The Laryngoscope C 2015 The American Laryngological, V

Rhinological and Otological Society, Inc.

Systematic Review

Hemostatic Glues in Tonsillectomy: A Systematic Review Rhona Sproat, BMBCh, MA(Oxon), MRCS(ENT); Peter Radford, BMBCh, MA(Cantab), MSc, MRCS, DOHNS; Alison Hunt, MBBS, BSc(Hons), FRCS-ORL Objectives/Hypothesis: The aim of this study was to compare use of hemostatic glues to conventional techniques of intraoperative hemostasis for tonsillectomy. Study Design: A systematic review of the literature and meta-analysis. Methods: All published prospective controlled trials that compared hemostatic glues to conventional techniques of hemostasis were identified. We performed a meta-analysis of articles comparing fibrin sealant to electrocautery, and of those comparing electrocautery to electrocautery plus fibrin hemostasis. Results: Seven studies were identified that made qualifications for review, with a total of 748 patients. Outcome measures were postoperative hemorrhage recorded by investigators, and visual analogue scores of pain for day 1, day 3, and day 10 postoperatively. Use of fibrin sealant was not associated with a reduction in hemorrhage rates following tonsillectomy when compared to electrocautery (pooled relative risk [RR] 0.315; 95% confidence intervals [CI]: 0.047-2.093, 224 patients). No statistical difference in bleeding rate was seen between electrocautery hemostasis alone, compared to electrocautery with fibrin sealant (pooled RR 1.742; 95% CI: 0.433-7.005, 108 patients). No statistically significant difference in pain was identified. Conclusions: Pain and bleeding are significant causes of morbidity post-tonsillectomy. We conclude that there is no significant evidence to support hemostatic glues over current techniques for reducing severity of these outcomes. Consequently, we do not recommended hemostatic glues for routine use in current clinical practice. Studies were generally of low quality and inadequately powered to detect a statistical difference, even when pooled. We advocate further research to facilitate future meta-analysis. Key Words: Meta-analysis, tonsillectomy, pain, hemorrhage. Level of Evidence: NA Laryngoscope, 00:000–000, 2015

INTRODUCTION Postoperative pain and bleeding remain significant postoperative morbidities associated with tonsillectomy. Tonsillectomy is one of the most common procedures performed in otolaryngology, and as such, is not an insignificant burden to patients and health services. In 2003/ 2004, over 50,000 tonsillectomies were recorded within the United Kingdom.1 The impact of post-tonsillectomy hemorrhage on post-operative morbidity cannot be overstated. Posttonsillectomy hemorrhage is defined as primary or secondary. Primary hemorrhage is classified as hemorrhage

From the Ear, Nose, and Throat Department (R.S.), Royal National Throat Nose and Ear, London; Ear, Nose, and Throat Department (P.R.), Wexham Park Hospital, Slough; Ear, Nose, and Throat Department (A.H.), Milton Keynes NHS Foundation Trust, Standing Way, Milton Keynes, United Kingdom. Editor’s Note: This Manuscript was accepted for publication February 18, 2015. The authors have no funding, financial relationships, or conflicts of interest to disclose. Rhona Sproat, BMBCh, and Peter Radford, BMBCh, contributed equally to this work. Send correspondence to Rhona Sproat, BMBCh, ENT Department, Royal National Throat Nose and Ear, 330 Grays Inn Rd., London WC1X 8DA, United Kingdom. E-mail: [email protected] DOI: 10.1002/lary.25256

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during the first 24 hours postoperatively, and secondary hemorrhage is the term used to classify bleeding experienced thereafter. The National Tonsillectomy Audit (NTA), an audit of over 40,000 patients in UK hospitals from 2003 to 2004, reported primary and secondary hemorrhage rates of 0.6% and 3%, respectively.1 Overall, 0.9% of all patients returned to the operating room for hemorrhage control. Of the patients in this study, this equated to 318 individual patients undergoing further surgery to halt bleeding. Poor pain control postoperatively can result in reluctance to eat and drink and delayed discharge. There is evidence to suggest that post-discharge, onefifth of patients re-present to their general practitioner for additional analgesia,2 and 23% of 1,309 readmissions post-tonsillectomy recorded by the NTA were due to posttonsillectomy pain.1 There is resultant motivation to find a method of hemostasis that is safe, provides comparable or improved primary and secondary hemorrhage rates, and is associated with reduced postoperative pain scores. Hemostatic agents are not new. Fibrin products as hemostats were first described by Bergel in 1909.3 Hemostatic glues are used for a variety of different applications in a range of surgical spheres including urology, cardiac, and neuro- and vascular surgery. Sproat et al.: Hemostatic Glues in Tonsillectomy

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A recent study of laparoscopic partial nephrectomy reported routine use of fibrin and thrombin-based agents among US nephrologists.4 In the sphere of otolaryngology, the thrombin glue Floseal has been shown to be safe for utilization in head and neck surgery,5 and there is some evidence to support its application for use in functional endoscopic sinus surgery to reduce postoperative pain and bleeding.6 Fibrin glues contain both thrombin and fibrinogen. In the presence of calcium and factor XIII, thrombin converts fibrinogen to fibrin monomers, producing a fibrin clot. Some agents also contain antifibrinolytics such as bovine aprotinin. Thrombin glues contain thrombin often mixed with a gelatin matrix. Thrombin glues act at several steps in the coagulation cascade. Not only do they activate the final step, but they also have direct action on platelets; factors V, VII, and XII; and smooth muscle cells. Considerable effort has been expended to compare the influence of differing intraoperative dissection techniques and analgesics on post-tonsillectomy pain and bleeding. As yet, to our knowledge, there have been no systematic reviews or meta-analyses conducted examining the use of hemostatic glues on postoperative pain and hemorrhage. The purpose of this study was to assess the effects of hemostatic glues on post-tonsillectomy hemorrhage and bleeding rates.

Fig. 1. QUOROM flow chart. RCT 5randomized controlled trial; VAS, visual analog score.

METHODS

Results of the Search

Search Strategy

Thirty-two records, excluding duplications, were identified from literature searching as detailed above. Two authors screened the title and abstract for inclusion and exclusion criteria as identified above. Seventeen full-text articles were assessed. Specific exclusion criteria included use of a fibrin fleece delivery method rather than glue, assessment of visual analog pain scores by different substances swallowed, and one study that did not use a VAS to measure pain nor measure postoperative hemorrhage rate. Two studies were noncontrolled observation studies, and one article was a letter. Eleven studies were included within this review (Fig. 1).

A systematic literature search was carried out of Embase (January 1980 to August 2014), MEDLINE (January 1966 to August 2014), and Cochrane Library databases on August 25, 2014 using the terms “tonsillectomy,” “hemorrhage,” “pain,” “fibrin,” “thrombin,” “glue,” and “Floseal.” No limits were applied to the database search. Additionally, the Current Controlled Trials Register (www.controlledtrials.com) was interrogated for pertinent studies.

Selection Criteria for Analysis Two authors (R.S., P.R.) screened articles for analysis first by title and abstract, then by full-text article. Criteria for selection were as follows. Study type. Prospective randomized controlled trials— double or single blinded—comparing use of hemostatic glue with control were included in this study. Letters, abstracts only, and noncontrolled studies were excluded. Population. Both adult and pediatric studies were included. We did not apply language restrictions to the search or selection process. Treatment type. Tonsillectomy by any dissection method was included with use of hemostatic glues, fibrin or thrombin, bovine or human, by any manufacturer, applied to the wound. Articles that used hemostatic agents not manufactured as glues (e.g., fibrin-coated fleeces) were excluded. Outcome. Studies that included assessment of postoperative hemorrhage rates and/or postoperative pain using a visual analogue score (VAS) from the day of operation to the 10th postoperative day. Both studies that compared tonsillar fossae of the same patient and those that compared operative techniques between patients were included.

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Outcome Measures for Meta-analysis The primary outcome measures were postoperative hemorrhage as recorded by investigators and VAS of pain for day 1, day 3, and day 10 postoperatively. Authors were contacted for further breakdown of results if there were omissions.

Quality Assessment Quality of the acquired articles was assessed by one of the authors (P.R.) using the Jadad method, and the results are listed in Table I.7 The Jadad method measures the quality of a study as indicated by the article’s description of randomization, double blinding, and withdrawals or dropouts. Scoring is from 0 to 5, whereby 5 is a study scoring maximum points. Of the studies identified, authors (R.S./P.R.) made the decision to exclude Stevens et al.8 on the basis of a Jadad score of 1, indicating low quality.

Potential for Meta-analysis The articles acquired by the literature review had a high degree of heterogeneity in study design (Table II), making

Sproat et al.: Hemostatic Glues in Tonsillectomy

TABLE I. Quality Assessment of Articles Using the Jadad Method. Author

Jadad Score

postoperative hemorrhage. Park et al.,12 Segal et al.,13 and Stoeckli et al.14 assessed pain on days 1, 3, and 10 with sufficient data for analysis. The studies employed a range of different designs based on altered control and study arms outlined below. Groups for comparison were: 1) electrocautery versus fibrin sealant hemostasis, 2) electrocautery versus electrocautery and fibrin sealant, 3) individual surgeon’s standard dissection method (varied) versus additional fibrin sealant, and 4) ties versus fibrin sealant alone.

Moralee

2

Stoeckli Gross

3 2

Kitajiri

2

Vaiman Stevens

2 1

Jo

3

Blackmore Segal

3 4

Electrocautery Versus Fibrin Sealant Hemostasis

Park

2

Mozet

3

Two studies11,15, compared cold steel dissection and electrocautery hemostasis to cold steel dissection with fibrin sealant hemostasis. Moralee et al.11 used bipolar diathermy, and Vaiman et al.14 stated that electrocautery ranged from bipolar to point monopolar. Postoperative hemorrhage rate. Vaiman et al.15 recorded all hemorrhages up to 7 days postoperatively at daily patient visits, and Moralee et al.11 measured all hemorrhage requiring inpatient stay. Fibrin sealant was not associated with a reduction in hemorrhage rate following tonsillectomy (pooled relative risk 0.315; 95% confidence intervals [CI]: 0.047-2.093, 224 patients). Forest plot for results is shown in Figure 2 Postoperative pain. Vaiman et al.15 did not assess postoperative pain. Moralee et al.11 assessed pain VAS on days 0 and 1 postoperatively, and found pain scores to be significantly lower in the fibrin group. The mean VAS difference reported between each group was 1.4 (95% CI: 0.3-2.5) at day 1 and 1.4 (95% CI: 0.3-2.5) at day 2.

The Jadad score7 is based on three questions, each scoring 0 for a negative response and 1 for a positive response. The questions are as follows: 1) Was the study described as randomized? 2) Was the study described as double blind? 3) Were withdrawals and dropouts described? An additional point can be scored for both randomization or blinding, respectively, if an appropriate description of the process in question is described. A negative mark can be awarded for both randomization and blinding respectively if the process was described, but this description was deemed inappropriate, as defined by Jadad. Each article can score a maximum of five points.

formal statistical analysis via meta-analysis inappropriate across the full range of studies. Where meta-analysis was appropriate, this was carried out using OpenMeta[Analyst] (available at http://www.cebm.brown.edu/open_meta). This heterogeneity included variation in the control and study arms of the articles. Further heterogeneity existed within the recording of outcome measures. These variations in study design are outlined in Table II. The systematic review is divided into two categories of studies assessing fibrin sealants and those assessing thrombin sealants.

Electrocautery Versus Electrocautery and Fibrin Sealant

RESULTS Fibrin Sealants Seven studies were identified that met qualification for review.9–15 Of these, all but Park et al.12 assessed for

Two studies12,14 compared electrocautery dissection and hemostasis to electrocautery dissection and hemostasis with additional fibrin sealant. Stoeckli et al.14 used

TABLE II. Characteristics of Included Studies. Country

Year

No. of Participants

Moralee

United Kingdom

1994

50

Human fibrin

Diathermy

Stoeckli

Switzerland

1999

34

Human fibrin and bipolar diathermy (to one fossa of same patient)

Bipolar diathermy (to one fossa of same patient)

Gross

United States

2001

20

Bovine fibrin plus pressure/silk thread

Pressure/silk thread

Kitajiri

Japan

2001

74

Silk thread

Vaiman

Israel

2003

179

Silk thread and fibrin glue 6 lidocaine chloride Human fibrin

Jo

United States

2007

68

Bovine thrombin

Diathermy

Blackmore Segal

United Kingdom Israel

2008 2008

26 96

Human thrombin on one fossa Human fibrin plus surgeons preference

Silk ties on the other fossa Surgeon’s preference

Park

Korea

2009

25

Monopolar plus fibrin (to one fossa of same patient)

Monopolar (to one fossa of same patient)

Mozet

Germany

2012

176

Human thrombin

Diathermy

First Author

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Intervention group

Control group

Bipolar to point monopolar

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Fig. 2. Forest plot of relative risk with 95% confidence interval (C.I.) of postoperative hemorrhage for electrocautery compared to fibrin hemostasis. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]

bipolar hemostasis, and Park et al.12 used monopolar diathermy, but did not assess hemorrhage rate. Postoperative hemorrhage rate. Stoeckli et al14 reported no significant difference in postoperative hemorrhage rate between the control and fibrin group, with what was reported as 2 “minor hemorrhages,” not requiring a return to the operating room or blood transfusion in both control and fibrin groups, respectively (2/15 of control group, 13%; vs. 2/19 of fibrin treated group, 11%). Postoperative pain. Park et al.12 and Stoeckli et al.14 both measured pain using a VAS at days 1, 3, and 10 postoperatively. The meta-analysis of these results showed no statistically significant difference in VAS at days 1, 3, and 10, and demonstrated results that markedly trended in opposite directions (Fig. 3, Fig. 4, Fig. 5).

Individual Surgeon’s Standard Dissection Method (Varied) Versus Additional Fibrin Sealant Segal et al.13 used a study design where various different methods of dissection and hemostasis were utilized as control depending on surgeon’s preference, with the addition of fibrin glue being determined by randomization. This article showed no statistically significant effect of fibrin sealant on postoperative bleeding as defined by any visible blood from the mouth or nose postoperatively (5/50 in the control group vs. 6/46 in the study group, P 5.855) or visual analog pain scores up to 10 days postoperatively (P 5.988).

Ties Versus Fibrin Sealant Alone Gross et al.9 and Kitajiri et al.10 published studies comparing conventional “cold-steel” dissection and ties

for hemostasis against “cold-steel” dissection with both ties and fibrin sealant for hemostasis. Kitajiri’s study assessed two different fibrin groups, with one group receiving a fibrin preparation with additional lidocaine.9 For purposes of comparative assessment we ignored this group. Postoperative hemorrhage rate. No study arm in either article had any postoperative bleeding. Gross et al.9 measured postoperative bleeding as significant bleeding requiring hospital admission or further admission, and Kitajiri et al.10 did not specify criteria. Postoperative pain. Gross et al.’s study showed significant reduction in postoperative pain VAS on the evening of the operation for the fibrin sealant group (1.2 units of VAS difference; 95 % CI: 0.10-2.3), but this effect had become nonsignificant by day 1.9 Kitajiri did not use the VAS, but instead identified the number of days of postoperative analgesia and the number of days until the resumption of normal eating and drinking.10 There was no significant difference in these metrics between the two treatment arms.

Thombin Glues Three studies analyzing the effect of thrombin glues on post-tonsillectomy pain and bleeding were retrieved. Meta-analysis of these was not possible due to heterogeneity of study design. Postoperative hemorrhage. Blackmore et al. carried out 30 tonsillectomies in adult patients whereby they applied thrombin to one tonsillar fossa and ligatures for hemostasis to the other, and found that two patients (6.7%) had a reactionary hemorrhage during their original admission on the thrombin side.16 Blackmore et al. did not follow up on patients to record hemorrhage after

Fig. 3. Forest plot of relative risk with 95% confidence interval (C.I.) of postoperative pain visual analog score at day 1 for electrocautery compared to electrocautery plus fibrin hemostasis. [Color figure can be viewed in the online issue, which is available at www.laryngoscope. com.]

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Sproat et al.: Hemostatic Glues in Tonsillectomy

Fig. 4. Forest plot of relative risk with 95% confidence interval (C.I.) of postoperative pain visual analog score at day 3 for electrocautery compared to electrocautery plus fibrin hemostasis. [Color figure can be viewed in the online issue, which is available at www.laryngoscope. com.]

discharge. Jo et al. did not report any postoperative hemorrhage of any severity in either diathermy or thrombin glue–treated groups, as recorded in patient diaries.17 Mozet et al. found no significant difference in bleeding between thrombin and glue-treated arms, as defined by postoperative hemorrhage that required return to the operating room (4.9% for fibrin patients vs. 6.0% for electrocautery patients, P 5.76).18 Postoperative pain scores. Jo et al. used VAS to study pain for 68 patients randomized to receive either diathermy or thrombin glue hemostasis.17 The scores showed that patients who had received thrombin glue had significantly less pain from day 2 to day 11 postoperatively (P

Hemostatic glues in tonsillectomy: A systematic review.

The aim of this study was to compare use of hemostatic glues to conventional techniques of intraoperative hemostasis for tonsillectomy...
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