Conditions: Pain, Postoperative Postoperative Hemorrhage
Keywords: Tonsillectomy Adenotonsillectomy Pain Hemorrhage
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 18
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate the effect of combining two interventions already in use at some institutions for reducing post-operative pain following tonsillectomy or adenotonsillectomy. The standard of care at most institutions is to leave the tonsillectomy wound bed exposed to heal on its own over one to two weeks. At many institutions, surgeons inject or topically apply local anesthetics such as bupivacaine hydrochloride to the tonsillectomy wound bed to help reduce post-operative pain. At other institutions, surgeons apply a layer of fibrin sealant, which is derived from the proteins that help form blood clots in blood, to the tonsillectomy wound bed in order to cover the site and reduce irritation and exposure of the wound bed. Use of fibrin sealant has the additional benefit of potentially reducing postoperative bleeding (hemorrhage) rates. Both the post-tonsillectomy use of bupivacaine (injection and topical) and the use of topical fibrin sealant application have been studied previously in the scientific literature; some studies show a clear benefit, others show no significant reduction in pain when they are used. No studies have documented harm. The purpose of this study is to evaluate the efficacy of infusing bupivacaine anesthetic into the fibrin sealant prior to application to the tonsillectomy wound bed. In this way, the combined product would function as a sort of "medicated bandaid" covering the painful wound bed and slowly delivering an entirely safe total dose of bupivacaine into the wound bed to reduce post-operative pain. Parents will be provided post-operative pain measurements to complete during the first 10 postoperative days and return to the researchers for data analysis.

Detailed description:
The purpose of this study is to evaluate the effect of combining two interventions already in use at some institutions for reducing post-operative pain following tonsillectomy or adenotonsillectomy. The standard of care at most institutions is to leave the tonsillectomy wound bed exposed to heal on its own over one to two weeks. At many institutions, surgeons inject or topically apply local anesthetics such as bupivacaine hydrochloride to the tonsillectomy wound bed to help reduce post-operative pain. At other institutions, surgeons apply a layer of fibrin sealant, which is derived from the proteins that help form blood clots in blood, to the tonsillectomy wound bed in order to cover the site and reduce irritation and exposure of the wound bed. Use of fibrin sealant has the additional benefit of potentially reducing postoperative bleeding (hemorrhage) rates. Both the post-tonsillectomy use of bupivacaine (injection and topical) and the use of topical fibrin sealant application have been studied previously in the scientific literature; some studies show a clear benefit, others show no significant reduction in pain when they are used. No studies have documented harm. The purpose of this study is to evaluate the efficacy of infusing bupivacaine anesthetic into the fibrin sealant prior to application to the tonsillectomy wound bed. In this way, the combined product would function as a sort of "medicated bandaid" covering the painful wound bed and slowly delivering an entirely safe total dose of bupivacaine into the wound bed to reduce post-operative pain.

The hypothesis of this study is that the application of the bupivacaine-infused fibrin sealant will 1) reduce post-operative mean pain scores in children undergoing tonsillectomy or adenotonsillectomy using a validated pediatric pain scoring system, 2) reduce post-operative hemorrhage rates, 3) reduce post-operative vomiting, 4) reduce total doses of post-operative pain medication and narcotic pain medication required, and 5) expedite recovery as determined by return to normal diet and activity level.

The questions specific for this study include: 1) Does bupivacaine-infused fibrin sealant significantly reduce mean postoperative pain scores compared to fibrin sealant alone and compared to leaving the wound bed open to heal?, 2) Does bupivacaine-infused fibrin sealant significantly reduce mean postoperative tonsil hemorrhage rates compared to fibrin sealant alone and compared to leaving the wound bed open to heal? 3) Do children receiving bupivacaine-infused fibrin sealant require less pain medication compared to fibrin sealant alone or to leaving the wound bed open to heal?, 4) Do children receiving bupivacaine-infused fibrin sealant return to normal diet and normal activity sooner compared to fibrin sealant alone or to leaving the wound bed open to heal?, 5) Do the parents of children receiving bupivacaine-infused fibrin sealant make less calls to the clinic or the physician on call compared to fibrin sealant alone or to leaving the wound bed open to heal?

After discussion of the risks and benefits of performing tonsillectomy or adenotonsillectomy per routine, parents will be offered (if child meets inclusion criteria elaborated below) to participate in this research study. This discussion will take place either during the clinic encounter when the patient is signed up for their surgical procedure or on the day of surgery. The Informed Consent Statement will be reviewed with the parent/patient and either the surgical staff, resident investigators, or clinic nursing personnel included in the IRB proposal will be the individuals performing the discussion with the parents. If parents are agreeable to participating in the study and all questions have been asked and no exclusion criteria met, then the child will be enrolled.

The child will be randomized to one of the three treatment arms elaborated in this application. Randomization arms include either: 1) leave wound bed open to heal, 2) application of unaltered fibrin sealant, and 3) application of bupivicaine-induced fibrin sealant. Children will undergo tonsillectomy or adenotonsillectomy per routine, but at the conclusion of the surgical procedure will have either of the 3 treatment options performed as above.

For some children who have clinical concern for sleep disordered breathing or obstructive sleep apnea on a sleep study, the surgical procedure may also involve a direct laryngoscopy and bronchoscopy performed prior to tonsillectomy or adenotonsillectomy. During the laryngoscopy and bronchoscopy, the airway from the level of the mouth to the branches of the windpipe into each lung are inspected with small rigid cameras (endoscopes); if floppiness/collapse (laryngomalacia) of the supraglottis (tissue above the vocal cords) is observed, the child will undergo a laser supraglottoplasty to remove the floppy tissue and relieve the obstruction. If a child has laryngomalacia and supraglottoplasty is performed, the child will then be excluded from the study. Exclusion at this time is based on the creation of an additional wound bed in the throat which could weaken our ability to determine if application of fibrin sealant or bupivacaine-infused fibrin sealant is effective. If during direct laryngoscopy and bronchoscopy, no laryngomalacia is observed and no supraglottoplasty is performed, then the child will continue into the treatment arm into which they were randomized.

After inclusion, randomization, and proceeding with treatment based on the study arm to which the child was randomize, all parents/participants will received standardized post-operative discharge instructions with regard to pain medicine regimens and diet as well as an envelope containing pain assessment questionnaires to be completed 3 times daily for 10 days as a means of documenting pain scores among other data points. The parents will receive a pre-addressed, pre-stamped envelop to facilitate return of their data to the researchers. Currently our clinic nurses call the family of patients approximately 2-3 weeks after surgery to inquire as to how the child is doing and to ensure that if the family desires a follow up appointment that one will be made. Parents of children included in this study will receive a similar phone call during the same approximate time frame either by the clinic nurses or by the surgical staff or resident investigators, but additional specific questions regarding post-operative bleeding and pain control will be documented for research purposes. Additionally, during this phone call, parents will be reminded to complete and return their post-operative pain assessment sheets in the provided pre-addressed, pre-stamped envelopes they received on the day of surgery.

Arms:
arm 1: 44 patients will be randomized to receive no topical treatment to their tonsillectomy (or adenotonsillectomy) wound bed as is the current standard of care at our institution. The wound bed will be treated with instrumentation in the operating room to ensure adequate hemostasis alone. arm 2: 44 patients will be randomized to receive application of topical fibrin sealant to their tonsillectomy (or adenotonsillectomy) wound bed to assess the pain reduction benefits of fibrin sealant alone. Prior to application of fibrin sealant, the wound bed will be treated with instrumentation in the operating room to ensure adequate hemostasis. arm 3: 44 patients will be randomized to receive application of topical bupivacaine-infused fibrin sealant to their tonsillectomy (or adenotonsillectomy) wound bed to assess the pain reduction benefits of fibrin sealant alone. Prior to application of fibrin sealant, the wound bed will be treated with instrumentation in the operating room to ensure adequate hemostasis.

Interventions: intervention 1: Bupivacaine intervention 2: Fibrin Sealant
Intervention descriptions: intervention 1: 1 milliliter (mL) of 0.75% Bupivacaine Hydrochloride will be infused into 4mL of fibrin sealant (diluting the Bupivacaine HCl to 0.15%). The bupivacaine-infused fibrin sealant will then be applied to the tonsillectomy (or adenotonsillectomy) wound bed. intervention 2: Fibrin sealant will be applied to the wound bed topically as per product instructions.

Protocol document:
Prot_SAP_000.pdf: 
Wannemuehler, 1  
RESIDENT RESEARCH PROPOSAL TEMPLATES:  
7/16/2015 
 
 
 
 
 
Effect of bupivacaine-infused fibrin sealant 
application on post-tonsillectomy pain & 
hemorrhage: A clinical trial 
 
IRB Study # 1501306006 
Clinicaltrials.gov # NCT02343263 
 
 
Principal Investigator’s name and address 
Bruce H. Matt, MD, MS(Otolaryng.) 
Associate Professor 
Department of Otolaryngology-Head and Neck Surgery 
Indiana University School of Medicine 
Gatch Hall 
1120 W. Michigan Street 
Indianapolis, IN  46202 
 
Co-Investigators: 
Todd J. Wannemuehler, MD, 
 
Please indicate whether it is for Grant/Publication/Meeting or Publication/Meeting 
only: 
 
___ This is a research proposal for grant submission (and future publication and 
national meeting) 
 
_x_ This is a research proposal for publication and national meeting only 
 
 
To which Journal are you considering submission (using Author Guidelines from 
which journal)? 
 
Otolaryngology – Head & Neck Surgery (Official Journal of the American Academy of 
Otolaryngology-Head & Neck Surgery) 


Wannemuehler, 2  
Table of Contents: 
Study Schema 
1.0 
Background 
2.0 
Rationale, Hypothesis, and Specific Aims / Outcomes 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Reporting of Adverse Events or Unanticipated Problems Involving Risk 
to Participants or Others 
7.0 
Study Withdrawal/Discontinuation 
8.0 
Statistical Considerations 
9.0 
Privacy/Confidentiality Issues 
10.0 Follow-up and Record Retention 
11.0 Anticipated Results, Potential Issues, Alternative Approaches 
12.0 Grant Targets 
13.0 Contacts 
14.0 References 
15.0 Infusing the Tisseel® Duo Set® System with Bupivacaine 
16.0 Infusing the Evicel® Application Device with Bupivacaine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Wannemuehler, 3  
Study Schema 
 
1.0 Background: 
 
A History of Tonsillectomy Surgical Technique 
 
The effort by surgeons to reduce post-tonsillectomy hemorrhage and pain is as 
ancient as the procedure itself. Blunt digital tonsillectomy was first described in detail by 
Roman physician Aulus Cornelius Celsus who operated in Rome in the first century B.C. 
(McNeill, Júnior). The Greek physician and philosopher Galen of Pergamon later 
described a snare technique for tonsil amputation in the late 2nd century A.D. which 
was presumably the most common technique in use at that time (McNeill). In the late 5th 
century A.D., the Byzantine Aëtius of Amida first advocated partial tonsillectomy by 
removing only the exophytic visible tonsil tissue; this method protected the more robust 
hemorrhage-prone vasculature deep to the tonsil capsule and reduced pain-inducing 
injury to the peritonsillar musculature (McNeill, Júnior). Two centuries later, another 
Byzantine physician known as Paulus of Aegina recommended complete tonsillectomy 
with hook and curved scalpel while warning against operating on acutely inflamed tonsils 
in order to reduce hemorrhage risk. Further refinements in tonsillectomy technique were 
developed over the subsequent centuries (McNeill). 
By the dawn of the 1700s, the Scottish physician Peter Lowe described only 
three techniques then in use: the snare, the ligature, and the excision; but all three 
were associated with varying degrees of postoperative pain and hemorrhage risk 
(McNeill). The first guillotine tonsillotome was developed as an alteration of the then 
centuries-old uvulotome in the late 1820s by Philip Physick, an American surgeon who 
trained in Philadelphia and abroad in Scotland; this instrument purportedly offered 
reduced postoperative pain as well as reduced hemorrhage risk compared to prior 
methods (McNeill, Júnior). The guillotine tonsillotome underwent modifications by 
Physick himself and later by William Fahnestock in the early 1800s (Júnior). 
Guillotine tonsillotome dissection remained the mainstay of surgical approaches 
during the early part of the nineteenth century (McNeill). However, the surgical 
experiences and reports of American surgeons W. L. Ballenger and later Greenfield 
Sluder as well as British surgeons George Waugh, Samuel Whillis and Frederick Pybus 
cumulatively led to a return of complete tonsillectomy as the standard of care (McNeill, 
Júnior). With the development of modern anesthesia, intubation techniques, and the 
specialty field of Otorhinolaryngology, more rapid progress in reducing post-
tonsillectomy pain and hemorrhage were developed (Júnior). An emphasis on utilizing 
cold steel with forceps and scalpels was reported to produce less intraoperative and 
postoperative bleeding. General anesthesia allowed Dr. Lee Cohen to develop and 
promote routine peritonsillar vessel ligation for prevention of postoperative tonsil 
hemorrhage in 1910 (Júnior, Cohen L). This hemostatic development was subsequently 
followed in the 1930s by Dr. Gregg Dillinger’s use of electrical diathermy to cauterize the 
wound bed during complete tonsillectomy and thereby reduce postoperative 
hemorrhage although this thermal injury increased postoperative pain (Júnior). 
By the 1940s, tonsillectomy had become the most frequently performed surgical 
procedure in the United States with nearly two million performed annually for a variety 
of appropriate and questionable indications (Júnior, Myers). Reports indicate that 


Wannemuehler, 4  
procedure requests by patients because of the publicity of a famous person having 
undergone tonsillectomy were not uncommon (McNeill). Despite the popularity and 
incidence of tonsillectomy at that time, the problem of postoperative pain and 
hemorrhage remained. Monopolar cautery, which had been previously invented for other 
surgical approaches, was adapted and became the mainstay approach to tonsillectomy 
in the following years in the United States (Myers). 
The last several decades, has seen an increasing prevalence of American 
otolaryngologists (Ear, Nose & Throat physicians or ENTs) favoring electrocautery 
techniques and a concomitant proliferation of such techniques. Approximately 50% of 
ENTs now utilize monopolar cautery handheld instruments (Myers). A smaller but 
growing proportion of surgeons are using coblation electrosurgery which utilizes bipolar 
electrical current to induce a plasma field capable of dissecting tissue at temperatures 
much lower than that of monopolar cautery (Myers). In fact, coblation temperatures 
range from 40° Celsius (C) to 70°C while monopolar cautery temperatures are known to 
exceed 400°C (Walner). Coblation offers similar or less postoperative pain compared to 
monopolar cautery, similar postoperative hemorrhage rates, and the ability to perform 
concurrent adenoidectomy with a single instrument as well (Myers). Less than 10% of 
surgeons in the United States continue to use cold steel sharp dissection with vessel 
ligation for hemostasis (Myers, Walner). A variety of other modern but less commonly 
performed techniques exist which include laser ablation, radiofrequency ablation, 
harmonic scalpel excision, and partial/intracapsular tonsillectomy with powered 
instruments (Myers). 
 
History of Perioperative Interventions to Reduce Post-Tonsillectomy 
Pain & Hemorrhage 
 
While the surgical technique for tonsillectomy has progressed dramatically in the 
last two millennia, adjunctive medicinal efforts to improve post-tonsillectomy pain and 
hemorrhage have also improved. Celsus (1st century B.C.) recommended milk and 
vinegar styptic application for perioperative hemorrhage while acknowledging the 
discomfort of acid application to the tonsil fossae (McNeill, Júnior). Paulus of Aegina (7th 
century) recommended prophylactic cold water or oxycrate rinses, but in the case of 
active hemorrhage prescribed rinsing with water containing essence of boiled brambles, 
rose, or myrtles leaves (McNeill). British pioneer of laryngology Morrell MacKenzie (19th 
century) described use of tanno-gallic acid application for control of post-tonsillectomy 
hemorrhage as well as the utility of marshmallow consumption on postoperative pain 
control (McNeill). Later in the 19th century, Dr. Jacob Cohen in his book, “Diseases of the 
Throat” described the use of persulfate of iron to control postoperative tonsil bleeding 
(Cohen, JS). 
More recent common medicinal adjuncts including perioperative systemic steroid 
use, perioperative antibiotics, scheduled postoperative oral pain medication regimens, 
intraoperative local anesthetic injection, and intraoperative topical anesthetic usage have 
been evaluated as well. The 2011 Clinical Practice Guidelines for Tonsillectomy in 
Children produced by the American Academy of Otolaryngology – Head & Neck Surgery 
strongly recommended the administration of a single intraoperative dose of intravenous 
dexamethasone which has been shown to significantly decrease postoperative emesis as 
well as pain (Baugh). The same source strongly recommended a well-articulated parent-
friendly weight-based pain control regimen including acetaminophen with or without 


Wannemuehler, 5  
narcotic and non-steroidal anti-inflammatory medications such as ibuprofen (Baugh). 
The Guidelines strongly recommended against routine perioperative antibiotic use for 
lack of evidence demonstrating benefit and the frequency of adverse events (Baugh). 
A 1999 Cochrane Systematic Review evaluated the literature at that time 
supporting the routine use of local anesthetic injection and the 5 studies which met 
inclusion criteria demonstrated no clear benefit in postoperative pain control based on 
what the reviewers felt were appropriate pain assessment tools (Hollis). The same 
review article analyzed a single study which evaluated the efficacy of topical anesthetic 
spray and also found a lack of appropriate data to support sustained improvement in 
postoperative pain control (Hollis). The lack of efficacy for local anesthetic use is likely 
secondary to the fact that postoperative pain continues for a week or more after the 
surgery and local anesthetics are likely cleared from sites and metabolized within a day 
(Hollis). 
Tonsillectomy and adenotonsillectomy remain among the most frequently 
performed ambulatory pediatric surgeries in the United States with common indications 
for this surgery in adults and children including chronic tonsillitis and obstructive sleep 
apnea. Less common indications for these surgeries include peritonsillar abscesses, 
tonsillar asymmetry, and concern for malignancy (Myers). Yet despite the great progress 
in surgical and medicinal techniques, post-tonsillectomy pain and hemorrhage continue 
to be not infrequent complications. Pediatric patients are particularly prone to 
inadequate postoperative pain control which often leads to a downward spiral of 
worsening pain, decreasing oral tolerance, refusal of pain medications, and ultimately 
dehydration prompting emergency room evaluation. Hemorrhage rates remain between 
1 and 7% in the United States and similarly prompt emergency room visits, 
readmissions, and return trips to the operating room for hemorrhage control (Myers). 
Addressing post-tonsillectomy pain and hemorrhage continue to be one of the most 
frequent and troublesome issues facing the otolaryngologist on call overnight. 
Therefore great incentive and potential benefit exists, for both patients and 
surgeons, to continue research efforts toward further ameliorating post-tonsillectomy 
pain and hemorrhage.  Despite the 1999 Cochrane Systematic Review’s recommendation 
against use of injection and topical local anesthetics, researchers have continued to 
analyze the relative effect of different local anesthetics on postoperative tonsillectomy 
pain.  The most commonly studied local anesthetics include lidocaine and bupivacaine, 
the latter known for its greater potency and longer half-life. 
Kaygusuz in 2003 compared topical dexamethasone, topical bupivacaine, and 
topical lidocaine to each other and against placebo and determined that all medications 
were superior to placebo in reducing postoperative pain during the first week after 
pediatric tonsillectomy, with lidocaine scores superior to bupivacaine only on 
postoperative day 3 (Kaygusuz). In 2011, Ozmen & Ozmen compared topical lidocaine 
with epinephrine to topical bupivacaine administration in a randomized controlled trial of 
60 patients and found that while both anesthetics were superior to saline placebo, the 
topical bupivacaine remained superior to lidocaine from postoperative hour 17 through 
postoperative day 4 (Ozmen). A meta-analysis performed by Sun et al. included 7 
studies comparing bupivacaine injection to saline placebo and found that bupivacaine 
injection significantly reduced postoperative analgesia requirements and improved 
postoperative pain control (Sun). More recently in 2014, Haksever et al. compared 
injection bupivacaine to topical bupivacaine in pediatric patients and found that topical 
bupivacaine was superior in reducing postoperative pain than injection bupivacaine from 


Wannemuehler, 6  
the 5th postoperative hour up to the 5th postoperative day (Haksever). Cumulatively 
these more recent studies call into question the findings of the older Cochrane Review 
and suggest the superiority of topical bupivacaine over topical lidocaine, injection 
lidocaine, or injection bupivacaine in reducing postoperative tonsillectomy pain. 
 Another adjunctive medical treatment which has been explored in recent 
literature is the application of the hemostatic fibrin sealant to the tonsil fossae following 
tonsillectomy. Fibrin sealants utilize clotting factors to imitate the natural coagulation 
process and have been utilized in a wide variety of applications across surgical 
specialties (Dhillon). Several brand name fibrin sealants exist, but each has similar 
pharmacodynamics which involve mixing a solution of fibrinogen/anti-fibrinolytic with a 
solution of thrombin/calcium-chloride to produce a cross-linked protein matrix which 
demonstrates both hemostatic, adhesive, and porous properties (Dhillon, Spicer). Over 
time, the fibrin sealant is lysed slowly by endogenous enzymes in the patient’s tissues 
and absorbed (Dhillon). Stiller-Timor et al. analyzed the serum of patients who had fibrin 
sealant applied to the tonsil fossae following tonsillectomy and determined there was a 
significant reduction in the postoperative elevation of serum inflammatory cytokines and 
neutrophils immediately postoperatively and 12 hours postoperatively compared to 
patients who did not receive fibrin sealant; this suggests topical fibrin sealant may blunt 
the postoperative systemic inflammatory response (Stiller-Timor). 
Moralee et al. first evaluated use of fibrin sealant application to the tonsil fossae 
in 1994 and found that its use resulted in less postoperative pain than diathermy 
hemostasis (Moralee). In 1999, Stoeckli et al. reported a small study comparing bipolar 
electrocautery alone for hemostasis on one tonsil fossa versus bipolar electrocautery 
followed by application of fibrin sealant on the contralateral tonsil fossae within the 
same patient but found no significant difference between patient self-assessment of 
which tonsil fossa had more pain nor in hemorrhage rates between sides (Stoeckli). 
Another small study by Gross et al. in 2001 evaluated the addition of fibrin sealant to 
blunt dissection tonsillectomy with ligature hemostasis in pediatric patients; they found 
significant reductions in postoperative pain and emesis on the first postoperative day 
and a non-significant trend toward less pain the subsequent days (Gross). 
Stevens & Stevens in 2005 compared electrocautery alone for hemostasis versus 
electrocautery with the addition of fibrin sealant in adults and found that the treatment 
arm was narcotic free 48 hours earlier and more rapidly returned to work and regular 
activities (Stevens). Three subsequent studies by Vaiman and various colleagues in 
2003, 2006, and 2007, also demonstrated that fibrin sealant hemostasis alone resulted 
in less postoperative adenotonsillectomy pain than electrocautery hemostasis and 
suggested benefits in preventing postoperative tonsil hemorrhage as well (Vaiman 2003, 
Vaiman 2006, Vaiman 2007). Jo et al. in 2007 applied Floseal®, a product containing 
similar hemostatic components to fibrin sealant, to one tonsil fossa and utilized 
electrocautery alone on the other tonsil fossa and found significantly reduced 
intraoperative blood loss and operative times as well as significant reductions in pain 
from postoperative days 2 through 11 and significantly faster returns to normal activity 
and normal diet (Jo). Segal in 2008 and Nam in 2011, however, found no difference in 
postoperative pain, analgesic use, or time to return to normal activities or diet when 
comparing electrocautery hemostasis alone to electrocautery hemostasis followed by 
fibrin sealant application (Segal, Nam). Park et al. in 2009, in contradistinction to Segal 
and Nam’s studies, reported significantly reduced pain scores on postoperative days 1, 
3, and 10 on the tonsil fossa which received fibrin sealant application after 


Wannemuehler, 7  
electrocautery hemostasis compared to control tonsil fossae receiving only 
electrocautery hemostasis without fibrin sealant application (Park). 
While the literature offers promising but conflicting evidence of the efficacy of 
local anesthetics and fibrin sealants, a growing body of literature exists which 
demonstrates fibrin sealant as an effective drug delivery medium for a variety of clinical 
applications including delivery of local anesthetics (Spicer, Kitajiri, Zhibo). A large 
number of in vitro and in vivo studies have explored the use of fibrin sealant in the 
delivery of growth factors, chemotherapeutic agents, adenoviral gene vectors and 
synthetic medications (Spicer, Tofuku). An in vitro study by Itokazu in 1996 
demonstrated the sustained release of lidocaine from fibrin sealant over 4 days 
(Itokazu). In 2001, Kitajiri et al. evaluated the application of fibrin sealant mixed with 
4% lidocaine to the tonsillectomy wound bed and found that the lidocaine/fibrin sealant 
mixture significantly reduced the number of days when patients required analgesics and 
to return to normal diet compared to no sealant use; the fibrin sealant alone group did 
not achieve significant reductions and no adverse events in any group were noted 
(Kitajiri). Literature review demonstrates no other reports of using fibrin sealant mixed 
with topical anesthetic to provide sustained local anesthetic release and postoperative 
pain control following tonsillectomy or adenotonsillectomy. In 2009, Zhibo & Miaobo 
utilized a similar technique to significantly reduce postoperative pain following 
subpectoral breast augmentation by mixing lidocaine with fibrin sealant and applying it 
to the wound bed whereas lidocaine alone or fibrin sealant alone were significantly less 
effective (Zhibo). More recently, Haddock et al. in 2014 reported significantly reduced 
post-anesthesia care unit postoperative pain scores following hand surgery with the 
combination of lidocaine and bupivacaine with topical thrombin applied to the wound 
bed before closure compared to patients who received only the topical anesthetics 
without thrombin (Haddock). 
 
2.0 Rationale, Hypothesis, and Specific Aims / Outcomes 
 
Rationale for this Research 
 
Keeping in mind the ongoing need for improved postoperative tonsillectomy pain 
management and hemorrhage prevention, as well as the above cited recent advances in 
the use of fibrin sealant and local anesthetics, it is the purpose of this protocol to 
evaluate the effects of applying fibrin sealant infused with 0.75% bupivacaine to the 
tonsil fossae (and adenoid bed, if appropriate) following pediatric and adult 
tonsillectomy or adenotonsillectomy. The studies above demonstrate the superiority of 
bupivacaine over lidocaine in the treatment of post-tonsillectomy pain (Ozmen, Sun, 
Haksever). Bupivacaine offers several general advantages over lidocaine which include 
greater potency and longer duration of action; both local anesthetics are primarily 
metabolized by the liver, but the safe maximum dose for bupivacaine without 
epinephrine injection is lower at 2.5mg/kg compared to 5mg/kg allowed for lidocaine 
without epinephrine (Lerman). 
 
Hypothesis 
 
We hypothesize that children undergoing tonsillectomy or adenotonsillectomy 
followed by application of bupivacaine-infused fibrin sealant to the tonsil fossae (and 


Wannemuehler, 8  
adenoid bed, if appropriate) will experience less postoperative pain as determined by 
validated pain scoring systems, less postoperative hemorrhage rates, less postoperative 
emesis events, reduced total required doses of pain medication, and more rapid return 
to normal activity and normal diet, when compared to those treated with fibrin sealant 
alone or no fibrin sealant. 
 
Approach to Test Hypothesis 
 
Pre-clinical Phase: 
Prior to initiating evaluation of the bupivacaine-infused fibrin sealant in patients, 
evaluating the effect of adding the bupivacaine to the fibrin sealant with regard to 
adhesion strength and gross time to coagulation will be necessary to ensure that no 
deleterious effects are inadvertently achieved (Kitajiri). See procedures section below for 
more specific details regarding pre-clinical testing materials and methods. 
 
Clinical Phase: 
The effectiveness of bupivacaine-infused fibrin sealant on reducing postoperative 
pain and hemorrhage in children undergoing tonsillectomy or adenotonsillectomy will be 
evaluated. Children undergoing tonsillectomy or adenotonsillectomy at Riley Hospital for 
Children will be considered for inclusion. Patients included in the study will undergo 
tonsillectomy or adenotonsillectomy with the coblation device (ArthroCare® Corporation, 
Austin, TX) and be randomized to one of three experimental arms: 1. topical application 
of the bupivacaine-infused fibrin sealant to the tonsil fossae and adenoid bed (if 
adenoidectomy was also performed), or 2. topical application of fibrin sealant alone to 
the tonsil fossae and adenoid bed (if adenoidectomy was performed), or 3. no topical 
application with wound bed open to the air (current standard practice at our institution). 
Meta-analysis have found no clear benefit in local anesthetics alone so a local anesthetic 
only arm will not be included (Hollis). Patients and parents/guardians will be blinded to 
their treatment arm as will individuals performing study data analysis. See procedures 
section below for specific details regarding materials and methods. 
 
Outcome Measures 
 
Primary clinical outcome measures evaluated in each arm of the experiment will 
include age-appropriate validated pain scale measurement data as well as post-
tonsillectomy primary and secondary hemorrhage rates. Secondary outcome measures 
will include overnight pain medications usage, daily occurrence of emesis, total 
postoperative days until cessation of all analgesic requirements, total postoperative days 
until resumption of normal activities, total postoperative days until resumption of normal 
diet, total analgesic doses required per day (including narcotic dose component if 
applicable), necessity of contacting ENT doctor on-call, and necessity of contacting the 
ENT clinic. 
 
Pain Assessment: 
For children 1 year of age through 12 years of age, the Parent’s Postoperative 
Pain Measure (PPPM) will be utilized to provide parents with assessment tools for 
accurately measuring and recording young children’s pain levels. The PPPM was 
developed by Chambers et al. in 1996 and has been independently tested and validated 


Wannemuehler, 9  
as a well-established assessment of postoperative pain by parents for young children; 
this assessment demonstrates high inter-rater reliability and internal consistency and 
correlates well with validated self-assessment measures in older children (Chambers, 
Baeyer 2007). No single pain assessment scale among the well-validated and widely 
used scales in pediatric populations have been demonstrated to be superior to another, 
but the author of one review article recommends the PPPM specifically for postoperative 
pain (Tomlinson, Baeyer 2007). This assessment involves parents providing binary 
answers (0 or 1) to 15 questions and summating all questions (Chambers, Baeyer 2007). 
Parents/guardians for all treatment arms will be provided pain recording data 
sheets as well as pre-addressed pre-stamped envelopes for returning pain recording 
data sheets to the research facility. Parents/guardians will be encouraged to utilize pain 
assessments as these will enable them to most accurately assess and adequately treat 
their child’s pain. Pain assessments will be performed three times daily: morning, 
afternoon, evening. Paperwork and patient information handling is discussed in the 
privacy section below. Parents/guardians of all treatment arms will be contacted 
approximately 2 to 3 weeks postoperatively to remind family to return their pain 
recording data sheets. 
 
Hemorrhage Assessment: 
 
All parents/guardians will be contacted approximately 2 to 3 weeks 
postoperatively. During this contact, the question of occurrence and timing of 
postoperative bleeding will be posed. Any bleeding requiring presentation to an 
emergency department, admission, and/or return to the operating room will be 
considered significant and recorded with degree of necessary intervention noted; self-
limited minimal bleeding (<15mL, 1 tablespoon) or subjective reports of tasting blood 
without visually observing blood will not be considered significant bleeding. Primary 
tonsil hemorrhage (occurring <24 hours following surgery) versus secondary tonsil 
hemorrhage (occurring >24 hours following surgery) will be distinguished in data 
analysis. 
 
Assessment of Secondary Outcomes: 
 
The pain recording data sheets will include daily assessment of total analgesic 
doses required for day (including narcotic dose component if applicable). The pain 
recording data sheets described above will also contain daily “Yes/No” assessments of 
questions regarding: 1) “Did your child require pain medications during sleeping hours 
last night?”, 2) “Did your child throw up today (include number of times)?”, 3)  
“Did your child resume their normal activity level today?”, 4) “Did your child resume 
their normal diet today?”, 5) “Did you need to call ENT MD after business hours?”, and 
6) “Did you need to call the ENT clinic during the day?”. Additionally, pain medicine 
usage will be evaluated with the following input statements: 1) “Total Doses of narcotic 
pain medication required in last 24 hours?” and “Total Doses of non-narcotic pain 
medication required in last 24 hours.” This information will be returned simultaneously 
on the pain recording data sheets in the same pre-addressed pre-stamped envelopes. 
Parents/guardians will be reminded by phone correspondence approximately 2 to 3 
weeks postoperatively to include this data in their pain recording data sheets before 
mailing them back to researchers. 
 
 


Wannemuehler, 10  
3.0 Inclusion/Exclusion Criteria  
 
Inclusion 
• Age: 1 year old through 12 years of age. 
• Weight: 10 kilograms or more. 
• Undergoing tonsillectomy or adenotonsillectomy for the following conditions: 
o Chronic Pharyngitis / Recurrent Tonsillitis 
o PAPFA Syndrome 
o Upper Aerodigestive Obstruction Symptoms (sleep disordered breathing, 
dysphagia deemed secondary to tonsil size, etc) 
o Adenotonsillar Hypertrophy (ATH) 
o Obstructive Sleep Apnea (OSA; clinical diagnosis or by polysomnogram) 
o Chronic/Recurrent Tonsillolithiasis (Tonsil stones) 
 
Exclusion: 
• Undergoing additional surgical procedures within 14 days preceding or following 
the tonsillectomy or adenotonsillectomy. 
• Undergoing additional procedures concurrently with tonsillectomy or 
adenotonsillectomy other than (children receiving supraglottoplasty (SGP) will be 
excluded): 
o direct laryngoscopy (DL) 
o bronchoscopy (B) 
o nasal endoscopy 
o ear examination under anesthesia (E-EUA) and/or cerumen removal 
o bilateral myringotomy with insertion of ventilation tubes (BMT) 
• Tonsillectomy or adenotonsillectomy being performed for concern of malignancy 
of unknown primary. 
• Documented aprotinin allergy. 
• Documented allergy to amide local anesthetics (lidocaine, bupivacaine, etc). 
• Documented bleeding disorder or chronic anticoagulant use. 
• History of chronic pain disorder. 
• Chronic use of prescription narcotics or methadone. 
• Documented history of substance abuse or illicit drug use. 
• Documented history of alcoholism or alcohol abuse. 
• Gastrostomy/orogastric/nasogastric tube placement/use. 
• Planned intensive care unit (ICU) placement postoperatively. 
• Refusal to participate (Jehovah’s Witness – Fibrin sealant contains blood product) 
• Exclusion at the judgment of the investigator (e.g. ward of court, language 
barriers, etc.). 
 
 
4.0 Enrollment/Randomization 
 
Randomization will occur using an a priori computerized schedule. The 
computerized schedule will be consulted by the surgeon in the operating room (OR) on 
the day of surgery to determine into which arm the subject will be placed. Surgeons will 
not know prior to OR time into which arm the patient will be randomized. Patients or 
guardians/parents will not be informed into which arm they have been randomized. 
All randomizations will occur in the ORs at Riley Hospital for Children. 


Wannemuehler, 11  
5.0 Study Procedures 
 
Outline of Research Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion Criteria: Scheduled for adenotonsillectomy or tonsillectomy, children ages 1 year 
through 12 years, weight ≥10kg, undergoing procedure for the following indications: 
Chronic Pharyngitis/Recurrent Tonsillitis, PAPFA Syndrome, Upper Aerodigestive 
Obstruction Symptoms, ATH, OSA, Tonsil stones. 
Does patient meet exclusion criteria? Undergoing additional surgical procedures within 14 
days preceding or following the tonsillectomy or adenotonsillectomy, additional 
concurrent procedures (other than DL, B, nasal endoscopy, E-EUA, cerumen removal, 
BMT), undergoing SGP, Tonsillectomy or adenotonsillectomy for concern of malignancy of 
unknown primary, documented aprotinin allergy, documented amide anesthetic allergy, 
documented bleeding disorder, documented anticoagulant use, documented chronic pain 
disorder, documented chronic use of prescription narcotics or methadone, documented 
history of substance abuse or illicit drug use, documented history of alcoholism or alcohol 
abuse, gastrostomy/orogastric/nasogastric tube placement/use, planned postoperative 
ICU placement, refusal to participate, exclusion at judgment of investigator. 
Out of study. Standard 
postoperative care. 
RANDOMIZE 
1/3: tonsillectomy (or 
adenotonsillectomy) 
with no topical 
application. 
Yes 
Yes 
No; Obtain Informed Consent 
1/3: tonsillectomy (or 
adenotonsillectomy) + 
fibrin sealant application to 
tonsil fossae (and adenoid 
bed if applicable). 
1/3: tonsillectomy (or 
adenotonsillectomy) + 
bupivacaine-infused fibrin 
sealant application to tonsil 
fossae (and adenoid bed if 
applicable). 
Receive age-appropriate weight-based pain control regimen and pain recording data 
sheets. Data recorded for 10 days postoperatively by patient or parent/guardian. 
Approximately 2 to 3 week postoperative phone call to remind parent/guardian to 
return pain recording data sheet and to assess for postoperative hemorrhage. 
Data aggregation and analysis. 
Receipt of patient pain data 
recording sheets. 


Wannemuehler, 12  
Preclinical Evaluation 
 
Synthesis of Bupivacaine-infused Fibrin Sealant: 
 
1mL 0.75% bupivacaine solution will be added to EITHER the 4mL Baxter® 
Health Corporation Tisseel® brand fibrin sealant Duo Set® prefilled dual syringe system 
OR the 4mL Ethicon® Corporation Evicel® brand fibrin sealant Application Device by 
injecting 0.5mL bupivacaine solution into each syringe barrel using the technique 
described in Section 15 or Section 16 below (equivalent products by different venders). 
Then bupivacaine-infused sealant will be applied to the wound beds. It is anticipated 
that this will dilute the fibrin sealant components by 20% while infusing the bupivacaine 
to a concentration of 0.15% (or 1.5mg per 1 mL). While it might be supposed that 
reducing the fibrin sealant concentration would lower the adhesion strength, Kitajiri et 
al. found that the addition of lidocaine actually increased adhesion strength despite 
prolonging time to coagulation because of the removal of CaCl from the fibrin sealant 
components (Kitajiri). As the proposed infusion of bupivacaine does not require the 
removal of the CaCl component, there is not anticipated to be an unduly prolonged 
coagulation time. In fact, preliminary testing demonstrated no gross difference in time 
to coagulation with both the unaltered fibrin sealant and the bupivacaine fibrin sealant 
coagulating within several seconds after application. 
 
Assessing Adhesion Strength: 
 
A uniform aliquot of unaltered fibrin sealant will be utilized to affix the head of a 
2.38mm diameter plastic cylinder to a flat plastic sheet. This will be allowed to dry for 3 
minutes as per fibrin sealant instruction. Then, a sheering force will be applied in plane 
with the flat plastic sheet in order to determine the sheering strength in grams/cm2 
required to dislodge the plastic cylinder. This will be repeated for a total sample size of 
10. An identical procedure will be performed to assess the adhesion strength for the 
bupivacaine-infused fibrin sealant prepared as described above. Again, this will be 
repeated 10 times. Means between groups will be compared with 2-tailed T-tests. 
 
Clinical Evaluation 
 
Preoperative Management: 
As per our routine, the patient will initially be placed under general anesthesia by 
the anesthesia personnel using intravenous (IV) or inhaled anesthetic and 
cardiopulmonary monitoring is continued throughout the case. The patient generally 
receives 1mg/kg dose of IV dexamethasone up to 10 or 20mg (surgeon dependent). No 
perioperative antibiotics are administered unless the patient has an indication (e.g. 
artificial heart valve or significant valvular defect). Preoperative antiemetics are not 
routinely administered. Some patients may undergo airway evaluation with direct 
laryngoscopy or bronchoscopy and typically receive a half maximum dose (2-3mg/kg) of 
topical lidocaine sprayed directly onto the supraglottis and vocal folds. If supraglottlasty 
is performed, the patient will not be included in the study as this contributes an 
additional wound bed in the throat. After the patient is intubated with an oral Ring Adair 
and Elwyn (RAE) endotracheal tube (ETT) and the ETT is secured in place over the 
midline lower lip, the patient is draped for tonsillectomy or adenotonsillectomy. 
If the patient has been randomized to the bupivacaine-infused fibrin sealant arm 
or the fibrin sealant alone arm of the study, then the fibrin sealant will be thawed as per 


Wannemuehler, 13  
brand instructions. For the bupivacaine-infused fibrin sealant arm of the study, 1mL of 
0.75% bupivacaine preservative free solution will be drawn into the fibrin sealant 
applicator (approximately 0.5mL into each of the two coupled syringes). This mixture 
will be hand agitated to further facilitate mixing. The total dose of bupivacaine will be 
7.5mg (1.5mg bupivacaine per 1mL bupivacaine-infused fibrin sealant). This represents 
a less than half maximum dose for a 10kg patient so the half maximum dose of topical 
lidocaine which may have been used during direct laryngoscopy as noted above would 
be considered safe (total of all local anesthetics would not be over 100% of maximum 
dose). Either the unaltered fibrin sealant or the bupivacaine-infused fibrin sealant will 
remain available until needed during the case. 
 
Surgical Technique: 
 
Either a McIvor or Crowe-Davis mouth gag is utilized to provide exposure of the 
oral cavity and oropharynx and the mouth gag is expanded and suspended from the 
Mayo stand. If the adenoid bed is to be inspected for removal, the soft palate is 
palpated to ensure the absence of submucosal clefting and a red rubber catheter is 
inserted through the nostril and used to retract the soft palate while an angled dental 
mirror is utilized to inspect the degree of nasopharyngeal obstruction. If the adenoid bed 
is to be removed with an appropriately-sized adenoid curette, this is generally performed 
at this time and the nasopharynx is packed with oxymetazoline-soaked sponges. Then, 
either the left or right tonsil is grasped with a clamp and retracted toward the midline 
while the Coblator device (ArthroCare® Corporation, Austin, TX), with settings of 7 
ablation and 3 coagulation, is used with the other hand to excise the tonsil in a capsular 
plane between the tonsil and the pharyngeal constrictor muscles laterally. Care is taken 
to avoid injury to the surrounding musculature and mucosa. The tonsil is amputated and 
removed from the oral cavity. The same procedure is performed on the remaining tonsil. 
Areas of bleeding in the tonsil fossae are treated with the coagulation setting of the 
coblation device to achieve hemostasis. 
 
The adenoid bed, if not previously excised with an appropriately-sized adenoid 
curette prior to beginning tonsillectomy, is then ablated away utilizing the Coblator 
device with an ablation setting of 9. Whether curette or Coblator ablation was utilized to 
remove the adenoid pad, adenoid wound bed hemostasis is subsequently achieved as 
necessary with the Coblator device using a coagulation setting of 5. 
 
An orogastric tube is passed to suction away gastric and esophageal contents. 
 
Study Interventions: 
If patients have been randomized to the fibrin sealant alone application group, 
then approximately 2mL of fibrin sealant will be applied to each tonsil fossa (enough to 
cover the entire wound bed) and any remaining fibrin sealant will be applied to the 
adenoid bed; application will be facilitated using either the 4mL Baxter® Health 
Corporation Tisseel® brand fibrin sealant Duo Set® prefilled dual syringe system OR the 
4mL Ethicon® Corporation Evicel® brand fibrin sealant Application Device. As per fibrin 
sealant instruction, the product will be allowed to dry for 3 minutes. 
 
If the patients have been randomized to the bupivacaine-infused fibrin sealant 
group, then approximately 2mL of the bupivacaine-infused fibrin sealant will be applied 
to each tonsil fossa (approximately 3mg bupivacaine per tonsil fossa) and any remaining 
bupivacaine-infused fibrin sealant will be applied to the adenoid bed (approximately 
1.5mg bupivacaine applied to adenoid bed); as above, application will be facilitated 


Wannemuehler, 14  
using the 4mL Baxter® Health Corporation Tisseel® brand fibrin sealant Duo Set® 
prefilled dual syringe system OR the 4mL Ethicon® Corporation Evicel® brand fibrin 
sealant Application Device. As per fibrin sealant instruction, the product will be allowed 
to dry for 3 minutes. 
 
Whether patient has been randomized to receive bupivacaine-infused fibrin 
sealant, fibrin sealant alone, or no topical application, the mouth gag and red rubber 
catheter are then removed. All patients are extubated postoperatively in the operating 
room or occasionally the recovery room. 
 
Postoperative Care: 
Cardiopulmonary monitoring is continued for the duration of the hospital stay.  
Postoperative antibiotics are not routinely administered. If myringotomy with tube 
placement (BMT) is performed, most patients receive ototopical antibiotics to be used 
for several days to prevent clogging of the myringotomy tube and reduce postoperative 
tube otorrhea. BMT pain is negligible in most patients after the first postoperative day; 
BMT pain is much less on the first postoperative day than the pain caused by 
tonsillectomy so we do not anticipate that concurrently BMT will confound pain data 
recording. While in the post-anesthesia care unit (PACU), patients may receive an ice 
collar to the neck or other general nursing techniques to improve patient comfort. 
Acute post-anesthetic nausea may be appropriately treated with an antiemetic in 
the PACU or hospital ward if the patient is kept for observation. Patients may also 
receive IV pain medication if necessary during PACU or hospital ward stay, but 
preference is always given to oral pain medications. Patients are advised to pursue a 
soft diet as tolerated with emphasis on cold/liquid foods if as needed in the first few 
days with advancement to regular diet as tolerated. As stated above, parents/guardians 
will receive pain recording data sheets to be documented three times daily. Patients 
remaining in the hospital ward for observation will have parent documentation of pain 
and emesis as though they were at home; where gaps in assessment exist, the medical 
record will be consulted. 
Routine tonsillectomy and adenotonsillectomy postoperative pain regimens 
include weight-based acetaminophen oral solution (15mg/kg PO Q6H prn pain) or for 
older children and adults acetaminophen/hydrocodone 7.5mg/325mg/15mL elixir (0.2mL 
to 0.3mL/kg PO Q6H prn pain) or acetaminophen/hydrocodone tablets (5mg/325mg 1-2 
tabs PO Q6H prn pain). Typically, the acetaminophen containing medication is alternated 
with ibuprofen oral solution (10mg/kg PO Q6H prn pain) or ibuprofen tablets (400mg or 
600mg, dependent upon weight, PO Q6H prn pain) so the patient may receive a pain 
medication as frequently as every 3 hours if needed. Patients with liver or kidney 
pathology or history of gastric ulcers or NSAID intolerance may be provided alternate 
pain regimens. Parents/guardians are typically advised to schedule pain medications the 
first postoperative day and to set an alarm for pain medication overnight in order to 
prevent falling behind on pain control. 
All patients and parents/guardians will receive standardized postoperative care 
instructions with regard to diet, pain control regimen, wound changes, bleeding, and 
journal recording. 
 
 
 
 


Wannemuehler, 15  
6.0 Reporting of Adverse Events or Unanticipated Problems 
involving Risk to Participants or Others 
 
Adverse events (AEs) will be reported to the Internal Review Board (IRB).  
For AEs requiring prompt reporting, the appropriate PROMPT REPORTING FORM 
will be used. These will be submitted to the IU Human Subjects Office at (317) 278-
8289. 
For AEs not requiring prompt report, the information will be included in the 
continuing review forms. 
Tonsil hemorrhage or need to return to the OR to control tonsil hemorrhage are 
not considered AEs for this study. 
 
Safety Monitoring 
 
At all times we are available for questions and concerns, and should at any time 
a subject in any arm of the study experience a complication or adverse event, we will 
intervene as appropriate.  A theoretical risk exists of allergic reaction to the aprotinin 
component of the fibrin sealant and thus patients with known aprotinin allergy will be 
excluded from this study. As the fibrin sealant is synthesized from human plasma, a 
theoretical risk of viral particle transmission exists (Tisseel® Prescriber Information 
Document, Dhillon), but no confirmed cases of HIV or Hepatitis C transmission have 
occurred (Joch).  Prior studies documenting use of fibrin sealant in the setting of 
adenotonsillectomy or tonsillectomy have reported no adverse events (Dhillon, Gross, 
Kitajiri, Moralee, Nam, Segal, Stevens, Stoeckli, Vaiman 2003, Vaiman 2006, Vaiman 
2007, Jo, Park). Similarly, studies cited above documenting the topical use of 
bupivacaine in the setting of tonsillectomy or adenotonsillectomy have reported no 
significant adverse events or complications (Haksever, Kaygusuz, Ozmen). 
If a patient in any arm clinically deteriorates or manifests one of the exclusion 
criteria postoperatively, we will treat them as needed.  If any significant negative trend 
of adverse events related to the study intervention is noted, we will immediately 
postpone or terminate the study and notify the IRB of our findings. 
 
7.0 Study Withdrawal/Discontinuation 
 
The subject may choose to leave the study at any time, whether by declaring he 
or she is withdrawing or by failing to return the pain recording data sheets.  The subject 
may also be withdrawn from the study, if in the opinion of the investigator, continued 
participation would be detrimental for the care or health of the subject. Leaving the 
study will not result in any penalty or loss of benefits. The decision whether or not to 
participate in this study will not affect the subject’s current or future relations with Riley 
Hospital, Indiana University School of Medicine, nor Indiana University Health 
Physicians. Subjects who withdraw from the study will not continue to be followed for 
the purposes of this study. Any viable data obtained during the study on withdrawn 
subjects will be kept though as part of the study and included in the final results.  A 
referral to their withdrawal will be mentioned. 
 
 


Wannemuehler, 16  
8.0 Statistical Considerations 
 
A prior study demonstrated an average pain score of 7.2 on the first 
postoperative day for tonsillectomy without post-operative fibrin sealant application or 
local anesthetic injection with a standard deviation of 3, thus with a sample size of 44 
per treatment arm, this study will have 80% power to detect a 25% difference in pain 
scores between two treatment arms, assuming two-sided tests each conducted at a 5% 
significance level (Segal). Repeated measures analysis of variance (ANOVA) will be 
utilized to analyze pain score differences between groups and over time; distributional 
assumptions for the ANOVA will be checked, and nonparametric analyses will be 
performed if the assumptions are not satisfied. For hemorrhage rates, the low incidence 
in the general population makes power-scaling impractical and thus chi-square tests will 
be utilized to make comparisons between arms. For postoperative emesis frequency rate 
and necessity to contact the clinic or the physician on call, analysis of arms will likely 
proceed by Kruskal-Wallis or Wilcoxon Rank Sum tests. Days until narcotic 
discontinuation, days until analgesic discontinuation, days until resumption of normal 
activities, and days until resumption of normal diet will be analyzed between treatment 
arms likely using log-rank survival analysis and Kaplan-Meier curves. 
 
9.0 Privacy/Confidentiality Issues 
 
Efforts will be made to keep all personal information confidential. Subject identity 
will be excluded in published reports and databases in which results may be stored. 
• 
To assure confidentiality, the initial data will be entered into a database located 
in a password-protected desktop computer.  Once data is entered into the 
database, paper forms will scanned electronically and stored as .PDF files on the 
abovementioned desktop computer prior to being placed in appropriate HIPAA 
compliant shredder bins for disposal. All study information will be located in an 
area with limited public access. 
• 
Privacy will be ensured by confirming with the patient or parents/guardians that 
they are in a place where they feel comfortable discussing their or their child’s 
medical management before proceeding further with the study. 
• 
Any publication resulting from this investigation will protect the patient’s privacy 
by excluding any identifier.   
 
10.0 Follow-up and Record Retention 
 
Enrollment will continue until 44 subjects per treatment arm have had their 
postoperative pain recording data sheets returned (see statistical section above). Should 
a patient be enrolled but data not be returned for analysis, they will be considered 
withdrawn from the study and another enrollment will be required to achieve final 
sample size for adequate statistical power. 
Data will be retained before discarding for a minimum of 7 years for health data, 
per Indiana State law. When data will be discarded: any remaining paper documents will 
be placed in HIPAA compliant shredding bins for disposal and there will be a permanent 
deletion of the data from the desktop.   
 


Wannemuehler, 17  
11.0 Anticipated Results, Potential Issues, Alternative 
Approaches  
 
A reduction in the postoperative validated pain scores during the first 4 to 5 
postoperative days is anticipated. As mentioned above, prior studies have demonstrated 
the maintenance of fibrin sealant on the tonsillectomy site for at least this long and 
studies of local anesthetic release dynamics from fibrin sealant have suggested release 
for at least 4 days or more with release duration dependent on fibrin/thrombin 
concentrations (Itokazu, Spicer). Prior studies have not consistently reported a reduction 
in post-tonsillectomy hemorrhage and uncertainty remains in whether this study will find 
a reduction. 
With regard to secondary outcome measures, reduced postoperative emesis has 
been reported in association with fibrin sealant application following tonsillectomy and 
we anticipate similar reduction in our study (Gross). We also anticipate reduced total 
days to cessation of analgesic usage, reduced total days to cessation of narcotic usage, 
reduced total days to return to normal diet, and reduced total days to return to normal 
activity when bupivacaine-infused fibrin sealant is applied following tonsillectomy or 
adenotonsillectomy compared to fibrin sealant alone or no topical application. 
One concern of this study is the possibility of poor compliance on the part of 
parents/guardians in recording their pain scores consistently or failure to return their 
pain recording data sheets as requested. Segal in 2007 demonstrated an approximately 
60% return rate for pain journal materials by included patients (Segal). In order to 
improve compliance, the pain recording data sheet will be composed as simply as 
possible and with patient/parent-friendly language. Pre-addressed pre-stamped 
envelopes will also be provided. Clinic nurses will conduct phone calls approximately 2 to 
3 weeks postoperatively to remind parents/guardians to complete and return their pain 
recording data sheets. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Wannemuehler, 18  
12.0 Grant Targets 
 
American Academy of Otolaryngology – Head & Neck Surgery Foundation (AAO-
HNSF) Resident Research Award—Open to any AAO-HNS member in good standing who 
is a resident in an accredited otolaryngology-head and neck surgery training program in 
the U.S. or Canada. One year, any topic, non-renewable, $10,000 maximum total costs, 
up to eight available annually. 
 
AAO-HNSF Resident Research Grant sponsored by Cook Medical- Open to any 
AAO-HNS member in good standing who is a resident in an accredited otolaryngology-
head and neck surgery training program in the U.S. or Canada. Proposed projects may 
be related to paranasal sinus disease, salivary gland disease, sleep medicine, voice 
therapy, airway, ultrasound and tissue engineering. One year, non-renewable, $10,000. 
 
Indiana Clinical and Translational Sciences Institute Research Invention and 
Scientific Commercialization Program (CTSI RISC) – Projects with immediate potential to 
commercialize inventions, technologies or intellectual property. Grants open to IU faculty 
applicants, requires IURTC endorsement letter. $25,000 maximum, one-year project. 
 
Baxter® Healthcare Corporation BioScience Research Grant – Open to any clinical 
researcher. Proposed projects are reviewed quarterly (Submission due August 31, 2014). 
No listed duration restriction, $5,000 to $125,000 maximum cost.  
 
13.0 Contacts 
 
Baxter: 
Mindy Duffer – 363-6417; mindy_duffer@baxter.com;  
Brian Werne – 626-9591; brian_werne@baxter.com 
 
Dental Adhesive Research IU School of Dentistry: 
Tien-Min Gabriel Chu, PhD – tgchu@iu.edu 
 
Riley Pharmacy: 
Francine Breckler, PharmD – 944-2026; FBreckler@iuhealth.org 
Michael McGregory, Director of Pharmacy – mmcgrego@iuhealth.org 
 
Statistics IU Informatics: 
George Eckert, MAS – 274-2884; geckert@iu.edu 
 
IU Research & Technology Corporation 
Wesley Pennington – 278-1913; wwpennin@iu.edu 
 
Postoperative Parent Pain Measure Developers 
Christine Chambers, MD – Christin.Chambers@Dal.Ca 
Jennifer Parker, PhD – 902-470-7706; JenniferA.Parker@iwk.nshealth.ca 


Wannemuehler, 19  
14.0 References 
 
McNeill RA. (1 June 1960). "A History of Tonsillectomy: Two Millennia of Trauma, Hæmorrhage and 
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Júnior JFN, Hermann DR, Américo RR, Stamm RG, Hirata CW. (4 September 2006) “A Brief History 
of Tonsillectomy.” International Archives of Otorhinolaryngology 10(4): 314-317. 
 
Cohen, L (September 1910). “Routine Use of Ligature in Tonsillar Bleeding with Description of 
Technique.” Laryngoscope 29(9): 893-902. 
 
Myers, E. N., & Carrau, R. L. (2008). Operative Otolaryngology: Head and Neck Surgery, 2nd Ed., 
Chapter 23: Tonsillectomy. Philadelphia: Saunders/Elsevier. 169-181. 
 
Walner, DL et al. (2007). “Past and present instrument use in pediatric adenotonsillectomy. 
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Cohen, JS. (1872). Diseases of the throat. New York: William Wood & Company. 130-131. 
 
Baugh, et al. (4 January 2011). “Clinical Practice Guideline: Tonsillectomy in Children”. 
Otolaryngology – Head & Neck Surgery 144: S1-S30. 
 
Hollis, L J, Burnon, M J, Millar, J M. (25 October 1999). “Perioperative local anaesthesia for 
reducing pain following tonsillectomy.” The Cochrane Database Systematic Reviews 2(4, CD001874): 1-16. 
 
Kaygusuz, I, Susaman, N. (February 2003).  “The effects of dexamethasone, bupivacaine and 
topical lidocaine spray on pain after tonsillectomy.” International Journal of Pediatric Otorhinolaryngology 
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Sun, J, Wub, X, Meng, Y, Jin, L. (2 February 2010). “Bupivacaine versus normal saline for relief of 
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Ozmen OA, Ozmen S (10 November 2010). “Topical bupivacaine compared to lidocaine with 
epinephrine for post-tonsillectomy pain relief in children: A randomized controlled study.” International 
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Haksever, M, Ozmen, S, Akduman, D, Solmaz, F. (20 March 2014). “Topical bupivacaine compared 
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Dhillon, S. (2011). “Fibrin Sealant (Evicel [Quixil/Crosseal]): A Review of its Use as a Supportive 
Treatment for Haemostasis in Surgery.” Drugs 71(14):1893-9115. 
 
Spicer, PP, Mikos, AG. (20 November 2010). “Fibrin Glue as a Drug Delivery System.” Journal of 
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K. Tofuku, H. Koga, M. Yanase, and S. Komiya (2011). “The use of antibiotic-impregnated fibrin 
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Journal, vol. 21, no. 10, pp. 2027–2033, 2012. 
 
Stiller-Timor, L, et al. (23 January 2012). “Circulating cytokines in patients undergoing 
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Moralee, SJ, et al. (December 1994). “The effect of fibrin sealant haemostasis on post-operative 
pain in tonsillectomy.” Clinical Otolaryngology & Allied Sciences. 19(6):526-528. 
 
Stoeckli, SJ, Moe, KS, Huber, A, Schmid, S. (April 1999). “A Prospective Randomized Double-Blind 
Trial of Fibrin Glue for Pain and Bleeding After Tonsillectomy.” The Laryngoscope 109: 652-655. 


Wannemuehler, 20  
 
Gross, CW, et al. (February 2001). “Autologous Fibrin Sealant Reduces Pain after Tonsillectomy.” 
The Laryngoscope 111:259-263. 
 
Stevens, MH, Stevens, DC. (June 2005). “Pain Reduction by Fibrin Sealant in Older children and 
Adult Tonsillectomy.” The Laryngoscope 115:1093-1096. 
 
Vaiman, M, et al. (May 2003). “Effect of modern fibrin glue on bleeding after tonsillectomy and 
adenoidectomy.” Annals of Otology, Rhinology, & Laryngology 112(5):410-414. 
 
Vaiman, M, Krakovski, D, Gavrieli, H. (July 2006). “Fibrin sealant reduces pain after tonsillectomy: 
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Vaiman, M, Krakovski, D, Gavrieli, H. (5 April 2007). “Electromyography in evaluation of pain after 
different types of tonsillectomy: prospective randomized study.” Journal for Otorhinolaryngology 69(4): 256-
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Joch, C. (2003). “The safety of fibrin sealants.” Cardiovascular Surgery 11(S1): 23-28. 
 
 
 


Wannemuehler, 21  
15.0 Infusing the Tisseel® Duo Set® System with Bupivacaine 
 
The following figures and descriptions will be provided to personnel preparing 
the 0.75% bupivacaine-infused fibrin sealant for use in this study: 
 
Step 1: Material Acquisition & Arrangement: 
The 4mL Baxter® Health Corporation Tisseel® brand fibrin sealant Duo Set® 
prefilled dual syringe system must first be thawed per included instructions and 
arranged on the sterile field including the dual syringe barrels, the red plunger, the 
joining Y-connector piece with fastening strap, and the application cannula. Two empty 
sterile 5 mL syringes are also arranged on the sterile field. Two 5 mL sterile syringes 
containing 0.5mL each of 0.75% bupivacaine solution (with all air bubbles evacuated) 
are placed on the sterile field with the other supplies. Finally, two sterile 4-way stop-
cocks are arranged on the sterile field. The sterile syringes and stopcocks are contained 
in the anesthesia storage within each OR. The 0.75% bupivacaine solution will be kept 
at appropriate temperature in the OR or obtained from the OR pharmacy. 
 
 
 
 
 
 
 
 
 
 
 


Wannemuehler, 22  
Step 2: Inserting the Plunger Unilaterally. 
 
The red plunger should be oriented perpendicularly (90°) to the plane of the face 
of the dual syringe so that only a single syringe barrel plunger head is engaged. Eject all 
air bubbles from the dual syringe barrel. 
 
 
 
Step 3: Attaching the 0.75% Bupivacaine Syringe to the Duo Set® Syringe Barrel 
 
The 2 protective caps should be unscrewed from the female ends of one of the 
4-way stop-cocks while the larger male end cap of the 4-way stop-cock should remain in 
place. One of the two 5 mL syringes prefilled with 0.5mL 0.75% bupivacaine solution 
should be firmly screwed to one female end of the 4-way stop-cock. The “off” valve of 
the 4-way stop-cock should be oriented to point toward the large still capped male end. 
The syringe barrel male tip of the side with the single red plunger shaft inserted should 
be pushed firmly (does not screw) into the available female end of the 4-way stop-cock.  
 
 


Wannemuehler, 23  
Step 4: Injecting the Fibrin Sealant Component Syringe Barrel Contents into the 5 mL 
Syringe Containing 0.5mL of 0.75% Bupivacaine Solution. 
 
While supporting the 4-way stop-cock’s attachment to the Duo Set® syringe 
barrel with one hand, the red plunger is depressed with the other hand. This forces the 
fibrin sealant component through the 4-way stop-cock into the 5 mL syringe containing 
0.75% bupivacaine solution. NOTE: Failure to manually support the connection between 
the 4-way stop-cock and the Duo Set® syringe male end could result in spillage of the 
fibrin sealant contents as this connection is not affixed by screwing the attachments. 
The cost per fibrin sealant kit is ~$200. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Wannemuehler, 24  
Step 5: Mixing the Fibrin Sealant Component with the 0.75% Bupivacaine Solution. 
 
Detach the male end of the Duo Set® syringe from the female end of the 4-way 
stop-cock (some minute spillage of contents may occur with this). Then screw on one of 
the empty 5 mL syringes to the female end of the 4-way stop-cock. Again, ensure the 
“off” valve of the 4-way stop-cock is oriented to point toward the large still-capped male 
end. Alternatingly compress the plungers of each of the 5 mL syringes attached to the 4-
way stop-cock to force fluid contents from one 5 mL syringe to the other. Continue this 
process for 30 seconds. This will agitate and mix the fibrin sealant component with the 
0.75% bupivacaine. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Wannemuehler, 25  
Step 6: Injecting the Fibrin Sealant Bupivacaine Mixture Back Into the Duo Set® Syringe. 
 
Compress all of the fibrin sealant 0.75% bupivacaine mixture into a single 5 mL 
syringe on one side of the 4-way stop-cock by completely depressing the opposite 5 mL 
syringe plunger. Detach the empty 5 mL syringe and discard from sterile field. Eject any 
air bubbles from the 5 mL syringe and the 4-way stopcock. Firmly reinsert the male end 
of the empty Duo Set® syringe barrel to the free female end of the 4-way stop-cock. 
Slowly depress the 5 mL syringe barrel while supporting the connection between the 4-
way stop-cock and the Duo Set® syringe barrel (failure to do so could result in spillage 
of contents, ~$200). Entirely discard the now empty 5 mL syringe and 4-way stop-cock 
from the sterile field. This side of the Duo Set® syringe barrel will now contain 2.5mL of 
fibrin sealant component and 0.75% bupivacaine mixture and the grey plunger gasket 
will have been pushed past the 2mL hash mark. NOTE: It is essential the used 5mL 
syringes and 4-way stop-cock from steps 2-5 be entirely discarded from the sterile field 
at this time as inadvertently prematurely mixing contents between the Duo Set® syringe 
barrels will activate the fibrin sealant. 
 
 
 
Step 7: Steps 2-6 are Now Repeated for the Contralateral Duo Set® Syringe Barrel. 
 
At this time, the same steps above are repeated using the fresh unused 5 mL 
syringe containing 0.5mL of 0.75% bupivacaine solution, the fresh unused 4-way stop-
cock, and the fresh unused empty 5 mL syringe. Again, the used leftover 5 mL syringes 
and the 4-way stop-cock should discarded. 
 
 
 
 


Wannemuehler, 26  
Step 8: Arranging the Bupivacaine-infused Duo Set® System for Use. 
 
Each barrel of the Duo Set® system now contains 2.5mL of 0.15% bupivacaine-
infused fibrin sealant component and should have its gray plunger gasket positioned 
beyond the 2 mL hash mark as 0.5mL of 0.75% bupivacaine has been added to each 
barrel. This results in 1.5mg/mL concentration of bupivacaine. The red plunger can be 
inserted parallel to the plane of the Duo Set® syringe so each plunger head engages the 
gray plunger gasket of its respective syringe barrel. The plunger may be depressed to 
remove any air bubbles in the Duo Set® syringe barrels. The joining Y-connector piece’s 
female ends are aligned with the male ends of the Duo Set® syringe barrels and 
attached. The fastening strap male piece is inserted into one of the holes on the face of 
the Duo Set® syringe. Finally, the application cannula is screwed onto the end of the 
joining Y-connector. 
 
 
 
 
 


Wannemuehler, 27  
Step 9: Application of Bupivacaine-infused Fibrin Sealant to the Wound Beds. 
 
The applicator tip is placed over the tonsil fossa and an even layer of 
bupivacaine-infused fibrin sealant is applied at a steady rate by plunger depression. 
Approximately 2 mL of the bupivacaine-infused fibrin sealant (3mg bupivacaine) should 
be applied to a single tonsil fossa in order to evenly and entirely coat the exposed 
muscular wound bed. The application cannula should be removed and discarded if it 
becomes clogged and a fresh application cannula should be screwed on to complete 
application as necessary. Any remaining bupivacaine-infused fibrin sealant can be 
applied to the adenoidectomy wound bed as able. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Wannemuehler, 28  
16.0 Infusing the Evicel® Application Device with 
Bupivacaine 
 
The following figures and descriptions will be provided to personnel preparing 
the 0.75% bupivacaine-infused fibrin sealant for use in this study: 
 
Step 1: Material Acquisition & Arrangement: 
The 4mL Ethicon® Corporation Evicel® brand fibrin sealant Application Device 
must first be pre-filled with 2mL of the BAC2 (fibrinogen) solution in one syringe barrel 
and 2mL of the thrombin solution in the other syringe barrel per included instructions. 
The Application Device contents should then be arranged on the sterile field including 
the dual syringe barrel applicator and the joining Y-connector with attached cannula. 
Two 5 mL sterile syringes containing 0.5mL each of 0.75% bupivacaine solution (with all 
air bubbles evacuated) are placed on the sterile field with the other supplies. Finally, two 
sterile 4-way stop-cocks are arranged on the sterile field. The sterile syringes and 
stopcocks are contained in the anesthesia storage within each OR. The 0.75% 
bupivacaine solution will be kept at appropriate temperature in the OR or obtained from 
the OR pharmacy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Wannemuehler, 29  
Step 2: Attaching the 0.75% Bupivacaine Syringes to the Application Device 
 
The 2 protective caps should be unscrewed from the female ends of one of the 
4-way stop-cocks while the larger male end cap of the 4-way stop-cock should remain in 
place. One of the two 5 mL syringes prefilled with 0.5mL 0.75% bupivacaine solution 
should be firmly screwed to one female end of one the 4-way stop-cocks; the other 5 
mL syringe prefilled with 0.5mL 0.75% bupivacaine solution should be firmly screwed to 
the other 4-way stop-cock’s female end. The “off” valve of the 4-way stop-cocks should 
be oriented to point toward the large still capped male end. The free female ends of the 
two stop-cocks should be firmly screwed onto the free ends of the Application Device’s 
syringe barrels as shown below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Wannemuehler, 30  
Step 3: Mixing the Fibrin Sealant Component with the 0.75% Bupivacaine Solution.
 
After the stop-cocks are firmly affixed to the Application Device’s two syringes 
containing fibrin sealant components and the stop-cocks’ other female ends are each 
attached to the two 5mL syringes containing 0.5mL of 0.75% bupivacaine solution, the 
syringe barrel plungers are alternatingly depressed to force the fibrin sealant 
components to mix with bupivacaine solution through their respective stop-cocks. 
Alternatingly compress the plungers of each of the 5 mL syringes attached to the 4-way 
stop-cocks with the plungers of the Application Device to force fluid contents from the 
application device to the 5mL syringes and back again. Continue this process for 30 
seconds. This will agitate and mix the fibrin sealant component with the 0.75% 
bupivacaine. Complete this step by depressing the 5mL syringe plungers to push the 
newly mixed bupivacaine infused fibrin sealant components back into the Application 
Device. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Wannemuehler, 31  
Step 4: Removing the Stop-cocks and Empty 5mL Syringes From the Application Device. 
 
After compress all of the bupivacaine-infused fibrin sealant components back into 
the Application Device, detach the empty 5 mL syringes and stop-cocks and discard from 
sterile field. 
 
 
 
 
Step 5: Arranging the Bupivacaine-infused Application Device for Use. 
 
Each barrel of the Application Device now contains 2.5mL of 0.15% bupivacaine-
infused fibrin sealant component and should have its black plunger gasket positioned 
near the 2.5mL hash mark as 0.5mL of 0.75% bupivacaine has been added to each 
barrel. This results in 1.5mg/mL concentration of bupivacaine. The plungers of the 
Application Device may be depressed carefully to remove any air bubbles in the syringe 
barrels. The joining Y-connector piece’s female ends are aligned with the male ends of 
the Application Device syringe barrels and attached. 
 
 


Wannemuehler, 32  
Step 6: Application of Bupivacaine-infused Fibrin Sealant to the Wound Beds. 
 
The applicator tip is placed over the tonsil fossa and an even layer of 
bupivacaine-infused fibrin sealant is applied at a steady rate by plunger depression. 
Approximately 2 mL of the bupivacaine-infused fibrin sealant (3mg bupivacaine) should 
be applied to a single tonsil fossa in order to evenly and entirely coat the exposed 
muscular wound bed. The Y-piece/application cannula should be removed and discarded 
if it becomes clogged and a fresh application cannula should be screwed on to complete 
application as necessary. Any remaining bupivacaine-infused fibrin sealant can be 
applied to the adenoidectomy wound bed as able.