性、有效性和潜在的不良反应。

检索策略

我们检索了临床试验注册网站和以下生物医学数据库: Cochrane 图书馆 (2018, 4期), MEDLINE (1946 至 2018年4月12日), Embase (1980 至 2018年4月12日), SCIE (1900 至 2018年4月12日), 中国生物医学文献数据库 (CBM) (1978 至 2018年4月12日)。

标准/纳入排除标准

我们纳入所有关于接受胰腺手术受试者使用纤维蛋白胶组 (纤维蛋白胶水或纤维蛋白胶贴) 与对照组 (没有纤维蛋白密封剂或安慰剂) 比较的随机对照试验。

数据收集与分析

两名研究人员根据纳入排除标准,独立筛选、提取并评估偏倚风险。我们使用Review Manager(RevMan)进行数据分析。我们计算了二分类结局的危险比(RR)(或非常罕见的结局的优势比(OR)),和连续结局的平均差(MD),以及95%可信区间(CIS)。

主要结果

本研究,我们共纳入了11项试验,涉及1462名受试者。

纤维蛋白密封剂在胰尾切除术后胰尾残端闭合加固中的应用

我们纳入了7项研究,涉及了860名受试者。胰尾切除术后, 428 例被随机分到纤维蛋白密封剂组,432例被分到对照组。纤维蛋白密封剂可能导致术后胰瘘 (应用纤维蛋白组为19.3%;对照组为20.1%;RR=0.96, 95% CI= 0.68 ‐ 1.35;755名受试者;四项研究;低质量的证据)。纤维蛋白密封剂对导致术后死亡率的影响很少或没有差异 (0.3% 对比0.5%;OR=0.52, 95% CI=0.05 ‐ 5.03;804名受试者;六项研究;低质量的证据), 或总的术后发病率亦是如此 (28.5%对比 23.2%;RR =1.23, 95% CI= 0.97 ‐ 1.58;646名受试者;三项研究;低质量的证据)。我们不确定纤维蛋白密封剂是否能降低再手术率 (2.0% 对比 3.8%;RR= 0.51, 95% CI =0.15 ‐ 1.71;376名受试者;两项研究;非常低质量的证据)。两组之间的住院时间可能很少或没有差别 (12.1 天对比11.4 天;MD =0.32 天, 95% CI= ‐1.06 ‐ 1.70;755名受试者;四项研究;中等质量的证据)。这些研究都没有关于不良事件、 生活质量和成本效益的报道。

纤维蛋白密封剂在胰十二指肠切除术后增强胰腺吻合中的应用

我们纳入了3项研究,共有251名受试者。胰尾切除术后, 115例被随机分到纤维蛋白密封剂组,136人被分到对照组。我们不确定纤维蛋白密封剂是否能降低术后胰瘘 (2.0% 对比 3.8%;RR= 0.51, 95% CI =0.15 ‐ 1.71;57名受试者;一项研究;非常低质量的证据)。纤维蛋白密封剂对导致术后死亡率的影响很少或没有差异 (0.1% 对比 0.7%;OR =0.15, 95% CI =0.00 ‐ 7.76;251名受试者;三项研究;低质量的证据),对住院时间影响较少或没有差异 (12.8 天对比14.8 天;MD= ‐1.58 天, 95% CI= ‐3.96‐ 0.81;181名受试者;两项研究;低质量的证据)。我们不确定纤维蛋白密封剂是否能降低整体术后发病率 (33.7% 对比34.7%;RR= 0.97, 95% CI =0.65 ‐ 1.45;181名受试者;两项研究;非常低质量的证据), 不确定是否能降低再手术率 (7.6% 对比 9.2%;RR= 0.83, 95% CI =0.33‐ 2.11;181名参加者;两项研究, 非常低质量的证据)。这些研究都没有关于不良事件、 生活质量和成本效益的报道。

纤维蛋白封闭剂在胰十二指肠切除术后胰管栓塞中的应用

我们纳入两个研究,涉及351名受试者:胰十二指肠切除术后,188名被随机分到纤维蛋白封闭剂组,163例被随机分到对照组。纤维蛋白密封剂对术后死亡率的影响很少或没有差异 (8.4% 对比 6.1%;OR =1.41,95% CI =0.63 ‐ 3.13;351名受试者;两项研究;低质量证据) ,对住院时间的影响也是同样的 (17.0 天对比16.5 天;MD =0.58 天, 95% CI= ‐5.74 ‐ 6.89;351名受试者;两项研究;低质量的证据)。我们不确定纤维蛋白密封剂是否能降低术后发病率 (32.0% 对比 27.6%;RR =1.16, 95% CI =0.67 ‐ 2.02;351名受试者;两项研究;非常低质量的证据),及再手术率 (13.6% 对比 16.0%;RR=0.85, 95% CI =0.52 ‐ 1.41;351名受试者;两项研究;非常低质量的证据)。在一项研究中报道了严重的不良事件:在3个月的随访 (33.7% 纤维蛋白密封剂组对比10.8% 对照组;29名受试者对比9名受试者) 和12个月随访 (33.7% 纤维蛋白密封剂组对比14.5% 对照组;29 名受试者对比12名受试者)中,纤维蛋白密封胶用于胰管栓塞组,有更多的受试者患上糖尿病。这些研究都没有关于不良事件、 生活质量和成本效益的报道。

作者结论

根据现有的证据, 认为纤维蛋白密封剂对远端胰腺患者术后胰瘘的影响不大或没有。纤维蛋白密封剂对胰十二指肠切除术后胰瘘预防的影响是不确定的。

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Plain language summary

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应用外科组织粘合剂预防胰腺手术后胰瘘

系统综述问题

外科组织粘合剂是否能减少胰腺手术后胰瘘的发生?

背景

术后胰瘘是胰腺癌或胰腺炎手术后常见的并发症。该消化腺位于上腹部的后部。 手术包括将胰腺从附近的肠道切开,并切除胰腺头,然后重新吻合,使含有消化酶的胰液进入消化系统。胰腺残端通常留在手术切除胰尾后愈合。当重新吻合或残端无法正常愈合时, 就会出现瘘管, 从而造成胰腺中的胰腺汁泄漏至腹部组织。这会延缓手术后的恢复, 并经常需要进一步的治疗, 以确保完全愈合。纤维蛋白封闭剂(外科组织粘合剂)是否能够在胰腺手术后起到减少术后胰瘘的作用是有争议的。

研究特征

我们检索了在2018年4月之前的所有相关的、实施良好的研究报告。我们纳入了十一项研究,这些研究可以分为三项比较。首先,十一项试验中的七项,将共860位受试者随机分为使用纤维蛋白密封剂 (428 人) 增强胰残端闭合组,和未使用纤维蛋白密封剂 (432人) 增强胰残端闭合组。第二,有三项研究,共251名受试者接受了“惠普尔手术”(手术切除胰头),将其随机分为使用了纤维蛋白封闭剂组(115名),和未使用纤维蛋白封闭剂(136名)强化胰腺残端闭合组。第三, 有两项研究随机,共351人接受 "惠普" 手术,并随机分为使用纤维蛋白密封剂(188 人)用于胰管堵塞,和未用纤维蛋白密封剂 (163 名)用于胰管堵塞。

主要结果

纤维蛋白密封剂在胰尾切除术后胰残端闭合加固中的应用

在手术切除胰尾后, 纤维蛋白密封剂用于残端闭合加固术后胰瘘或术后死亡可能没有什么差别。

纤维蛋白密封剂在胰十二指肠切除术后胰腺吻合加固中的应用

我们不确定纤维蛋白密封剂是否能够改善"惠普" 手术后胰管吻合术的胰瘘的发生。纤维蛋白密封剂在术后死亡方面可能有少许差别,甚至没有差别。

纤维蛋白密封剂在"惠普" 手术后的胰导管栓塞中的应用

在所有的研究中均未报告术后胰瘘。当应用于"惠普" 手术后的胰管栓塞时,纤维蛋白密封剂在术后死亡方面可能有少许差别,甚至没有差别。

纤维蛋白密封剂对于手术切除胰尾的患者的术后胰瘘,可能有很少或根本没有益处。我们不能从我们的结果中判断纤维蛋白密封剂是否对术后胰瘘具有显著的影响, 因为样本量小, 结果不准确。

证据质量

大多数纳入的研究,在实施过程或报告方面存在一些缺陷。总的来说,证据的质量在非常低到中等之间。

Authors' conclusions

Implications for practice

Based on the current available evidence, fibrin sealants may have little or no effect on postoperative pancreatic fistula or mortality in people undergoing distal pancreatectomy. The effects of fibrin sealants on the prevention of postoperative pancreatic fistula are uncertain in people undergoing pancreaticoduodenectomy.

Implications for research

  1. Future studies should assess the effect of fibrin sealants for people undergoing pancreaticoduodenectomy.

  2. Future studies should report the rate and the grade of the postoperative pancreatic fistula according to the updated definition of the International Study Group on Pancreatic Fistula (Bassi 2005; Bassi 2017).

  3. Future randomized studies should use adequate methods of randomization and allocation concealment. Future studies need to employ blinding of participants and outcome assessors.

  4. The long‐term occlusion of the pancreatic duct by any means may cause atrophy of the pancreatic parenchyma and chronic pancreatitis in the occluded segment; consequently, the risk of diabetes mellitus with this procedure must be considered (Spanier 2008; Tran 2002).

Summary of findings

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Summary of findings for the main comparison. Application of fibrin sealants to pancreatic stump closure reinforcement for the prevention of postoperative pancreatic fistula following distal pancreatectomy

Application of fibrin sealants to pancreatic stump closure reinforcement for the prevention of postoperative pancreatic fistula following distal pancreatectomy

Patient or population: people undergoing distal pancreatectomy

Setting: hospital

Intervention: fibrin sealant
Comparison: no fibrin sealant

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with no fibrin sealants

Risk with fibrin sealants

Postoperative pancreatic fistula (ISGPF definition)

Follow up: 30 days

Study population

RR 0.96
(0.68 to 1.35)

755
(4 studies)

⊕⊕⊝⊝
low1,2,3

201 per 1000

193 per 1000
(136 to 271)

Moderate

203 per 1000

195 per 1000
(138 to 274)

Postoperative mortality

Study population

Peto OR 0.52
(0.05 to 5.03)

804
(6 studies)

⊕⊕⊝⊝
low2,4

5 per 1000

3 per 1000
(0 to 25)

Moderate

0 per 1000

0 per 1000
(0 to 0)

Overall postoperative morbidity

Follow up: 30 days

Study population

RR 1.23
(0.97 to 1.58)

646
(3 studies)

⊕⊕⊝⊝
low1,2,3

232 per 1000

285 per 1000
(225 to 367)

Moderate

239 per 1000

294 per 1000
(232 to 378)

Reoperation rate

Follow up: 30 days

Study population

RR 0.51
(0.15 to 1.71)

376
(2 studies)

⊕⊝⊝⊝
very low1,2,4

38 per 1000

20 per 1000
(6 to 65)

Moderate

27 per 1000

14 per 1000
(4 to 46)

Serious adverse events

This outcome was not reported in any of the included studies.

Quality of life

This outcome was not reported in any of the included studies.

Cost effectiveness

This outcome was not reported in any of the included studies.

Length of hospital stay (days)

The mean length of hospital stay was

11.4 days

The mean length of hospital stay was 0.32 days higher

(1.06 lower to 1.70 higher)

MD 0.32

(‐1.06 to 1.70)

755
(4 studies)

⊕⊕⊕⊝
moderate1,2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio; OR: Odds ratio; MD: Mean difference; ISGPF: International Study Group on Pancreatic Fistula

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded one level for serious risk of bias.
2 Publication bias could not be assessed because of there being few studies.
3 Downgraded one level for serious imprecision (the confidence interval of risk ratio overlapped 0.75 and 1.25).
4 Downgraded two levels for very serious imprecision (very few events, confidence intervals of risk ratios overlapped 0.75 and 1.25).

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Summary of findings 2. Application of fibrin sealants to pancreatic anastomosis reinforcement for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy

Application of fibrin sealants to pancreatic anastomosis reinforcement for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy

Patient or population: people undergoing pancreaticoduodenectomy
Setting: hospital

Intervention: fibrin sealant

Comparison: no fibrin sealant

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with no fibrin sealants

Risk with fibrin sealants

Postoperative pancreatic fistula (ISGPF definition)

Follow up: 30 days

Study population

RR 0.25
(0.01 to 5.06)

57
(1 study)

⊕⊝⊝⊝
very low1,2,3

62 per 1000

16 per 1000
(1 to 316)

Moderate

63 per 1000

16 per 1000
(1 to 319)

Postoperative mortality

Follow up: 30 days

Study population

Peto OR 0.15
(0 to 7.76)

251
(3 studies)

⊕⊕⊝⊝
low2,3

7 per 1000

1 per 1000
(0 to 54)

Moderate

0 per 1000

0 per 1000
(0 to 0)

Overall postoperative morbidity

Follow up: 30 days

Study population

RR 0.97
(0.65 to 1.45)

181
(2 studies)

⊕⊝⊝⊝
very low1,2,3

347 per 1000

337 per 1000
(226 to 503)

Moderate

370 per 1000

359 per 1000
(240 to 537)

Reoperation rate

Follow up: 30 days

Study population

RR 0.83
(0.33 to 2.11)

181
(2 studies)

⊕⊝⊝⊝
very low1,2,3

92 per 1000

76 per 1000
(30 to 194)

Moderate

133 per 1000

110 per 1000
(44 to 281)

Serious adverse events

This outcome was not reported in any of the included studies.

Quality of life

This outcome was not reported in any of the included studies.

Cost effectiveness

This outcome was not reported in any of the included studies.

Length of hospital stay (days)

The mean length of hospital stay was

14.8 days

The mean length of hospital stay was

1.58 days lower
(3.96 lower to 0.81 higher)

MD −1.58
(‐3.96 to 0.81)

181
(2 studies)

⊕⊕⊝⊝
low1,3,4

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio; OR: Odds ratio; MD: Mean difference; ISGPF: International Study Group on Pancreatic Fistula

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded one level for serious risk of bias.
2 Downgraded two levels for very serious imprecision (small sample size, confidence intervals of risk ratios overlapped 0.75 and 1.25).
3 Publication bias could not be assessed because of there being few studies.
4 Downgraded one level for serious imprecision (total population size was less than 400).

Open in table viewer
Summary of findings 3. Application of fibrin sealants to pancreatic duct occlusion for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy

Application of fibrin sealants to pancreatic duct occlusion for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy

Patient or population: people undergoing pancreaticoduodenectomy
Setting: hospital

Intervention: fibrin sealant

Comparison: no fibrin sealant

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with no fibrin sealants

Risk with fibrin sealants

Postoperative pancreatic fistula (ISGPF definition)

This outcome was not reported in any of the included studies.

Postoperative mortality

Follow up: 30 days

Study population

Peto OR 1.41
(0.63 to 3.13)

351
(2 studies)

⊕⊕⊝⊝
low1,2

61 per 1000

84 per 1000
(40 to 170)

Moderate

61 per 1000

84 per 1000
(40 to 170)

Overall postoperative morbidity

Follow up: 30 days

Study population

RR 1.16
(0.67 to 2.02)

351
(2 studies)

⊕⊝⊝⊝
very low1,2,3,4

276 per 1000

320 per 1000
(185 to 558)

Moderate

277 per 1000

321 per 1000
(185 to 559)

Reoperation rate

Follow up: 30 days

Study population

RR 0.85
(0.52 to 1.41)

351
(2 studies)

⊕⊝⊝⊝
very low1,2,3

160 per 1000

136 per 1000
(83 to 225)

Moderate

160 per 1000

136 per 1000
(83 to 226)

Serious adverse events (Diabetes mellitus)

Follow‐up: 3 to 12 months

3 months follow up

169

(1 study)

⊕⊕⊝⊝
low1,3,5

108 per 1000

337 per 1000

12 months follow up

145 per 1000

337 per 1000

Quality of life

This outcome was not reported in any of the included studies.

Cost effectiveness

This outcome was not reported in any of the included studies.

Length of hospital stay (days)

The mean length of hospital stay was

16.5 days

The mean length of hospital stay was

0.58 days higher

(5.74 lower to 6.89 higher)

MD 0.58

(‐5.74 to 6.89)

351

(2 studies)

⊕⊕⊝⊝
low1,3,5

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio; OR: Odds ratio; MD: Mean difference; ISGPF: International Study Group on Pancreatic Fistula

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded two levels for very serious imprecision (small sample size, confidence intervals of risk ratios overlapped 0.75 and 1.25).
2 Publication bias could not be assessed because of there being few studies.
3 Downgraded one level for serious risk of bias.
4 Downgraded one level for serious heterogeneity
5 Downgraded one level for serious imprecision (small sample size; total population size was less than 400).

Background

See 'Glossary' for an explanation of terms (Appendix 1).

Description of the condition

Pancreatic cancer ranks 13th in terms of most common cancers and 8th as a cause of cancer death from a global viewpoint (Anderson 2006; Dragovich 2015; Lowenfels 2006). Regional differences exist in the incidence of pancreatic cancer (Anderson 2006; Dragovich 2015; Lowenfels 2006), though the overall incidence is approximately four to ten cases per 100,000 persons per year (Anderson 2006; Dragovich 2015; Lowenfels 2006). Pancreatic cancer has become the third leading cause of death from cancer in the European Union countries (Ferlay 2016). The most common cause of pancreatic cancer is heavy tobacco usage (Anderson 2006; Dragovich 2015; Lowenfels 2006).

Although the exact incidence of chronic pancreatitis worldwide is unknown, the estimated incidence of chronic pancreatitis is six cases per 100,000 persons per year in European, and probably all Western, countries (Spanier 2008). The prevalence of chronic pancreatitis in the United Kingdom, France, Japan, and south India is three cases, 26 cases, four cases, and 114 to 200 cases per 100,000 persons, respectively (Bornman 2001; Braganza 2011; Garg 2004; Lévy 2006). The most common cause of chronic pancreatitis is alcohol abuse (Braganza 2011; Spanier 2008).

Pancreatic surgery is performed to treat pancreatic and extra‐pancreatic diseases, including pancreatic cancers, chronic pancreatitis, as well as biliary, ampullary, and duodenal malignancy (Cheng 2014; Cheng 2016a; Cheng 2016b; Connor 2005; Diener 2014; Gurusamy 2013; Lillemoe 2004). Although the mortality of pancreatic surgery has been reduced to less than 5% currently, the overall morbidity is still high, ranging from 30% to 60% (Bassi 2005; Connor 2005; Gurusamy 2013). Postoperative pancreatic fistula (POPF) is one of the most frequent and potentially life‐threatening complications (Cheng 2016a; Dong 2016; Gurusamy 2013). It is defined by the International Study Group on Pancreatic Fistula (ISGPF) as "Grade B POPF requires a change in the postoperative management; drains are either left in place >3 weeks or repositioned through endoscopic or percutaneous procedures. Grade C POPF requires reoperation or leads to single or multiple organ failure and/or mortality attributable to the POPF" (Bassi 2017). Its reported incidence varies between 2% and 24% in different studies (Bassi 2005; Connor 2005; McMillan 2016).

Generally, POPF originates from the pancreatic stump following pancreatic resection, as well as from the pancreatic‐enteric anastomosis following pancreaticoduodenectomy (Bassi 2005; Hackert 2011). The natural history of POPF is variable in different people (Case 1960). Many factors have been considered to influence the development of POPF (e.g. age, obesity, cardiovascular diseases, diabetes mellitus, pancreatic texture, pancreatic duct size) (Ramacciato 2011). It seems that older (i.e. more than 60 years of age), overweight people with cardiovascular diseases, diabetes mellitus, soft pancreatic texture, a small pancreatic duct diameter (i.e. less than 3 mm) are more likely to suffer POPF (Ramacciato 2011; Riall 2008).

Description of the intervention

Various methods have been suggested for the prevention of POPF, such as modification of anastomotic techniques, application of pancreatic duct stents, and administration of somatostatin or its analogues (Gurusamy 2013; Schulick 2009; Cheng 2017; Dong 2016), but one of the most common and convenient interventions during an operation has been the application of fibrin sealants (Fingerhut 2009; Kuroki 2005; Ohwada 1998). Fibrin sealants are administered to seal the pancreatic stump, pancreatic‐enteric anastomosis, or main pancreatic duct during pancreatic surgery.

How the intervention might work

Fibrin sealant (also known as fibrin glue) is a kind of surgical tissue adhesive that is widely used worldwide in various surgical procedures for bleeding control, incision closure, etc. (Chow 2010; Spotnitz 2010). It is a product derived from human or animal blood (Carless 2003). Fibrin sealants are commercial products containing two separate components: primarily fibrinogen and thrombin (Carless 2003; Mobley 2002; NLM 1990). Mixing of the two components by single‐ or dual‐syringe systems in a liquid form promotes blood clotting and cross‐linking of fibrin (Mobley 2002; NLM 1990). This process mimics the final stages of blood coagulation and forms a stable fibrin clot that provides a sealing barrier (Carless 2003; Spotnitz 2010). This kind of commercial product is termed fibrin glue.

Another common type is a fibrin sealant patch which consists of felt coated with a mixture of freeze‐dried fibrinogen and thrombin, and which can be applied directly to the tissue surface without additional manipulations (Chirletti 2009; Ochiai 2010; Rickenbacher 2009). Approximately 10 ml fibrin glue or several fibrin sealant patches are applied to stump closure reinforcement, pancreatic anastomosis reinforcement, or main pancreatic duct occlusion (Fingerhut 2009; Schulick 2009). Theoretically, they have the potential to reduce the incidence of POPF by mechanically sealing (Fingerhut 2009; Schulick 2009). As POPF often develops into various further abdominal complications (e.g. intra‐abdominal abscess, subsequent serious infection, bleeding) and significantly contributes to mortality and morbidity (Kuroki 2005; Schulick 2009), a reduction in the incidence of POPF might reduce mortality, morbidity, and length of hospital stay (Fingerhut 2009; Gurusamy 2013; Schulick 2009).

Why it is important to do this review

The use of fibrin sealants during pancreatic surgery is controversial. Fibrin sealants may potentially reduce the incidence of POPF, but it is also possible that they may have no benefits and may be associated with some adverse effects (Carless 2003; Fingerhut 2009; Siedentop 2001). Fibrin sealants are products derived from human or animal blood. Thus, they have the risk of allergy and transmission of some diseases (Carless 2003; Siedentop 2001). In addition, a recent experimental study performed in rats indicated that the fibrin sealants resulted in pancreatic toxicity (harmfulness). Theoretically, they may also be harmful to humans (Lämsä 2008). This is an update of a previous Cochrane Review assessing the role of fibrin sealants for the prevention of POPF following pancreatic surgery. We conducted this systematic review to explore uncertainty arising from conflicting results in a number of studies in this area.

Objectives

To assess the safety, effectiveness, and potential adverse effects of fibrin sealants for the prevention of postoperative pancreatic fistula following pancreatic surgery.

Methods

Criteria for considering studies for this review

Types of studies

We included all randomized controlled trials, regardless of sample size, publication status, language, or publication date, that compared fibrin sealant with control for the prevention of postoperative pancreatic fistula (POPF) in people undergoing pancreatic resections. We excluded quasi‐randomized trials, in which the allocation was performed on the basis of a pseudo‐random sequence (e.g. odd/even hospital number or date of birth, alternation), and non‐randomized studies because of the potential for bias (Reeves 2011).

Types of participants

We included people, regardless of age, sex, or race, who underwent elective pancreatic resections (open or laparoscopic) for any pancreatic or extra‐pancreatic disease.

We excluded people who underwent total pancreatectomy as this eliminates any source for a POPF.

Types of interventions

Intervention: fibrin sealant, regardless of glue or patch, which was applied to stump closure reinforcement, pancreatic anastomosis reinforcement, or main pancreatic duct occlusion.

Comparison: placebo or no fibrin sealant treatment.

Types of outcome measures

Primary outcomes

  1. Postoperative pancreatic fistula (30 days; defined by the International Study Group on Pancreatic Fistula; Bassi 2017).

  2. Postoperative mortality (30 days).

Secondary outcomes

  1. Overall postoperative morbidity (30 days; classified by the Clavien‐Dindo classification of surgical complications; Clavien 2009).

    1. Pancreas‐associated morbidity (e.g. postoperative pancreatic fistula, delayed gastric emptying, postoperative pancreatitis).

    2. Other general postoperative morbidity (e.g. wound infection, pulmonary complications, renal failure).

  2. Reoperation rate (30 days).

  3. Number of people with any serious adverse events attributed to fibrin sealants.

    1. Hepatitis transmission.

    2. HIV transmission.

    3. Allergy.

    4. Others.

  4. Quality of life.

  5. Cost effectiveness.

  6. Length of hospital stay.

Search methods for identification of studies

We designed the search strategies with the help of a Cochrane Upper Gastrointestinal and Pancreatic Diseases (UGPD) Information Specialist before searching. We placed no restrictions on the language of publication when searching the electronic databases or reviewing reference lists in identified studies.

Electronic searches

For the initial version of this review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 7), MEDLINE (1946 to 26 August 2015), Embase (1980 to 26 August 2015), Science Citation Index Expanded (1900 to 26 August 2015), and Chinese Biomedical Literature Database (CBM) (1978 to 26 August 2015) (New Reference). For this updated review, we searched the following electronic databases from 2015 to 12 April 2018, with no restrictions on language or date of publication:

  1. CENTRAL (Appendix 2);

  2. MEDLINE (Ovid) (Appendix 3);

  3. Embase (Ovid) (Appendix 4);

  4. Science Citation Index Expanded (Web of Science) (Appendix 5); and

  5. Chinese Biomedical Literature Database (CBM) (Appendix 6).

Searching other resources

We checked reference lists of all primary studies and review articles for additional references. We contacted authors of identified studies and asked them to identify other published and unpublished studies.

We searched PubMed for errata or retractions from eligible studies and reported the date this was done within the review (www.ncbi.nlm.nih.gov/pubmed). We also searched the meeting abstracts via the HPB journal (onlinelibrary.wiley.com/journal/10.1111/(ISSN)1477‐2574; accessed 12 April 2018) and Conference Proceedings Citation Index to explore further relevant clinical studies.

Clinical study registers/study result registers

We searched the following databases to identify ongoing studies (accessed 12 April 2018).

  1. World Health Organization International Clinical Trials Registry Platform search portal (apps.who.int/trialsearch/)

  2. ClinicalTrials.gov (www.clinicaltrials.gov/)

  3. Current Controlled Trials (www.controlled‐trials.com/)

  4. European (EU) Clinical Trials Register (www.clinicaltrialsregister.eu/)

  5. Chinese Clinical Trial Registry (www.chictr.org.cn/enindex.aspx)

Data collection and analysis

We conducted this systematic review according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a); and the Cochrane Upper Gastrointestinal and Pancreatic Diseases (UGPD) Group Module (Forman 2011).

Selection of studies

Two review authors (Junhua Gong, YC) independently screened the titles and abstracts of all the studies we identified as a result of the search and coded them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We retrieved the full‐text study reports/publications and two review authors (Junhua Gong, YC) independently screened the full text and identified studies for inclusion, and identified and recorded reasons for exclusion of the ineligible studies. We resolved any disagreements through discussion or, if required, we consulted a third review author (ZZ). We identified and excluded duplicates and collated multiple reports of the same study, so that each study, rather than each report, was the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram and a Characteristics of excluded studies table (Moher 2009).

Data extraction and management

We used a standard data collection form for study characteristics and outcome data, which had been piloted on at least one study in the review. Two review authors (NC, Jianping Gong) extracted the following study characteristics from included studies.

  1. Methods: study design, total duration study and run in, number of study centres and location, study setting, withdrawals, and date of study.

  2. Participants: number (N), mean age, age range, gender, severity of condition, diagnostic criteria, inclusion criteria, and exclusion criteria.

  3. Interventions: intervention, comparison.

  4. Outcomes: primary and secondary outcomes specified and collected, time points reported.

  5. Notes: funding for study, notable conflicts of interest of study authors.

Two review authors (NC, Jianping Gong) independently extracted outcome data from included studies. We noted in the Characteristics of included studies table if outcome data were not reported in a usable way. We resolved disagreements by consensus or by involving a third review author (ZZ). One review author (YC) copied across the data from the data collection form into Review Manager 5. We double checked that the data were entered correctly by comparing the study reports with how the data were presented in the systematic review. A second review author spot‐checked study characteristics for accuracy against the study report.

Assessment of risk of bias in included studies

Two review authors (Junhua Gong, YC) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We resolved any disagreements by discussion or by involving a third review author (ZZ). We assessed the risk of bias for the following domains:

  1. random sequence generation;

  2. allocation concealment;

  3. blinding of participants and personnel;

  4. blinding of outcome assessment;

  5. incomplete outcome data;

  6. selective outcome reporting;

  7. other bias.

We graded each potential source of bias as high, low, or unclear risk, and provided a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We summarized the 'Risk of bias' judgements across different studies for each of the domains listed. We considered blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a participant‐reported pain scale). Where information on risk of bias related to unpublished data or correspondence with a trialist, we noted this in the 'Risk of bias' table.

When considering treatment effects, we took into account the risk of bias for the studies that contributed to that outcome.

Assessment of bias in conducting the systematic review

We conducted the review according to the published protocol (Cheng 2012), and reported any deviations from it in the Differences between protocol and review section of the systematic review.

Measures of treatment effect

We analysed dichotomous data as risk ratio (RR) and continuous data as mean difference (MD) with 95% confidence intervals (CIs). In the case of rare events (e.g. mortality), we calculated the Peto odds ratio (Peto OR) (Deeks 2011). We ensured that higher scores for continuous outcomes had the same meaning for the particular outcome, explained the direction to the reader and reported where the directions were reversed if this was necessary.

We undertook meta‐analyses only where this was meaningful, that is, if the treatments, participants, and underlying clinical question were similar enough for pooling to make sense.

A common way that trialists indicated when they had skewed data was by reporting medians and interquartile ranges. When we encountered this, we noted that the data were skewed and considered the implication of this.

Where multiple study arms were reported in a single study, we included only the relevant arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) were entered into the same meta‐analysis, we halved the control group to avoid double counting.

Unit of analysis issues

The unit of analysis was the individual participant. We did not find any cross‐over or cluster‐randomized trials.

Dealing with missing data

We contacted investigators or study sponsors in order to verify key study characteristics, and obtained missing numerical outcome data where possible (e.g. when a study was identified as abstract only). However, there was no reply in most of the cases. Thus, we used only the available data in the analyses.

Assessment of heterogeneity

We used the I2 statistic to measure heterogeneity among the studies in each analysis (Higgins 2003). When we identified substantial heterogeneity (greater than 50%), we explored it by prespecified subgroup analysis, and we interpreted summary effect measures with caution.

Assessment of reporting biases

We did not perform funnel plots to assess reporting biases because the number of studies included under each comparison was less than 10 (Sterne 2011).

Data synthesis

We performed the meta‐analyses using Review Manager 5 software (RevMan 2014). For all analyses, we employed the random‐effects model for conservative estimation, except for the Peto odds ratio (OR) which only has a fixed method.

'Summary of findings' table

We created 'Summary of findings' tables using the following outcomes: postoperative pancreatic fistula, postoperative mortality, overall postoperative morbidity, reoperation rate, serious adverse events, quality of life, cost effectiveness and length of hospital stay. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it related to the studies which contributed data to the meta‐analyses for the prespecified outcomes. We used the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a), and used GRADEpro software (GRADEpro 2015). We justified all decisions to downgrade or upgrade the quality of studies using footnotes, and made comments to aid the reader's understanding of the review where necessary. We considered whether there was any additional outcome information that we were unable to incorporate into meta‐analyses and noted this in the comments, and stated if it supported or contradicted the information from the meta‐analyses.

Subgroup analysis and investigation of heterogeneity

We intended to perform the following subgroup analyses.

  1. Randomized controlled trials with low risk of bias versus randomized controlled trials with high risk of bias

  2. The type of fibrin sealants (glue and patch)

  3. Different etiologies (pancreatic cancer, chronic pancreatitis, and others)

  4. High‐risk people (e.g. fatty pancreas, soft pancreas, small pancreatic duct) versus low‐risk people

In previous versions of this review, we performed a meta‐analysis of fibrin sealants versus no fibrin sealants for overall pancreatic surgery, with subgroups of sealing location and type of operation. We have restructured this version of the review and the changes are detailed in the Differences between protocol and review section.

Sensitivity analysis

We performed sensitivity analyses to determine whether the conclusions were robust according to the decisions made during the review process, as follows.

  1. Changing between a fixed‐effect model and a random‐effects model

  2. Changing statistics between risk ratios (RR), risk differences (RD), and odds ratios (OR) for dichotomous outcomes

  3. Changing statistics between mean difference (MD) and standardized mean differences (SMD) for continuous outcomes

  4. Excluding randomized controlled trials with low quality

  5. Excluding studies published in languages other than English

If the results did not change, they were considered to have low sensitivity. If the results changed, they were considered to have high sensitivity.

Reaching conclusions

We based our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We avoided making recommendations for practice and our implications for research could give the reader a clear sense of where the focus of any future research in the area should be and what the remaining uncertainties were.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

We identified a total of 69 records through the electronic searches of The Cochrane Library (N = 5), MEDLINE (Ovid) (N = 9), Embase (Ovid) (N = 16), Science Citation Index Expanded (Web of Science) (N = 24), and Chinese Biomedical Literature Database (CBM) (N = 15). We excluded 13 duplicates and 51 clearly irrelevant records through reading titles and abstracts. We retrieved the remaining five records for further assessment. We excluded a quasi‐randomized study (Rehman 2016) and two non‐randomized studies (Mita 2015; Silvestri 2015). In total, two randomized controlled trials fulfilled the inclusion criteria for this update. The study flow diagram is shown in Figure 1.


Study flow diagram.

Study flow diagram.

Included studies

The first published version of this review from 2016 included nine studies published between 1994 and 2013 (Bassi 1999; Carter 2013; D'Andrea 1994; Lillemoe 2004; Martin 2013; Montorsi 2012; Suc 2003; Suzuki 1995; Tran 2002). We added two recent studies published after 2015 into this updated review (Park 2016; Sa Cunha 2015). Therefore, we included 11 studies and all of these provided data for the analyses. These studies were conducted in Italy (N = 3; Bassi 1999; D'Andrea 1994; Montorsi 2012), America (N = 2; Carter 2013; Lillemoe 2004), France (N = 2; Sa Cunha 2015; Suc 2003), Australia (N = 1; Martin 2013), Japan (N = 1; Suzuki 1995), South Korea (N = 1; Park 2016), and the Netherlands (N = 1; Tran 2002). A total of 1462 participants were randomized to either fibrin sealant (N = 731) or control (N = 731). The average age of participants varied between 50.0 years and 64.0 years. The mean proportion of females varied between 28.6% and 72.5%. The outcomes measured were postoperative pancreatic fistula (POPF), grade of pancreatic fistula, mortality, morbidity, reoperation rate, serious adverse events, and length of hospital stay. We split all of the studies into three comparisons according to different sealing locations and different operations: application of fibrin sealants to pancreatic stump reinforcement after distal pancreatectomy (Bassi 1999; Carter 2013; D'Andrea 1994; Montorsi 2012; Park 2016; Sa Cunha 2015; Suzuki 1995), pancreatic anastomosis reinforcement after pancreaticoduodenectomy (D'Andrea 1994; Lillemoe 2004; Martin 2013), and main pancreatic duct occlusion after pancreaticoduodenectomy (Suc 2003; Tran 2002). Details of the included studies are shown in the Characteristics of included studies table.

Excluded studies

We excluded five studies (Ohwada 1998; Pavlik Marangos 2011; Rehman 2016; Silvestri 2015; Tashiro 1987). Details are listed in the Characteristics of excluded studies table. None of these studies were randomized controlled trials.

Risk of bias in included studies

The risk of bias of the included studies is shown in Figure 2 and Figure 3. Following the evaluation of these seven domains, an included trial was judged to be at a low risk of bias if the risk of bias was evaluated as ‘low risk’ in all of the domains. If the risk of bias of any domain was judged as ’unclear risk’ or ’high risk’, the trial was listed as ’high risk of bias’. We considered all 11 studies to be at high risk of bias.


Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.


Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We judged six studies to have low risk of bias for random sequence generation (Carter 2013; Lillemoe 2004; Martin 2013; Park 2016; Suc 2003; Suzuki 1995). We judged four studies to have low risk of bias for allocation concealment (Carter 2013; Park 2016; Sa Cunha 2015; Suc 2003).

Blinding

We deemed three studies to be at high risk of bias for blinding of participants and personnel (Carter 2013; Park 2016; Suc 2003). Blinding of outcome assessment was at low risk of bias in four studies (Lillemoe 2004; Park 2016; Sa Cunha 2015; Suc 2003).

Incomplete outcome data

There were no post‐randomization dropouts in seven studies (Bassi 1999; D'Andrea 1994; Lillemoe 2004; Martin 2013; Suc 2003; Suzuki 1995; Tran 2002). Although there were some dropouts in one study, it performed the data analysis on an intention‐to‐treat basis (Montorsi 2012). We considered these eight studies to be free from risk of bias due to incomplete outcome data (Bassi 1999; D'Andrea 1994; Lillemoe 2004; Martin 2013; Montorsi 2012; Suc 2003; Suzuki 1995; Tran 2002).

Selective reporting

The study protocol was available for three studies (Montorsi 2012; Park 2016; Sa Cunha 2015). All of the studies' pre‐specified outcomes were reported. Thus, we considered these three studies to be free of selective reporting. Six studies reported all of the primary outcomes of this review (Bassi 1999; D'Andrea 1994; Lillemoe 2004; Martin 2013; Suc 2003; Tran 2002). There was some selective outcome reporting in the secondary outcomes, but the review authors considered the six studies to be free of selective reporting for the primary outcomes.

Other potential sources of bias

We judged two studies to be at high risk of bias due to baseline imbalance (Montorsi 2012; Suc 2003).

Effects of interventions

See: Summary of findings for the main comparison Application of fibrin sealants to pancreatic stump closure reinforcement for the prevention of postoperative pancreatic fistula following distal pancreatectomy; Summary of findings 2 Application of fibrin sealants to pancreatic anastomosis reinforcement for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy; Summary of findings 3 Application of fibrin sealants to pancreatic duct occlusion for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy

Application of fibrin sealants to pancreatic stump closure reinforcement after distal pancreatectomy

Seven studies (860 participants) compared fibrin sealant use with no fibrin sealant use for pancreatic stump closure reinforcement after distal pancreatectomy (Bassi 1999; Carter 2013; D'Andrea 1994; Montorsi 2012; Park 2016; Sa Cunha 2015; Suzuki 1995). Four hundred and twenty‐eight participants were randomized to the fibrin sealant group and 432 participants to the control group. See: summary of findings Table for the main comparison.

Postoperative pancreatic fistula (30 days)

Postoperative pancreatic fistula (POPF) at 30 days, as defined by the International Study Group on Pancreatic Fistula (ISGPF)(Bassi 2017). The POPF rate was 19.3% in the fibrin sealant group and 20.1% in the control group. The estimated risk ratio (RR) for clinically significant pancreatic fistula was 0.96 (95% confidence interval (CI) 0.68 to 1.35, 4 studies, 755 participants) (Analysis 1.1). We downgraded our assessment of the quality of evidence from high to low due to high risk of bias, serious imprecision, and concerns of publication bias.

Postoperative mortality (30 days)

Postoperative mortality was 0.3% in the fibrin sealant group and 0.5% in the control group. The estimated Peto odds ratio (OR) for postoperative mortality was 0.52 (95% CI 0.05 to 5.03, 6 studies, 804 participants) (Analysis 1.2). We downgraded our assessment of the quality of evidence from high to low due to very serious imprecision and concerns of publication bias.

Overall postoperative morbidity (30 days)

Overall postoperative morbidity at 30 days, as defined by the Clavien‐ Dindo classification of surgical complications (Clavien 2009). The overall postoperative morbidity was 28.5% in the fibrin sealant group and 23.2% in the control group. The estimated RR for overall postoperative morbidity was 1.23 (95% CI 0.97 to 1.58, 3 studies, 646 participants) (Analysis 1.3). We downgraded our assessment of the quality of evidence from high to low due to high risk of bias, serious imprecision, and concerns of publication bias.

Reoperation rate (30 days)

The reoperation rate was 2.0% in the fibrin sealant group and 3.8% in the control group. The estimated RR for reoperation rate was 0.51 (95% CI 0.15 to 1.71, 2 studies, 376 participants) (Analysis 1.4). We downgraded our assessment of the quality of evidence from high to very low due to high risk of bias, very serious imprecision, and concerns of publication bias.

Serious adverse events

None of the studies reported any serious adverse events related to fibrin sealants.

Quality of life

None of the studies reported this outcome.

Cost effectiveness

None of the studies reported this outcome.

Length of hospital stay

The mean length of hospital stay was 12.1 days in the fibrin sealant group and 11.4 days in the control group. The estimated mean difference (MD) for length of hospital stay was 0.32 days (95% CI ‐1.06 to 1.70, 4 studies, 755 participants, Analysis 1.5). We downgraded our assessment of the quality of evidence from high to very low due to high risk of bias, very serious imprecision, and concerns of publication bias.

Application of fibrin sealants to pancreatic anastomosis reinforcement after pancreaticoduodenectomy

Three studies (251 participants) compared fibrin sealant use with no fibrin sealant use for pancreatic anastomosis reinforcement after pancreaticoduodenectomy (D'Andrea 1994; Lillemoe 2004; Martin 2013). One hundred and fifteen participants were randomized to the fibrin sealant group and 136 participants to the control group. See: summary of findings Table 2.

Postoperative pancreatic fistula (30 days)

Postoperative pancreatic fistula (POPF) at 30 days, as defined by the International Study Group on Pancreatic Fistula (ISGPF)(Bassi 2017). The POPF rate was 1.6% in the fibrin sealant group and 6.2% in the control group. The estimated RR for clinically significant pancreatic fistula was 0.25 (95% CI 0.01 to 5.06, 1 study, 57 participants, Analysis 2.1). We downgraded our assessment of the quality of evidence from high to very low due to high risk of bias, very serious imprecision, and concerns of publication bias.

Postoperative mortality (30 days)

Postoperative mortality was 0.1% in the fibrin sealant group versus 0.7% in the control group. The estimated Peto OR for postoperative mortality was 0.15 (95% CI 0.00 to 7.76, 3 studies, 251 participants, Analysis 2.2). We downgraded our assessment of the quality of evidence from high to low due to very serious imprecision and concerns of publication bias.

Overall postoperative morbidity (30 days)

Overall postoperative morbidity at 30 days, as defined by the Clavien‐ Dindo classification of surgical complications (Clavien 2009). Overall postoperative morbidity was 33.7% in the fibrin sealant group and 34.7% in the control group. The estimated RR for overall postoperative morbidity was 0.97 (95% CI 0.65 to 1.45, 2 studies, 181 participants, Analysis 2.3). We downgraded our assessment of the quality of evidence from high to very low due to high risk of bias, very serious imprecision, and concerns of publication bias.

Reoperation rate (30 days)

The reoperation rate was 7.6% in the fibrin sealant group and 9.2% in the control group. The estimated RR for reoperation rate was 0.83 (95% CI 0.33 to 2.11, 2 studies, 181 participants, Analysis 2.4). We downgraded our assessment of the quality of evidence from high to very low due to high risk of bias, very serious imprecision, and concerns of publication bias.

Serious adverse events

None of the studies reported any serious adverse events related to fibrin sealants.

Quality of life

None of the studies reported this outcome.

Cost effectiveness

None of the studies reported this outcome.

Length of hospital stay

The mean length of hospital stay was 12.8 days in the fibrin sealant group and 14.8 days in the control group. The estimated MD for length of hospital stay was ‐1.58 days (95% CI ‐3.96 to 0.81, 2 studies, 181 participants, Analysis 2.5). We downgraded our assessment of the quality of evidence from high to low due to high risk of bias, serious imprecision, and concerns of publication bias.

Application of fibrin sealants to pancreatic duct occlusion after pancreaticoduodenectomy

Two studies (351 participants) compared fibrin sealant use with no fibrin sealant use for pancreatic duct occlusion after pancreaticoduodenectomy (Suc 2003; Tran 2002). One hundred and eighty‐eight participants were randomized to the fibrin sealant group and 163 participants to the control group. See: summary of findings Table 3.

Postoperative pancreatic fistula (30 days)

Postoperative pancreatic fistula (POPF) at 30 days, as defined by the International Study Group on Pancreatic Fistula (ISGPF)(Bassi 2017). Neither study reported on POPF.

Postoperative mortality (30 days)

The postoperative mortality was 8.4% in the fibrin sealant group and 6.1% in the control group. The estimated Peto OR for postoperative mortality was 1.41 (95% CI 0.63 to 3.13, 2 studies, 351 participants) (Analysis 3.1). We downgraded our assessment of the quality of evidence from high to low due to very serious imprecision and concerns of publication bias.

Overall postoperative morbidity (30 days)

Overall postoperative morbidity at 30 days, as defined by the Clavien‐ Dindo classification of surgical complications (Clavien 2009). Overall postoperative morbidity was 32.0% in the fibrin sealant group and 27.6% in the control group. The estimated RR for overall postoperative morbidity was 1.16 (95% CI 0.67 to 2.02, 2 studies, 351 participants, Analysis 3.2). We downgraded our assessment of the quality of evidence from high to very low due to high risk of bias, very serious imprecision, concerns of publication bias, and inconsistency in the direction and magnitude of effects across the studies (I2 = 65%).

Reoperation rate (30 days)

The reoperation rate was 13.6% in the fibrin sealant group and 16.0% in the control group. The estimated RR for reoperation rate was 0.85 (95% CI 0.52 to 1.41, 2 studies, 351 participants, Analysis 3.3). We downgraded our assessment of the quality of evidence from high to very low due to high risk of bias, very serious imprecision, and concerns of publication bias.

Serious adverse events

One study found that more participants developed diabetes mellitus when fibrin sealants were applied to pancreatic duct occlusion, both at three months' follow‐up (33.7% fibrin sealant group versus 10.8% control group; 29 participants versus 9 participants) and 12 months' follow‐up (33.7% fibrin sealant group versus 14.5% control group; 29 participants versus 12 participants) (Tran 2002). The other study did not report any serious adverse events related to fibrin sealants.

Quality of life

None of the studies reported this outcome.

Cost effectiveness

None of the studies reported this outcome.

Length of hospital stay

The mean length of hospital stay was 17.0 days in the fibrin sealant group and 16.5 days in the control group. The estimated MD for length of hospital stay was 0.58 days (95% CI ‐5.74 to 6.89; participants = 351; studies = 2) (Analysis 3.4). We downgraded our assessment of the quality of evidence from high to low due to high risk of bias, serious imprecision, and concerns of publication bias.

Subgroup analysis

We performed planned subgroup analyses based on the type of fibrin sealants (glue or patch) (Analysis 1.1; Analysis 1.2; Analysis 2.1; Analysis 2.2; Analysis 3.1). These subgroup analyses did not show any difference in the primary outcomes in the review.

We were unable to perform subgroup analysis based on the risk of bias in the studies as none of the studies was at low risk of bias. We were unable to perform planned subgroup analyses of different etiologies (pancreatic cancer, chronic pancreatitis, and others) and different risk of POPF (e.g. fatty pancreas, soft pancreas, small pancreatic duct), as the outcome data for the different subgroups were not available from the studies.

Sensitivity analysis  

We performed the following planned sensitivity analyses.

  1. Changing between a fixed‐effect model and a random‐effects model.

  2. Changing statistics between risk ratio (RR), risk differences (RDs), and odds ratios (ORs) for dichotomous outcomes.

  3. Changing statistics between mean difference (MD) and standardized mean differences (SMDs) for continuous outcomes.

We observed no change in results by changing between a fixed‐effect model and a random‐effects model, calculating RDs and ORs for dichotomous outcomes, or calculating SMDs for continuous outcomes. We did not perform the other planned sensitivity analyses because none of the studies were at low risk of bias or were published in the non‐English language literature.

Discussion

Summary of main results

Evidence from seven studies in 860 people undergoing distal pancreatectomy contributed data to the primary outcomes of this review. The results showed that fibrin sealants may have little to no difference in the postoperative pancreatic fistula (POPF) rate or mortality, compared to control. The impact of fibrin sealants on POPF rate and mortality was less certain when fibrin sealants were applied to pancreatic anastomosis reinforcement or pancreatic duct occlusion after pancreaticoduodenectomy. One study showed more participants developing diabetes mellitus at three and 12 months' follow‐up when fibrin sealants were applied to pancreatic duct occlusion after pancreaticoduodenectomy. None of the other studies reported any serious adverse events related to fibrin sealants.

The definition of POPF varied in different studies. The incidence of POPF ranged from 11% to 65%, according to the different definitions applied in each study (Bassi 1999; Carter 2013; D'Andrea 1994; Lillemoe 2004; Martin 2013; Montorsi 2012; Park 2016; Sa Cunha 2015; Suc 2003; Suzuki 1995; Tran 2002). The International Study Group on Pancreatic Fistula (ISGPF) proposed a definition of POPF by consensus in order to compare different surgical experiences in pancreatic surgery (Bassi 2005; Bassi 2017). POPF has been graded as B and C (Bassi 2005; Bassi 2017): grade B requires a change in the management of the patient or persistent drainage more than 3 weeks; and grade C requires reoperation or leads to organ failure or death (or both) attributable to the POPF. Both POPF grade B and C have significant clinical impact and may be associated with increased morbidity and mortality (Bassi 2005; Gurusamy 2013). In this review, the incidence of POPF (grade B or C) was similar in the fibrin sealant group and the control group in various pancreatic resections.

The safety of fibrin sealants for people undergoing pancreatic surgery is another major concern for patients, surgeons, and healthcare funders (Siedentop 2001). Only one study reported that fibrin sealants were associated with higher risk of endocrine pancreatic insufficiency (diabetes mellitus) when fibrin sealants were applied to pancreatic duct occlusion (Tran 2002). None of the other studies reported any serious adverse events (e.g. hepatitis transmission, HIV transmission, allergy) related to fibrin sealants. The safety of fibrin sealants for people undergoing pancreatic surgery needs further evaluation.

The cost of fibrin sealants varies, but is relatively high (Carter 2013; Lillemoe 2004; Siedentop 2001). For example, the commercial fibrin glue Tissucol costs approximately USD 100 per 1 ml (Lovisetto 2007). In other words, it costs approximately USD 500 per case using 5 ml Tissucol for pancreatic surgery. None of the studies reported the quality of life in participants, so that a formal cost‐effectiveness analysis cannot be conducted. Further cost‐effectiveness evaluation of fibrin sealants in pancreatic surgery is necessary.

Overall completeness and applicability of evidence

This review included people undergoing distal pancreatectomy, pancreatoduodenectomy, and other pancreatic procedures such as those for malignancy and chronic pancreatitis. Thus, the results of this review are applicable to people undergoing various pancreatic resections.

Quality of the evidence

None of the studies were at low risk of bias. The studies included in each comparison were too few to assess publication bias. There was no indirectness of evidence because the studies did not perform the indirect comparison of one type of fibrin sealant versus another. The confidence intervals of the majority of outcomes were wide, indicating that the estimates of effect obtained were imprecise. Overall, we considered the quality of the evidence to be very low to moderate (summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 3).

Potential biases in the review process

We did not create funnel plots to assess the publication bias due to the small number of studies included in each analysis. In addition, the data for length of hospital stay were skewed. The lack of normality for this outcome measure might introduce bias in this review. We contacted study investigators or study sponsors in order to verify key study characteristics, and obtained missing numerical outcome data. However, there was incomplete correspondence with study investigators or sponsors.

Agreements and disagreements with other studies or reviews

Another systematic review, Fingerhut 2009, included six studies that we included (Bassi 1999; D'Andrea 1994; Lillemoe 2004; Suc 2003; Suzuki 1995; Tran 2002). Because of the heterogeneity and lack of high‐level evidence, the review by Fingerhut and colleagues did not draw a definitive conclusion on the role of fibrin sealants for preventing POPF (Fingerhut 2009). Since then, many systematic reviews and meta‐analyses on this topic have published (Hüttner 2016; Orci 2014; Smits 2015; Weniger 2016). All of these systematic reviews and meta‐analyses found that fibrin sealant use was associated with similar POPF rate as no fibrin sealant use following pancreatic surgery. This review agrees with most of the findings of these four systematic reviews and meta‐analyses (Hüttner 2016; Orci 2014; Smits 2015; Weniger 2016). We included two recent studies in the update of our review (Park 2016; Sa Cunha 2015). We found that fibrin sealants may have little to no difference in the POPF rate for people undergoing distal pancreatectomy, and that the impact of fibrin sealants on POPF rate was uncertain for people undergoing pancreaticoduodenectomy.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1 Fibrin sealants versus no fibrin sealant (pancreatic stump closure reinforcement after distal pancreatectomy), Outcome 1 Postoperative pancreatic fistula (ISGPF definition).
Figures and Tables -
Analysis 1.1

Comparison 1 Fibrin sealants versus no fibrin sealant (pancreatic stump closure reinforcement after distal pancreatectomy), Outcome 1 Postoperative pancreatic fistula (ISGPF definition).

Comparison 1 Fibrin sealants versus no fibrin sealant (pancreatic stump closure reinforcement after distal pancreatectomy), Outcome 2 Postoperative mortality.
Figures and Tables -
Analysis 1.2

Comparison 1 Fibrin sealants versus no fibrin sealant (pancreatic stump closure reinforcement after distal pancreatectomy), Outcome 2 Postoperative mortality.

Comparison 1 Fibrin sealants versus no fibrin sealant (pancreatic stump closure reinforcement after distal pancreatectomy), Outcome 3 Overall postoperative morbidity.
Figures and Tables -
Analysis 1.3

Comparison 1 Fibrin sealants versus no fibrin sealant (pancreatic stump closure reinforcement after distal pancreatectomy), Outcome 3 Overall postoperative morbidity.

Comparison 1 Fibrin sealants versus no fibrin sealant (pancreatic stump closure reinforcement after distal pancreatectomy), Outcome 4 Reoperation rate.
Figures and Tables -
Analysis 1.4

Comparison 1 Fibrin sealants versus no fibrin sealant (pancreatic stump closure reinforcement after distal pancreatectomy), Outcome 4 Reoperation rate.

Comparison 1 Fibrin sealants versus no fibrin sealant (pancreatic stump closure reinforcement after distal pancreatectomy), Outcome 5 Length of hospital stay.
Figures and Tables -
Analysis 1.5

Comparison 1 Fibrin sealants versus no fibrin sealant (pancreatic stump closure reinforcement after distal pancreatectomy), Outcome 5 Length of hospital stay.

Comparison 2 Fibrin sealants versus no fibrin sealant (pancreatic anastomosis reinforcement after pancreaticoduodenectomy), Outcome 1 Postoperative pancreatic fistula (ISGPF definition).
Figures and Tables -
Analysis 2.1

Comparison 2 Fibrin sealants versus no fibrin sealant (pancreatic anastomosis reinforcement after pancreaticoduodenectomy), Outcome 1 Postoperative pancreatic fistula (ISGPF definition).

Comparison 2 Fibrin sealants versus no fibrin sealant (pancreatic anastomosis reinforcement after pancreaticoduodenectomy), Outcome 2 Postoperative mortality.
Figures and Tables -
Analysis 2.2

Comparison 2 Fibrin sealants versus no fibrin sealant (pancreatic anastomosis reinforcement after pancreaticoduodenectomy), Outcome 2 Postoperative mortality.

Comparison 2 Fibrin sealants versus no fibrin sealant (pancreatic anastomosis reinforcement after pancreaticoduodenectomy), Outcome 3 Overall postoperative morbidity.
Figures and Tables -
Analysis 2.3

Comparison 2 Fibrin sealants versus no fibrin sealant (pancreatic anastomosis reinforcement after pancreaticoduodenectomy), Outcome 3 Overall postoperative morbidity.

Comparison 2 Fibrin sealants versus no fibrin sealant (pancreatic anastomosis reinforcement after pancreaticoduodenectomy), Outcome 4 Reoperation rate.
Figures and Tables -
Analysis 2.4

Comparison 2 Fibrin sealants versus no fibrin sealant (pancreatic anastomosis reinforcement after pancreaticoduodenectomy), Outcome 4 Reoperation rate.

Comparison 2 Fibrin sealants versus no fibrin sealant (pancreatic anastomosis reinforcement after pancreaticoduodenectomy), Outcome 5 Length of hospital stay.
Figures and Tables -
Analysis 2.5

Comparison 2 Fibrin sealants versus no fibrin sealant (pancreatic anastomosis reinforcement after pancreaticoduodenectomy), Outcome 5 Length of hospital stay.

Comparison 3 Fibrin sealants versus no fibrin sealant (pancreatic duct occlusion after pancreaticoduodenectomy), Outcome 1 Postoperative mortality.
Figures and Tables -
Analysis 3.1

Comparison 3 Fibrin sealants versus no fibrin sealant (pancreatic duct occlusion after pancreaticoduodenectomy), Outcome 1 Postoperative mortality.

Comparison 3 Fibrin sealants versus no fibrin sealant (pancreatic duct occlusion after pancreaticoduodenectomy), Outcome 2 Overall postoperative morbidity.
Figures and Tables -
Analysis 3.2

Comparison 3 Fibrin sealants versus no fibrin sealant (pancreatic duct occlusion after pancreaticoduodenectomy), Outcome 2 Overall postoperative morbidity.

Comparison 3 Fibrin sealants versus no fibrin sealant (pancreatic duct occlusion after pancreaticoduodenectomy), Outcome 3 Reoperation rate.
Figures and Tables -
Analysis 3.3

Comparison 3 Fibrin sealants versus no fibrin sealant (pancreatic duct occlusion after pancreaticoduodenectomy), Outcome 3 Reoperation rate.

Comparison 3 Fibrin sealants versus no fibrin sealant (pancreatic duct occlusion after pancreaticoduodenectomy), Outcome 4 Length of hospital stay.
Figures and Tables -
Analysis 3.4

Comparison 3 Fibrin sealants versus no fibrin sealant (pancreatic duct occlusion after pancreaticoduodenectomy), Outcome 4 Length of hospital stay.

Summary of findings for the main comparison. Application of fibrin sealants to pancreatic stump closure reinforcement for the prevention of postoperative pancreatic fistula following distal pancreatectomy

Application of fibrin sealants to pancreatic stump closure reinforcement for the prevention of postoperative pancreatic fistula following distal pancreatectomy

Patient or population: people undergoing distal pancreatectomy

Setting: hospital

Intervention: fibrin sealant
Comparison: no fibrin sealant

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with no fibrin sealants

Risk with fibrin sealants

Postoperative pancreatic fistula (ISGPF definition)

Follow up: 30 days

Study population

RR 0.96
(0.68 to 1.35)

755
(4 studies)

⊕⊕⊝⊝
low1,2,3

201 per 1000

193 per 1000
(136 to 271)

Moderate

203 per 1000

195 per 1000
(138 to 274)

Postoperative mortality

Study population

Peto OR 0.52
(0.05 to 5.03)

804
(6 studies)

⊕⊕⊝⊝
low2,4

5 per 1000

3 per 1000
(0 to 25)

Moderate

0 per 1000

0 per 1000
(0 to 0)

Overall postoperative morbidity

Follow up: 30 days

Study population

RR 1.23
(0.97 to 1.58)

646
(3 studies)

⊕⊕⊝⊝
low1,2,3

232 per 1000

285 per 1000
(225 to 367)

Moderate

239 per 1000

294 per 1000
(232 to 378)

Reoperation rate

Follow up: 30 days

Study population

RR 0.51
(0.15 to 1.71)

376
(2 studies)

⊕⊝⊝⊝
very low1,2,4

38 per 1000

20 per 1000
(6 to 65)

Moderate

27 per 1000

14 per 1000
(4 to 46)

Serious adverse events

This outcome was not reported in any of the included studies.

Quality of life

This outcome was not reported in any of the included studies.

Cost effectiveness

This outcome was not reported in any of the included studies.

Length of hospital stay (days)

The mean length of hospital stay was

11.4 days

The mean length of hospital stay was 0.32 days higher

(1.06 lower to 1.70 higher)

MD 0.32

(‐1.06 to 1.70)

755
(4 studies)

⊕⊕⊕⊝
moderate1,2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio; OR: Odds ratio; MD: Mean difference; ISGPF: International Study Group on Pancreatic Fistula

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded one level for serious risk of bias.
2 Publication bias could not be assessed because of there being few studies.
3 Downgraded one level for serious imprecision (the confidence interval of risk ratio overlapped 0.75 and 1.25).
4 Downgraded two levels for very serious imprecision (very few events, confidence intervals of risk ratios overlapped 0.75 and 1.25).

Figures and Tables -
Summary of findings for the main comparison. Application of fibrin sealants to pancreatic stump closure reinforcement for the prevention of postoperative pancreatic fistula following distal pancreatectomy
Summary of findings 2. Application of fibrin sealants to pancreatic anastomosis reinforcement for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy

Application of fibrin sealants to pancreatic anastomosis reinforcement for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy

Patient or population: people undergoing pancreaticoduodenectomy
Setting: hospital

Intervention: fibrin sealant

Comparison: no fibrin sealant

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with no fibrin sealants

Risk with fibrin sealants

Postoperative pancreatic fistula (ISGPF definition)

Follow up: 30 days

Study population

RR 0.25
(0.01 to 5.06)

57
(1 study)

⊕⊝⊝⊝
very low1,2,3

62 per 1000

16 per 1000
(1 to 316)

Moderate

63 per 1000

16 per 1000
(1 to 319)

Postoperative mortality

Follow up: 30 days

Study population

Peto OR 0.15
(0 to 7.76)

251
(3 studies)

⊕⊕⊝⊝
low2,3

7 per 1000

1 per 1000
(0 to 54)

Moderate

0 per 1000

0 per 1000
(0 to 0)

Overall postoperative morbidity

Follow up: 30 days

Study population

RR 0.97
(0.65 to 1.45)

181
(2 studies)

⊕⊝⊝⊝
very low1,2,3

347 per 1000

337 per 1000
(226 to 503)

Moderate

370 per 1000

359 per 1000
(240 to 537)

Reoperation rate

Follow up: 30 days

Study population

RR 0.83
(0.33 to 2.11)

181
(2 studies)

⊕⊝⊝⊝
very low1,2,3

92 per 1000

76 per 1000
(30 to 194)

Moderate

133 per 1000

110 per 1000
(44 to 281)

Serious adverse events

This outcome was not reported in any of the included studies.

Quality of life

This outcome was not reported in any of the included studies.

Cost effectiveness

This outcome was not reported in any of the included studies.

Length of hospital stay (days)

The mean length of hospital stay was

14.8 days

The mean length of hospital stay was

1.58 days lower
(3.96 lower to 0.81 higher)

MD −1.58
(‐3.96 to 0.81)

181
(2 studies)

⊕⊕⊝⊝
low1,3,4

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio; OR: Odds ratio; MD: Mean difference; ISGPF: International Study Group on Pancreatic Fistula

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded one level for serious risk of bias.
2 Downgraded two levels for very serious imprecision (small sample size, confidence intervals of risk ratios overlapped 0.75 and 1.25).
3 Publication bias could not be assessed because of there being few studies.
4 Downgraded one level for serious imprecision (total population size was less than 400).

Figures and Tables -
Summary of findings 2. Application of fibrin sealants to pancreatic anastomosis reinforcement for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy
Summary of findings 3. Application of fibrin sealants to pancreatic duct occlusion for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy

Application of fibrin sealants to pancreatic duct occlusion for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy

Patient or population: people undergoing pancreaticoduodenectomy
Setting: hospital

Intervention: fibrin sealant

Comparison: no fibrin sealant

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with no fibrin sealants

Risk with fibrin sealants

Postoperative pancreatic fistula (ISGPF definition)

This outcome was not reported in any of the included studies.

Postoperative mortality

Follow up: 30 days

Study population

Peto OR 1.41
(0.63 to 3.13)

351
(2 studies)

⊕⊕⊝⊝
low1,2

61 per 1000

84 per 1000
(40 to 170)

Moderate

61 per 1000

84 per 1000
(40 to 170)

Overall postoperative morbidity

Follow up: 30 days

Study population

RR 1.16
(0.67 to 2.02)

351
(2 studies)

⊕⊝⊝⊝
very low1,2,3,4

276 per 1000

320 per 1000
(185 to 558)

Moderate

277 per 1000

321 per 1000
(185 to 559)

Reoperation rate

Follow up: 30 days

Study population

RR 0.85
(0.52 to 1.41)

351
(2 studies)

⊕⊝⊝⊝
very low1,2,3

160 per 1000

136 per 1000
(83 to 225)

Moderate

160 per 1000

136 per 1000
(83 to 226)

Serious adverse events (Diabetes mellitus)

Follow‐up: 3 to 12 months

3 months follow up

169

(1 study)

⊕⊕⊝⊝
low1,3,5

108 per 1000

337 per 1000

12 months follow up

145 per 1000

337 per 1000

Quality of life

This outcome was not reported in any of the included studies.

Cost effectiveness

This outcome was not reported in any of the included studies.

Length of hospital stay (days)

The mean length of hospital stay was

16.5 days

The mean length of hospital stay was

0.58 days higher

(5.74 lower to 6.89 higher)

MD 0.58

(‐5.74 to 6.89)

351

(2 studies)

⊕⊕⊝⊝
low1,3,5

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio; OR: Odds ratio; MD: Mean difference; ISGPF: International Study Group on Pancreatic Fistula

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded two levels for very serious imprecision (small sample size, confidence intervals of risk ratios overlapped 0.75 and 1.25).
2 Publication bias could not be assessed because of there being few studies.
3 Downgraded one level for serious risk of bias.
4 Downgraded one level for serious heterogeneity
5 Downgraded one level for serious imprecision (small sample size; total population size was less than 400).

Figures and Tables -
Summary of findings 3. Application of fibrin sealants to pancreatic duct occlusion for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy
Comparison 1. Fibrin sealants versus no fibrin sealant (pancreatic stump closure reinforcement after distal pancreatectomy)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Postoperative pancreatic fistula (ISGPF definition) Show forest plot

4

755

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.68, 1.35]

1.1 Fibrin glue

1

109

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.44, 2.37]

1.2 Fibrin sealant patch

3

646

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.58, 1.45]

2 Postoperative mortality Show forest plot

6

804

Peto Odds Ratio (Peto, Fixed, 95% CI)

0.52 [0.05, 5.03]

2.1 Fibrin glue

3

158

Peto Odds Ratio (Peto, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Fibrin sealant patch

3

646

Peto Odds Ratio (Peto, Fixed, 95% CI)

0.52 [0.05, 5.03]

3 Overall postoperative morbidity Show forest plot

3

646

Risk Ratio (M‐H, Random, 95% CI)

1.23 [0.97, 1.58]

4 Reoperation rate Show forest plot

2

376

Risk Ratio (M‐H, Random, 95% CI)

0.51 [0.15, 1.71]

5 Length of hospital stay Show forest plot

4

755

Mean Difference (IV, Random, 95% CI)

0.32 [‐1.06, 1.70]

Figures and Tables -
Comparison 1. Fibrin sealants versus no fibrin sealant (pancreatic stump closure reinforcement after distal pancreatectomy)
Comparison 2. Fibrin sealants versus no fibrin sealant (pancreatic anastomosis reinforcement after pancreaticoduodenectomy)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Postoperative pancreatic fistula (ISGPF definition) Show forest plot

1

57

Risk Ratio (M‐H, Random, 95% CI)

0.25 [0.01, 5.06]

1.1 Fibrin glue

1

57

Risk Ratio (M‐H, Random, 95% CI)

0.25 [0.01, 5.06]

1.2 Fibrin sealant patch

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Postoperative mortality Show forest plot

3

251

Peto Odds Ratio (Peto, Fixed, 95% CI)

0.15 [0.00, 7.76]

2.1 Fibrin glue

3

251

Peto Odds Ratio (Peto, Fixed, 95% CI)

0.15 [0.00, 7.76]

2.2 Fibrin sealant patch

0

0

Peto Odds Ratio (Peto, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Overall postoperative morbidity Show forest plot

2

181

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.65, 1.45]

4 Reoperation rate Show forest plot

2

181

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.33, 2.11]

5 Length of hospital stay Show forest plot

2

181

Mean Difference (IV, Random, 95% CI)

‐1.58 [‐3.96, 0.81]

Figures and Tables -
Comparison 2. Fibrin sealants versus no fibrin sealant (pancreatic anastomosis reinforcement after pancreaticoduodenectomy)
Comparison 3. Fibrin sealants versus no fibrin sealant (pancreatic duct occlusion after pancreaticoduodenectomy)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Postoperative mortality Show forest plot

2

351

Peto Odds Ratio (Peto, Fixed, 95% CI)

1.41 [0.63, 3.13]

1.1 Fibrin glue

2

351

Peto Odds Ratio (Peto, Fixed, 95% CI)

1.41 [0.63, 3.13]

1.2 Fibring sealant patch

0

0

Peto Odds Ratio (Peto, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Overall postoperative morbidity Show forest plot

2

351

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.67, 2.02]

3 Reoperation rate Show forest plot

2

351

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.52, 1.41]

4 Length of hospital stay Show forest plot

2

351

Mean Difference (IV, Random, 95% CI)

0.58 [‐5.74, 6.89]

Figures and Tables -
Comparison 3. Fibrin sealants versus no fibrin sealant (pancreatic duct occlusion after pancreaticoduodenectomy)