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Effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing: A prospective, double-blind, controlled clinical study
Accepted Manuscript Title: Effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing: a prospective, double-blind, controlled clinical study Author: Deniz Hancı Huseyin Altun PII: DOI: Reference:
S0165-5876(15)00351-1 http://dx.doi.org/doi:10.1016/j.ijporl.2015.07.016 PEDOT 7674
To appear in:
International Journal of Pediatric Otorhinolaryngology
Received date: Revised date: Accepted date:
23-4-2015 10-6-2015 12-7-2015
Please cite this article as: D. Hanci, H. Altun, Effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing: a prospective, double-blind, controlled clinical study, International Journal of Pediatric Otorhinolaryngology (2015), http://dx.doi.org/10.1016/j.ijporl.2015.07.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
*Title Page
Effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing: a prospective, double-blind, controlled clinical study
Authors:
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Deniz Hancı, MD. (1), Huseyin Altun, MD.(2)
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2. Yunus Emre Hospital ENT department, Istanbul
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1. Okmeydanı Education and Research Hospital ENT department, Istanbul
Corresponding Author: Huseyin Altun, MD.
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Sırt sok. No:184A-23 Armaganevler Umraniye Istanbul
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Tel: +905326350965
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E-mail: [email protected]
Running title: Effectiveness of hyaluronic acid Keywords: Tonsillectomy, Hyaluronic acid, Wound healing, Pain, Double-blind study
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*Manuscript 1
Effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing
Running title: Effectiveness of hyaluronic acid
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Keywords: Tonsillectomy, Hyaluronic acid, Wound healing, Pain, Double-blind study
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Summary Objectives: To find the effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing Methods: Fifty patients were included in this prospective, double-blind, controlled clinical
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study (20 males, 30 females mean age of 13.56 years). Hyaluronic acid was applied to one side and the other side was used as a control during tonsillectomy. Therefore, the same patient
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evaluated and scored the post-tonsillectomy pain, excluding individual bias.
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Results: Results indicated that patients had significantly lower pain scores for hyaluronic acid treated side (p<0.001). At the end of two weeks follow-up period, the wound in the hyaluronic
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acid side was almost completely healed, indicating that the healing was faster with hyaluronic acid compared to control side (p<0.001).
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Conclusion: Hyaluronic acid could be recommended as an effective treatment for the
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management of post-tonsillectomy pain and wound healing.
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Introduction Tonsillectomy produces an open wound, therefore, associated with significant postoperative pain which can last up to 14 to 21 days with a 2-4% risk of immediate or delayed hemorrhage (1,3-5,6-8). The morbidity rate caused by postoperative pain and
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secondary bleeding was reported to be one in 35,000 (5,9). Little is known about the real cause of post-tonsillectomy pain; however the main reasons of this prolonged moderate to
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severe pain were described to be related with the sensitivity of tonsillar fossae to tissue
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damage, the disruption of mucosa, the pharyngeal muscle spasms and glossopharyngeal and/or vagal nerve fiber irritation causing inflammation (5,6,9).
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Oral opioids such as codeine and nonsteroidal anti-inflammatory drugs are usually used to manage pain after tonsillectomy (2,7). It was well reported that respiratory depression,
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sedation and bleeding resulted from the unpredictable metabolism of opioids were one of the reasons of morphine toxicity causing morbidity and life-threading post-tonsillectomy
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complications (2,5,10). Therefore, the use of safer opioid and non-opioid analgesics as an alternative approach to relieve the pain caused by tonsillectomy is getting more important.
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The American Academy of Otolaryngology—Head and Neck Surgery (AAO-HNS), for example, currently recommends the routine use of ibuprofen for pain relief after tonsillectomy (4,5,11).
Hyaluronic acid is a linear, hydrophilic, high molecular weight glycosaminoglycan
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naturally found in the joint synovial fluid and in the extracellular matrix of skin in the human body (12-15). It is naturally secreted during wound healing in proliferative phase to stimulate the migration and mitosis of fibroblasts and epithelial cells (16-18). It was shown to reduce the levels of inflammatory mediators and, therefore, can safely be used as an antiinflammatory agent (13,18,19). Being a growth factor and having lubricant properties, hyaluronic acid is commonly used as a naturally biocompatible, biodegradable and non-
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immunogenic biomaterial in biological dressing formulations (19). The positive effect of the use of hyaluronic acid in pain relief and wound healing in treatment of pressure ulcers (15), in management of osteoarthritis (12), in treatment of tendon disorders (12), in non-surgical treatment of deep wounds (20), in burns, epithelial surgical wounds and chronic wounds (18)
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and in vocal fold wound healing in animal models (21) were reported. However, to our best knowledge there is no study investigating the effectiveness of hyaluronic acid on the
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treatment of tonsillectomy.
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Therefore, the aim of this prospective, double-blind, controlled clinical study was to evaluate the effectiveness of hyaluronic acid on the reduction of post-tonsillectomy pain and
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wound healing during the first 14 postoperative days.
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Materials and methods Patients and surgical procedure Between January 2013 and March 2014 , 50 patients listed for tonsillectomy were included to the study at Liv Hospital. The 50 patients were consecutive patients admitted to
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the clinic for tonsillectomy. There were no patients refused to participate in the study. The study protocol was approved by the Local Hospital Ethics Committee and conducted
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according to the Declaration of Helsinki. An informed consent was obtained from adult
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patients and from parents of children patients.
Indicators for tonsillectomy in this study were recurrent tonsillitis (acute tonsillitis 7
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times in first year, 5 times in second year, 3 and more times in third year) , tonsillar hypertrophy resulting in snoring and chronic tonsillitis which was not responding to medical
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therapy(beta-lactamase–resistant antibiotics), difficulty in eating and talking. The indications for antibiotic treatment in tonsillitis were history of fever, exudate, anterior servical
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lymphadenopathy. Exclusion criteria were bleeding disorder, having chronic or severe systemic disease like diabetes, peritonsillar abscess formation, unilateral tonsil hypertrophy,
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patients with obstructive sleep apnea and patients who received steroids, antiemetics, antihistamines, or psychoactive drugs within 24 h of surgery. A prospective, double-blind study design was used in the study. Tonsillectomy was done under general anesthesia with oral intubation and with conventional dissection and snare
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technique performed by the same otolaryngologist. Adenoidectomy was performed for 5 patients. During surgery, a hyaluronic acid gel ( Pure regen gel sinus,BioRegen Biomedical Co. Ltd Hamburg Germany ) was placed to one of the randomly selected sides and both anterior and posterior tonsillar plica are sutured with 4/0 Vicril .To the other side only anterior and posterior tonsilar plica suture were performed and be used as a control. Patients and care providers (mostly parents) were blinded to the hyaluronic acid placed side. After the
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surgery, patients were transferred to the postanesthesia care unit. They were moved to Ear Nose Throat Ward when fully awake, stable, and comfortable. Patients who were fully awake, alert, able to drink liquids, had stable vital signs, no nausea and no bleeding were considered to be ready for discharge. All patients were discharged the day after surgery with same
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analgesic ( paracetamol 4x500 mg per day for adults, 10-15 mg/kg per day) and same antibiotiotic ( amoxicillin/ clavulanic asid) twice daily for one week postoperativly in weight-
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related doses. None of the patients have received steroid and opioid analgesic treatment. All
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patients stayed overnight. Liquids, soft diet and activity rectriction were recommended for 1 week.
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Effectiveness assessments
Postoperative care was the same for all patients. All effectiveness assessments were
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recorded by an independent otolaryngologist blinded to the hyaluronic acid (1 ml) placed side. Post-tonsillectomy throat pain was measured twice a day (in the morning and in the
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afternoon) for each side during the period of 14 postoperative days using visual analog scale (VAS) on a scale of 0-10 after 2 hours of analgesic intake. Wound healing was assessed by
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direct visual examination of the area of slough in each tonsillar fossa at 7th, 10th and 14th postoperative days and scored on a scale of 0 to 5 (0 = completely healed wound, 5 = not healed wound). The wound healing score was evaluated by the method described by the Magdy et al (21). (Table I)
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Statistical analysis
Statistical analysis was performed by the SPSS software package for Windows
(Statistical Package for Social Sciences, version 12.0, SPSS Inc., Chicago, Illinois, USA). Categorical variables were given as numbers and percentages and quantitative variables as mean±standard deviation (SD), median, minimum and maximum values. The normality of quantitative variables were analyzed by Kolmogorov-Smirnov test and normally distributed
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variables were compared with Student’s t-paired test. The level of significance was set at
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p<0.05.
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Results Fifty patients were included to this prospective, double-blind, controlled clinical study on the effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing. There were 20 males (40%) and 30 females (60%) between 9 and 22 years, averaging 13.56
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years(median age 14.02). 34 patients (22 boy, 12 girl) were child. No major complications such as airway abstruction, hemorrhage from tonsillar fossae, dehydration, or anesthetic
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toxicity were observed.
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Effectiveness of hyaluronic acid on the reduction of post-tonsillectomy pain
Results of post-tonsillectomy throat pain measured twice a day (in the morning and in
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the afternoon) for non-treated (control) and hyaluronic acid placed sides during the period of 14 postoperative days using visual analog scale (VAS) on a scale of 0-10 were summarized in
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Table II. Accordingly, patient pain scores were significantly different between hyaluronic acid treatment compared to control both in the mornings and in the afternoons at all times during
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the postoperative care (p<0.001 for all, Table II). Post-tonsillectomy pain evaluated in the mornings for 14 postoperative days were significantly lower with hyaluronic acid treatment
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except at 2nd, 5th, 6th and 13th days where similar pain scores were given by the patients for both sides (Table II, Figure 1A). Post-tonsillectomy pain evaluated in the afternoons for 14 postoperative days were also significantly lower with hyaluronic acid treatment except at 3rd, 8th, 9th and 14th days where similar pain scores were given by the patients for both sides
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(Table II, Figure 1B). Results indicated that hyaluronic acid was effective in reducing the post-tonsillectomy pain.
The in group comparison of pain scores evaluated in the mornings and in the afternoons were also given in Table II. In control side, there was a statistically significant difference in patient pain scores in the morning compared to that of afternoon except 6th and 13th postoperative days (Table II). Results indicated that for 6 out of 14 days (at 3rd, 4th, 8th,
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9th, 10th and 14th days), patients evaluated significantly more post-tonsillectomy pain for non-treated side in the mornings than afternoons (Figure 1). With hyaluronic acid, there was a statistically significant difference in patient pain scores in the morning compared to that of afternoon except 1th and 3rd postoperative days (Table II). Results indicated that patients
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evaluated significantly more post-tonsillectomy pain with hyaluronic acid in the mornings than afternoons for 6 out of 14 days (at 2nd, 4th, 5th, 6th, 10th and 13th days, Figure 1).
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Effectiveness of hyaluronic acid on wound healing
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Results of wound healing assessment scored on a scale of 0 to 5 (0 = completely healed wound, 5 = not healed wound) at 7th, 10th and 14th postoperative days by direct visual
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examination of the area of slough in each tonsillar fossa were given in Table III and Figure 2. Accordingly, hyaluronic acid significantly enhanced wound healing compared to non-treated
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(control) side at all times (p<0.001 for all). At the end of two weeks follow-up period, the wound in the hyaluronic acid side was almost completely healed (1±0.30) whereas that of
(Table III, Figure 2).
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control side was not (2±0.37), indicating that the healing was faster with hyaluronic acid
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The in group comparison of wound healing with respect to postoperative time indicated that the difference between wound healing scores at 7th and 10th days was not statistically significant both for control (p = 0.659) and for hyaluronic acid placed side (p = 0.709). The comparison between 7th and 14th days and between 10th and 14th days, on the
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other hand, indicated a statistically significant increase in wound healing for both the control and hyaluronic acid placed sides (p<0.001 for all).
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Discussion Tonsillectomy is a commonly performed procedure with potentially life threating complications. The surgery causes substantial local trauma in the oropharynx and a wound that heals by secondary intention, therefore, it is associated with significant postoperative pain
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due to the release of pro-inflammatory factors and chemokines (3-5,7,23). The healing of tonsillar fossa takes about 2 weeks and, although gradually decreasing over the first week,
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significant to moderate pain resides during that period (4). Post-tonsillectomy pain may lead
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to poor oral intake, dehydration, late hemorrhage, emesis, sleep disturbances and behavioral differences and, therefore, usually requires careful management by oral analgesics (2,5-
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7,10,11,24,25). The mostly prescribed opioids for post-tonsillectomy pain relief are acetaminophen with codeine and oxycodon or hydrocodone (4,5).
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Opioid related respiratory depression was reported to be one of the main reasons of post-tonsillectomy mortality especially in young children (2,10,25). Both the Food and Drug
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Administration (FDA) and The American Academy of Otolaryngology—Head and Neck Surgery (AAO-HNS) declared a safety warning for the use of codeine in treatment of pain
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following tonsillectomy (2,3,5,11). However, the commonly prescribed acetaminophen may not be adequate for post-tonsillectomy pain relief without codeine and at higher doses it may cause hepatic toxicity (5). Therefore, there is an ongoing research on the investigation of effectiveness of many surgical and pharmacological products in post-tonsillectomy pain
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management (2,4,5,7,9,23,26). Subramayam et al. (2) reported their own experience on the use of ATC acetaminophen, dexamethasone and ibuprofen in pain management as no increase in the incidence of inadequate pain control or serious complications. Dexamethasone was shown to be more effective than intravenous acetaminophen to reduce pain in children (25). The effect of ropivacaine plus dexamethasone and ropivacaine alone was compared and it was concluded that ropivacaine plus dexamethasone infiltration lowered pain, postoperative
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nausea and vomiting and improved oral intake in children after tonsillectomy and adenoidectomy (7). Javid et al. (27) showed the safety and effectiveness of ketamine injections during surgery in post-tonsillectomy pain management. Systemic or local preoperative ketamine administration (10) and local infiltration of bupivacaine (28) have
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recently been reported to relieve post-tonsillectomy pain in children. Dostbil et al. (6) have recently reported the effectiveness of peritonsillar dexamethasone infiltration on postoperative
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pain and morbidity in pediatric adenotonsillectomy patients. Topical administrations of
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bupivacaine hydrochloride (29) and sucralfate (30) were shown to provide efficient posttonsillectomy pain control. Topical sucralfate and clindamycin have recently been shown to
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reduce post-tonsillectomy pain in children (25). However, there is still limited evidence and no consensus regarding the optimal treatment for post-tonsillectomy pain.
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Hyaluronic acid is a linear, hydrophilic, polyionic high molecular weight polysaccharide, which is a natural lubricant component of joint synovial fluid and is also
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found in extracellular matrix of connective tissue (12,13,18). It is a nonsulfated glycosaminoglycan that is secreted during wound healing and new tissue formation
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(16,18,19,31,32). As such, hyaluronic acid is considered as a biocompatible, biodegradable and non-immunogenic biomaterial of choice in biological dressings (19,33). The wound healing effect of hyaluronic acid was extensively studied since its discovery in 1934 and it found a wide usage in orthopedics and cosmetic surgery (17,32). For example, it is commonly
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used for tendon injuries and treatment of chronic tendiopathies, where the use of hyaluronic acid was shown to reduce the formation of scars and granulation tissue in several studies (12,32). Its effectiveness in the management of osteoarthritis by viscosupplementation therapy (12) and in the pain relief of temporomandibular joint disorders has recently been proven (13). Gencer et al. (13) also mentioned other beneficial effects of hyaluronic acid as a relatively long half-life of 13 hours and safety and effectiveness in repetitive intra-articular injection.
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Hyaluronic acid was also shown to enhance the wound healing effect of platelet-rich growth factor in treatment of pressure ulcers (15). Onesti et al. (20) has recently reported their positive results in four cases with chronic ulcers in terms of wound healing with topical application of collagenase and hyaluronic acid. Hyaluronic acid was shown to be beneficial in
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the treatment of diabetic foot by increasing the rate of wound healing (34). In summary, there appears to be an overall positive effect of hyaluronic acid in wound healing and pain relief.
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However, we did not encounter any study analyzing the effectiveness of the use of hyaluronic
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acid for post-tonsillectomy pain and wound healing in the literature. Therefore, to our knowledge, this is the first controlled, double-blind prospective report on the evaluation of the
healing during the first 14 postoperative days.
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effectiveness of hyaluronic acid on the reduction of post-tonsillectomy pain and wound
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The comparison of patient pain scores for hyaluronic acid placed and control sides indicated that hyaluronic acid significantly reduced post-tonsillectomy pain. Pain scores were
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evaluated both in the mornings and afternoons for 14 postoperative days and only for 6 out of 14 days patients gave similar pain scores for hyaluronic acid placed and control sides both in
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the mornings and in the afternoons. Tonsillectomy wounds are known to be prone to become inflamed and infected (5). A transient increase in pain due to increase in intensity of inflammation on the 3rd and 5th postoperative days and more intense pain in the morning were reported by Isaacson (4) and Sutters and Isaacson (5). In accordance with the literature,
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the comparison of morning and afternoon pain scores given by the patients indicated that 6 out of 14 postoperative days, patients suffered more pain in the mornings. The effectiveness of hyaluronic acid on wound healing was assessed at 7th, 10th and 14th postoperative days and results indicated that hyaluronic acid significantly enhanced wound healing. At the end of two weeks, hyaluronic acid placed side was almost completely healed.
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The main strength of this study was the application of hyaluronic acid on one side during tonsillectomy and use the other side of the patient as a control. Therefore, the same patient evaluated and scored the post-tonsillectomy pain, excluding individual bias like age and gender during the assessment of pain scores. The main limitation of our study was the
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relatively small sample size. Further large-scale multi-centered research studies are needed to assess the effectiveness of hyaluronic acid on post-tonsillectomy pain relief and wound
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healing differentiated by age, gender and different operation techniques. In addition, further
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analyses are required to evaluate the effect of the use of hyaluronic acid on the side effects, complication rates, including nausea and vomiting, otalgia, trismus and hemorrhage, and
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patients’ quality of life after tonsillectomy.
This is the first report on the effectiveness of hyaluronic acid in post-tonsillectomy
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pain management and wound healing. We concluded that treatment with hyaluronic acid is effective in reducing post-tonsillectomy pain during 14 postoperative days, where patients
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evaluated significantly lower pain scores for hyaluronic acid treated side. Treatment with hyaluronic acid enhanced wound healing, therefore it can contribute to an earlier return to
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regular daily activities. Further studies are required for the investigation of the effects of age, gender and operation techniques on the effectiveness of hyaluronic acid treatment. Despite the limitations, we were able to show beneficial effect of hyaluronic acid on posttonsillectomy pain management and wound healing.
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Acknowledgements 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
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23. Magdalena ML, Caragol L, Solé A, Rodrigo JP. Comparison of two analgesic protocols for post-tonsillectomy pain control in outpatient adults. Acta Otorrinolaringol Esp 2014; 65: 102-108. 24. Dorkham MC, Chalkiadis GA, von Ungern Sternberg BS, Davidson AJ. Effective postoperative pain management in children after ambulatory surgery, with a focus on tonsillectomy: barriers and possible solutions. Paediatr Anaesth 2014; 24: 239-248.
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25. Faiz SH, Rahimzadeh P, Alebouyeh MR, Sedaghat M. A randomized controlled trial on analgesic effects of intravenous acetaminophen versus dexamethasone after pediatric tonsillectomy. Iran Red Crescent Med J 2013; 15: e9267. 26. Jahanshahi J, Pazira S, Farahani F, et al. Effect of topical sucralfate vs clindamycin on
clinical
trial.
JAMA
Otolaryngol
Head
Neck
Surg
2014;
doi:
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10.1001/jamaoto.2014.979.
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posttonsillectomy pain in children aged 6 to 12 years: A triple-blind randomized
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27. Javid MJ, Hajijafari M, Hajipour A, Makarem J, Khazaeipour Z. Evaluation of a low dose ketamine in post tonsillectomy pain relief: a randomized trial comparing
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intravenous and subcutaneous ketamine in pediatrics. Anesth Pain Med 2012; 2: 85-89.
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28. Zhang X, Su Y, Li P. [Effects of bupivacaine versus lidocaine infiltration on postoperative analgesia in pediatric tonsillectomy patients] [Article in Chinese] Lin
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Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2014; 28: 148-150. 29. Haksever M, Ozmen S, Akduman D, Solmaz F. Topical bupivacaine compared to
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bupivacaine infiltration for post-tonsillectomy pain relief in children: a prospective randomized controlled clinical study. Eur Arch Otorhinolaryngol 2014; 271: 25552559.
30. Siupsinskiene N, Zekonienė J, Padervinskis E, Zekonis G, Vaitkus S. Efficacy of
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sucralfate
for
the
treatment
of
post-tonsillectomy
symptoms.
Eur
Arch
Otorhinolaryngol 2014; Apr 2. 31. Goa KL, Benfield P. Hyaluronic acid. A review of its pharmacology and use as a surgical aid in ophthalmology, and its therapeutic potential in joint disease and wound healing. Drugs 1994; 47: 536-566.
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32. Price RD, Myers S, Leigh IM, Navsaria HA. The role of hyaluronic acid in wound healing: assessment of clinical evidence. Am J Clin Dermatol 2005; 6: 393-402. 33. Shimizu N, Ishida D, Yamamoto A, Kuroyanagi M, Kuroyanagi Y. Development of a functional wound dressing composed of hyaluronic acid spongy sheet containing
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bioactive components: evaluation of wound healing potential in animal tests. J
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Biomater Sci Polym Ed 2014; 25:1278-1291.
34. Chen CP, Hung W, Lin SH. Effectiveness of hyaluronic acid for treating diabetic foot:
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a systematic review and meta-analysis. Dermatol Ther 2014; doi: 10.1111/dth.12153.
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Table Legends Table I. Scoring system for tonsillar fossa wound healing. Table II. Comparison of pain scores in the control (non-treated) and hyaluronic acid sides evaluated by VAS (out of 10) in the mornings and in the afternoons according to
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postoperative time. Table III. Wound healing of control (non-treated) and hyaluronic acid sides scored on a scale
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0-5 (0 = completely healed wound, 5 = not healed wound) evaluated at 7th, 10th and 14th
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postoperative days.
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Figure Legends
Figure 1A. Mean patient pain scores in hyaluronic acid and control sides in the mornings. Figure 1B: Mean patient pain scores in hyaluronic acid and control sides in the afternoons.
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Figure 2. Mean wound healing scores of control (non-treated) and hyaluronic acid sides evaluated at 7th, 10th and 14th postoperative days. Vertical error bars represent standard
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deviation.
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Table 1
Table 1: Scoring system for tonsillar fossa wound healing. Absence 0 0 0 1
Presence 1 1 1 0
Severe 2
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Feature Erythema Oedema Fossa whitening Wound Healing
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Table(s) 2
Control side Time of
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Table II.
Hyaluronic acid side
Mornings(n=50)
Afternoons(n=50)
Mornings(n=50)
(A)
(B)
(C)
(D)
1th day
6±0.84
6±0.48
5±0.40
2nd day
6±0.40
6±0.49
3th day
6±0.00
5±0.50
4th day
6±0.00
5±0.14
5th day
5±0.40
6th day
5±0.39
7th day
5±0.39
8th day
5±0.00
9th day
p values
Afternoons(n=50) (C) vs. (D)
(A) vs. (C)
(B) vs. (D)
5±0.39
0.003
0.821
<0.001
<0.001
6±0.50
5±0.24
<0.001
<0.001
<0.001
<0.001
5±0.00
5±0.59
<0.001
0.472
<0.001
<0.001
5±0.00
4±0.49
<0.001
<0.001
<0.001
<0.001
5±0.49
5±0.50
4±0.40
0.003
<0.001
<0.001
<0.001
5±0.72
5±0.49
4±0.39
1.000
<0.001
<0.001
<0.001
5±0.75
4±0.49
4±0.27
<0.001
<0.001
<0.001
<0.001
4±0.00
4±0.40
4±0.46
<0.001
<0.001
<0.001
<0.001
5±0.39
4±0.78
4±0.39
4±0.48
<0.001
<0.001
<0.001
<0.001
10th day
5±0.50
4±0.39
4±0.46
3±0.24
<0.001
<0.001
<0.001
<0.001
11th day
4±0.00
4±0.49
3±0.50
3±0.33
<0.001
<0.001
<0.001
<0.001
12th day
4±0.00
4±0.49
3±0.00
3±0.33
<0.001
0.013
<0.001
<0.001
13th day
3±0.50
3±0.50
3±0.00
2±0.14
1.000
<0.001
<0.001
<0.001
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(A) vs. (B)
pain score
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2±0.50
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14th day
2±0.00
0.003
0.001
<0.001
<0.001
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Data given as mean±SD.
2±0.40
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Table(s) 3
Table III. Time of wound healing
Control side
Hyaluronic acid side p value
(n=50)
(n=50)
7th day
5±0.50
3±0.50
<0.001
10th day
5±0.49
3±0.49
<0.001
14th day
2±0.37
1±0.30
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score
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<0.001
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Data given as mean±SD.
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Figure IA
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Figure IB
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Figure 2
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S0165-5876(15)00351-1 http://dx.doi.org/doi:10.1016/j.ijporl.2015.07.016 PEDOT 7674
To appear in:
International Journal of Pediatric Otorhinolaryngology
Received date: Revised date: Accepted date:
23-4-2015 10-6-2015 12-7-2015
Please cite this article as: D. Hanci, H. Altun, Effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing: a prospective, double-blind, controlled clinical study, International Journal of Pediatric Otorhinolaryngology (2015), http://dx.doi.org/10.1016/j.ijporl.2015.07.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
*Title Page
Effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing: a prospective, double-blind, controlled clinical study
Authors:
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Deniz Hancı, MD. (1), Huseyin Altun, MD.(2)
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2. Yunus Emre Hospital ENT department, Istanbul
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1. Okmeydanı Education and Research Hospital ENT department, Istanbul
Corresponding Author: Huseyin Altun, MD.
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Sırt sok. No:184A-23 Armaganevler Umraniye Istanbul
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Tel: +905326350965
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E-mail: [email protected]
Running title: Effectiveness of hyaluronic acid Keywords: Tonsillectomy, Hyaluronic acid, Wound healing, Pain, Double-blind study
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*Manuscript 1
Effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing
Running title: Effectiveness of hyaluronic acid
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Keywords: Tonsillectomy, Hyaluronic acid, Wound healing, Pain, Double-blind study
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Summary Objectives: To find the effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing Methods: Fifty patients were included in this prospective, double-blind, controlled clinical
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study (20 males, 30 females mean age of 13.56 years). Hyaluronic acid was applied to one side and the other side was used as a control during tonsillectomy. Therefore, the same patient
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evaluated and scored the post-tonsillectomy pain, excluding individual bias.
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Results: Results indicated that patients had significantly lower pain scores for hyaluronic acid treated side (p<0.001). At the end of two weeks follow-up period, the wound in the hyaluronic
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acid side was almost completely healed, indicating that the healing was faster with hyaluronic acid compared to control side (p<0.001).
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Conclusion: Hyaluronic acid could be recommended as an effective treatment for the
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management of post-tonsillectomy pain and wound healing.
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Introduction Tonsillectomy produces an open wound, therefore, associated with significant postoperative pain which can last up to 14 to 21 days with a 2-4% risk of immediate or delayed hemorrhage (1,3-5,6-8). The morbidity rate caused by postoperative pain and
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secondary bleeding was reported to be one in 35,000 (5,9). Little is known about the real cause of post-tonsillectomy pain; however the main reasons of this prolonged moderate to
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severe pain were described to be related with the sensitivity of tonsillar fossae to tissue
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damage, the disruption of mucosa, the pharyngeal muscle spasms and glossopharyngeal and/or vagal nerve fiber irritation causing inflammation (5,6,9).
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Oral opioids such as codeine and nonsteroidal anti-inflammatory drugs are usually used to manage pain after tonsillectomy (2,7). It was well reported that respiratory depression,
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sedation and bleeding resulted from the unpredictable metabolism of opioids were one of the reasons of morphine toxicity causing morbidity and life-threading post-tonsillectomy
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complications (2,5,10). Therefore, the use of safer opioid and non-opioid analgesics as an alternative approach to relieve the pain caused by tonsillectomy is getting more important.
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The American Academy of Otolaryngology—Head and Neck Surgery (AAO-HNS), for example, currently recommends the routine use of ibuprofen for pain relief after tonsillectomy (4,5,11).
Hyaluronic acid is a linear, hydrophilic, high molecular weight glycosaminoglycan
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naturally found in the joint synovial fluid and in the extracellular matrix of skin in the human body (12-15). It is naturally secreted during wound healing in proliferative phase to stimulate the migration and mitosis of fibroblasts and epithelial cells (16-18). It was shown to reduce the levels of inflammatory mediators and, therefore, can safely be used as an antiinflammatory agent (13,18,19). Being a growth factor and having lubricant properties, hyaluronic acid is commonly used as a naturally biocompatible, biodegradable and non-
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immunogenic biomaterial in biological dressing formulations (19). The positive effect of the use of hyaluronic acid in pain relief and wound healing in treatment of pressure ulcers (15), in management of osteoarthritis (12), in treatment of tendon disorders (12), in non-surgical treatment of deep wounds (20), in burns, epithelial surgical wounds and chronic wounds (18)
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and in vocal fold wound healing in animal models (21) were reported. However, to our best knowledge there is no study investigating the effectiveness of hyaluronic acid on the
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treatment of tonsillectomy.
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Therefore, the aim of this prospective, double-blind, controlled clinical study was to evaluate the effectiveness of hyaluronic acid on the reduction of post-tonsillectomy pain and
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wound healing during the first 14 postoperative days.
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Materials and methods Patients and surgical procedure Between January 2013 and March 2014 , 50 patients listed for tonsillectomy were included to the study at Liv Hospital. The 50 patients were consecutive patients admitted to
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the clinic for tonsillectomy. There were no patients refused to participate in the study. The study protocol was approved by the Local Hospital Ethics Committee and conducted
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according to the Declaration of Helsinki. An informed consent was obtained from adult
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patients and from parents of children patients.
Indicators for tonsillectomy in this study were recurrent tonsillitis (acute tonsillitis 7
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times in first year, 5 times in second year, 3 and more times in third year) , tonsillar hypertrophy resulting in snoring and chronic tonsillitis which was not responding to medical
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therapy(beta-lactamase–resistant antibiotics), difficulty in eating and talking. The indications for antibiotic treatment in tonsillitis were history of fever, exudate, anterior servical
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lymphadenopathy. Exclusion criteria were bleeding disorder, having chronic or severe systemic disease like diabetes, peritonsillar abscess formation, unilateral tonsil hypertrophy,
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patients with obstructive sleep apnea and patients who received steroids, antiemetics, antihistamines, or psychoactive drugs within 24 h of surgery. A prospective, double-blind study design was used in the study. Tonsillectomy was done under general anesthesia with oral intubation and with conventional dissection and snare
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technique performed by the same otolaryngologist. Adenoidectomy was performed for 5 patients. During surgery, a hyaluronic acid gel ( Pure regen gel sinus,BioRegen Biomedical Co. Ltd Hamburg Germany ) was placed to one of the randomly selected sides and both anterior and posterior tonsillar plica are sutured with 4/0 Vicril .To the other side only anterior and posterior tonsilar plica suture were performed and be used as a control. Patients and care providers (mostly parents) were blinded to the hyaluronic acid placed side. After the
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surgery, patients were transferred to the postanesthesia care unit. They were moved to Ear Nose Throat Ward when fully awake, stable, and comfortable. Patients who were fully awake, alert, able to drink liquids, had stable vital signs, no nausea and no bleeding were considered to be ready for discharge. All patients were discharged the day after surgery with same
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analgesic ( paracetamol 4x500 mg per day for adults, 10-15 mg/kg per day) and same antibiotiotic ( amoxicillin/ clavulanic asid) twice daily for one week postoperativly in weight-
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related doses. None of the patients have received steroid and opioid analgesic treatment. All
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patients stayed overnight. Liquids, soft diet and activity rectriction were recommended for 1 week.
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Effectiveness assessments
Postoperative care was the same for all patients. All effectiveness assessments were
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recorded by an independent otolaryngologist blinded to the hyaluronic acid (1 ml) placed side. Post-tonsillectomy throat pain was measured twice a day (in the morning and in the
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afternoon) for each side during the period of 14 postoperative days using visual analog scale (VAS) on a scale of 0-10 after 2 hours of analgesic intake. Wound healing was assessed by
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direct visual examination of the area of slough in each tonsillar fossa at 7th, 10th and 14th postoperative days and scored on a scale of 0 to 5 (0 = completely healed wound, 5 = not healed wound). The wound healing score was evaluated by the method described by the Magdy et al (21). (Table I)
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Statistical analysis
Statistical analysis was performed by the SPSS software package for Windows
(Statistical Package for Social Sciences, version 12.0, SPSS Inc., Chicago, Illinois, USA). Categorical variables were given as numbers and percentages and quantitative variables as mean±standard deviation (SD), median, minimum and maximum values. The normality of quantitative variables were analyzed by Kolmogorov-Smirnov test and normally distributed
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variables were compared with Student’s t-paired test. The level of significance was set at
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p<0.05.
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Results Fifty patients were included to this prospective, double-blind, controlled clinical study on the effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing. There were 20 males (40%) and 30 females (60%) between 9 and 22 years, averaging 13.56
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years(median age 14.02). 34 patients (22 boy, 12 girl) were child. No major complications such as airway abstruction, hemorrhage from tonsillar fossae, dehydration, or anesthetic
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toxicity were observed.
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Effectiveness of hyaluronic acid on the reduction of post-tonsillectomy pain
Results of post-tonsillectomy throat pain measured twice a day (in the morning and in
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the afternoon) for non-treated (control) and hyaluronic acid placed sides during the period of 14 postoperative days using visual analog scale (VAS) on a scale of 0-10 were summarized in
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Table II. Accordingly, patient pain scores were significantly different between hyaluronic acid treatment compared to control both in the mornings and in the afternoons at all times during
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the postoperative care (p<0.001 for all, Table II). Post-tonsillectomy pain evaluated in the mornings for 14 postoperative days were significantly lower with hyaluronic acid treatment
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except at 2nd, 5th, 6th and 13th days where similar pain scores were given by the patients for both sides (Table II, Figure 1A). Post-tonsillectomy pain evaluated in the afternoons for 14 postoperative days were also significantly lower with hyaluronic acid treatment except at 3rd, 8th, 9th and 14th days where similar pain scores were given by the patients for both sides
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(Table II, Figure 1B). Results indicated that hyaluronic acid was effective in reducing the post-tonsillectomy pain.
The in group comparison of pain scores evaluated in the mornings and in the afternoons were also given in Table II. In control side, there was a statistically significant difference in patient pain scores in the morning compared to that of afternoon except 6th and 13th postoperative days (Table II). Results indicated that for 6 out of 14 days (at 3rd, 4th, 8th,
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9th, 10th and 14th days), patients evaluated significantly more post-tonsillectomy pain for non-treated side in the mornings than afternoons (Figure 1). With hyaluronic acid, there was a statistically significant difference in patient pain scores in the morning compared to that of afternoon except 1th and 3rd postoperative days (Table II). Results indicated that patients
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evaluated significantly more post-tonsillectomy pain with hyaluronic acid in the mornings than afternoons for 6 out of 14 days (at 2nd, 4th, 5th, 6th, 10th and 13th days, Figure 1).
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Effectiveness of hyaluronic acid on wound healing
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Results of wound healing assessment scored on a scale of 0 to 5 (0 = completely healed wound, 5 = not healed wound) at 7th, 10th and 14th postoperative days by direct visual
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examination of the area of slough in each tonsillar fossa were given in Table III and Figure 2. Accordingly, hyaluronic acid significantly enhanced wound healing compared to non-treated
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(control) side at all times (p<0.001 for all). At the end of two weeks follow-up period, the wound in the hyaluronic acid side was almost completely healed (1±0.30) whereas that of
(Table III, Figure 2).
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control side was not (2±0.37), indicating that the healing was faster with hyaluronic acid
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The in group comparison of wound healing with respect to postoperative time indicated that the difference between wound healing scores at 7th and 10th days was not statistically significant both for control (p = 0.659) and for hyaluronic acid placed side (p = 0.709). The comparison between 7th and 14th days and between 10th and 14th days, on the
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other hand, indicated a statistically significant increase in wound healing for both the control and hyaluronic acid placed sides (p<0.001 for all).
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Discussion Tonsillectomy is a commonly performed procedure with potentially life threating complications. The surgery causes substantial local trauma in the oropharynx and a wound that heals by secondary intention, therefore, it is associated with significant postoperative pain
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due to the release of pro-inflammatory factors and chemokines (3-5,7,23). The healing of tonsillar fossa takes about 2 weeks and, although gradually decreasing over the first week,
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significant to moderate pain resides during that period (4). Post-tonsillectomy pain may lead
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to poor oral intake, dehydration, late hemorrhage, emesis, sleep disturbances and behavioral differences and, therefore, usually requires careful management by oral analgesics (2,5-
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7,10,11,24,25). The mostly prescribed opioids for post-tonsillectomy pain relief are acetaminophen with codeine and oxycodon or hydrocodone (4,5).
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Opioid related respiratory depression was reported to be one of the main reasons of post-tonsillectomy mortality especially in young children (2,10,25). Both the Food and Drug
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Administration (FDA) and The American Academy of Otolaryngology—Head and Neck Surgery (AAO-HNS) declared a safety warning for the use of codeine in treatment of pain
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following tonsillectomy (2,3,5,11). However, the commonly prescribed acetaminophen may not be adequate for post-tonsillectomy pain relief without codeine and at higher doses it may cause hepatic toxicity (5). Therefore, there is an ongoing research on the investigation of effectiveness of many surgical and pharmacological products in post-tonsillectomy pain
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management (2,4,5,7,9,23,26). Subramayam et al. (2) reported their own experience on the use of ATC acetaminophen, dexamethasone and ibuprofen in pain management as no increase in the incidence of inadequate pain control or serious complications. Dexamethasone was shown to be more effective than intravenous acetaminophen to reduce pain in children (25). The effect of ropivacaine plus dexamethasone and ropivacaine alone was compared and it was concluded that ropivacaine plus dexamethasone infiltration lowered pain, postoperative
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nausea and vomiting and improved oral intake in children after tonsillectomy and adenoidectomy (7). Javid et al. (27) showed the safety and effectiveness of ketamine injections during surgery in post-tonsillectomy pain management. Systemic or local preoperative ketamine administration (10) and local infiltration of bupivacaine (28) have
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recently been reported to relieve post-tonsillectomy pain in children. Dostbil et al. (6) have recently reported the effectiveness of peritonsillar dexamethasone infiltration on postoperative
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pain and morbidity in pediatric adenotonsillectomy patients. Topical administrations of
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bupivacaine hydrochloride (29) and sucralfate (30) were shown to provide efficient posttonsillectomy pain control. Topical sucralfate and clindamycin have recently been shown to
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reduce post-tonsillectomy pain in children (25). However, there is still limited evidence and no consensus regarding the optimal treatment for post-tonsillectomy pain.
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Hyaluronic acid is a linear, hydrophilic, polyionic high molecular weight polysaccharide, which is a natural lubricant component of joint synovial fluid and is also
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found in extracellular matrix of connective tissue (12,13,18). It is a nonsulfated glycosaminoglycan that is secreted during wound healing and new tissue formation
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(16,18,19,31,32). As such, hyaluronic acid is considered as a biocompatible, biodegradable and non-immunogenic biomaterial of choice in biological dressings (19,33). The wound healing effect of hyaluronic acid was extensively studied since its discovery in 1934 and it found a wide usage in orthopedics and cosmetic surgery (17,32). For example, it is commonly
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used for tendon injuries and treatment of chronic tendiopathies, where the use of hyaluronic acid was shown to reduce the formation of scars and granulation tissue in several studies (12,32). Its effectiveness in the management of osteoarthritis by viscosupplementation therapy (12) and in the pain relief of temporomandibular joint disorders has recently been proven (13). Gencer et al. (13) also mentioned other beneficial effects of hyaluronic acid as a relatively long half-life of 13 hours and safety and effectiveness in repetitive intra-articular injection.
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Hyaluronic acid was also shown to enhance the wound healing effect of platelet-rich growth factor in treatment of pressure ulcers (15). Onesti et al. (20) has recently reported their positive results in four cases with chronic ulcers in terms of wound healing with topical application of collagenase and hyaluronic acid. Hyaluronic acid was shown to be beneficial in
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the treatment of diabetic foot by increasing the rate of wound healing (34). In summary, there appears to be an overall positive effect of hyaluronic acid in wound healing and pain relief.
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However, we did not encounter any study analyzing the effectiveness of the use of hyaluronic
us
acid for post-tonsillectomy pain and wound healing in the literature. Therefore, to our knowledge, this is the first controlled, double-blind prospective report on the evaluation of the
healing during the first 14 postoperative days.
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effectiveness of hyaluronic acid on the reduction of post-tonsillectomy pain and wound
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The comparison of patient pain scores for hyaluronic acid placed and control sides indicated that hyaluronic acid significantly reduced post-tonsillectomy pain. Pain scores were
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evaluated both in the mornings and afternoons for 14 postoperative days and only for 6 out of 14 days patients gave similar pain scores for hyaluronic acid placed and control sides both in
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the mornings and in the afternoons. Tonsillectomy wounds are known to be prone to become inflamed and infected (5). A transient increase in pain due to increase in intensity of inflammation on the 3rd and 5th postoperative days and more intense pain in the morning were reported by Isaacson (4) and Sutters and Isaacson (5). In accordance with the literature,
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the comparison of morning and afternoon pain scores given by the patients indicated that 6 out of 14 postoperative days, patients suffered more pain in the mornings. The effectiveness of hyaluronic acid on wound healing was assessed at 7th, 10th and 14th postoperative days and results indicated that hyaluronic acid significantly enhanced wound healing. At the end of two weeks, hyaluronic acid placed side was almost completely healed.
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The main strength of this study was the application of hyaluronic acid on one side during tonsillectomy and use the other side of the patient as a control. Therefore, the same patient evaluated and scored the post-tonsillectomy pain, excluding individual bias like age and gender during the assessment of pain scores. The main limitation of our study was the
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relatively small sample size. Further large-scale multi-centered research studies are needed to assess the effectiveness of hyaluronic acid on post-tonsillectomy pain relief and wound
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healing differentiated by age, gender and different operation techniques. In addition, further
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analyses are required to evaluate the effect of the use of hyaluronic acid on the side effects, complication rates, including nausea and vomiting, otalgia, trismus and hemorrhage, and
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patients’ quality of life after tonsillectomy.
This is the first report on the effectiveness of hyaluronic acid in post-tonsillectomy
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pain management and wound healing. We concluded that treatment with hyaluronic acid is effective in reducing post-tonsillectomy pain during 14 postoperative days, where patients
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evaluated significantly lower pain scores for hyaluronic acid treated side. Treatment with hyaluronic acid enhanced wound healing, therefore it can contribute to an earlier return to
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regular daily activities. Further studies are required for the investigation of the effects of age, gender and operation techniques on the effectiveness of hyaluronic acid treatment. Despite the limitations, we were able to show beneficial effect of hyaluronic acid on posttonsillectomy pain management and wound healing.
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Acknowledgements 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
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6. Dostbil A, Celik M, Yoruk O, et al. Pre-emptive peritonsillar dexamethasone vs.
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9. Rakesh S, Anand TS, Payal G, Pranjal K. A prospective, randomized, double-blind study of coblation versus dissection tonsillectomy in adult patients. Indian J Otolaryngol Head Neck Surg 2012; 64: 290-294. 10. Cho HK, Kim KW, Jeong YM, Lee HS, Lee YJ, Hwang SH. Efficacy of ketamine in
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the relief of temporomandibular joint disorder complaints. J Craniomaxillofac Surg 2014; doi: 10.1016/j.jcms.2014.01.041. 14. Park SY, Lee HU, Lee YC, et al. Wound healing potential of antibacterial microneedles loaded with green tea extracts. Mater Sci Eng C Mater Biol Appl 2014;
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42: 757-762.
15. Ramos-Torrecillas J, García-Martínez O, Luna-Bertos ED, Ocaña-Peinado FM, Ruiz C. Effectiveness of platelet-rich plasma and hyaluronic acid for the treatment and care of pressure ulcers. Biol Res Nurs 2014; pii: 1099800414535840. 16. MacKay D, Miller AL. Nutritional support for wound healing. Altern Med Rev 2003; 8: 359-377.
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17. Prosdocimi M, Bevilacqua C. Exogenous hyaluronic acid and wound healing: an updated vision. Panminerva Med 2012; 54: 129-135. 18. Voigt J, Driver VR. Hyaluronic acid derivatives and their healing effect on burns, epithelial surgical wounds, and chronic wounds: a systematic review and meta-analysis
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19. Boateng JS, Matthews KH, Stevens HN, Eccleston GM. Wound healing dressings and drug delivery systems: a review. J Pharm Sci 2008; 97: 2892-2923.
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20. Onesti MG, Fino P, Ponzo I, Ruggieri M, Scuderi N. Non-surgical treatment of deep
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wounds triggered by harmful physical and chemical agents: a successful combined use of collagenase and hyaluronic acid. Int Wound J 2014; doi: 10.1111/iwj.12215.
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21. Magdy EA, Elwany S, el-Daly AS, Abdel-Hadi M, Morshedy MA. Coblation tonsillectomy: a prospective, double-blind, randomised, clinical and histopathological
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23. Magdalena ML, Caragol L, Solé A, Rodrigo JP. Comparison of two analgesic protocols for post-tonsillectomy pain control in outpatient adults. Acta Otorrinolaringol Esp 2014; 65: 102-108. 24. Dorkham MC, Chalkiadis GA, von Ungern Sternberg BS, Davidson AJ. Effective postoperative pain management in children after ambulatory surgery, with a focus on tonsillectomy: barriers and possible solutions. Paediatr Anaesth 2014; 24: 239-248.
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25. Faiz SH, Rahimzadeh P, Alebouyeh MR, Sedaghat M. A randomized controlled trial on analgesic effects of intravenous acetaminophen versus dexamethasone after pediatric tonsillectomy. Iran Red Crescent Med J 2013; 15: e9267. 26. Jahanshahi J, Pazira S, Farahani F, et al. Effect of topical sucralfate vs clindamycin on
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posttonsillectomy pain in children aged 6 to 12 years: A triple-blind randomized
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27. Javid MJ, Hajijafari M, Hajipour A, Makarem J, Khazaeipour Z. Evaluation of a low dose ketamine in post tonsillectomy pain relief: a randomized trial comparing
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28. Zhang X, Su Y, Li P. [Effects of bupivacaine versus lidocaine infiltration on postoperative analgesia in pediatric tonsillectomy patients] [Article in Chinese] Lin
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Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2014; 28: 148-150. 29. Haksever M, Ozmen S, Akduman D, Solmaz F. Topical bupivacaine compared to
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bupivacaine infiltration for post-tonsillectomy pain relief in children: a prospective randomized controlled clinical study. Eur Arch Otorhinolaryngol 2014; 271: 25552559.
30. Siupsinskiene N, Zekonienė J, Padervinskis E, Zekonis G, Vaitkus S. Efficacy of
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sucralfate
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32. Price RD, Myers S, Leigh IM, Navsaria HA. The role of hyaluronic acid in wound healing: assessment of clinical evidence. Am J Clin Dermatol 2005; 6: 393-402. 33. Shimizu N, Ishida D, Yamamoto A, Kuroyanagi M, Kuroyanagi Y. Development of a functional wound dressing composed of hyaluronic acid spongy sheet containing
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bioactive components: evaluation of wound healing potential in animal tests. J
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Biomater Sci Polym Ed 2014; 25:1278-1291.
34. Chen CP, Hung W, Lin SH. Effectiveness of hyaluronic acid for treating diabetic foot:
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a systematic review and meta-analysis. Dermatol Ther 2014; doi: 10.1111/dth.12153.
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Table Legends Table I. Scoring system for tonsillar fossa wound healing. Table II. Comparison of pain scores in the control (non-treated) and hyaluronic acid sides evaluated by VAS (out of 10) in the mornings and in the afternoons according to
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postoperative time. Table III. Wound healing of control (non-treated) and hyaluronic acid sides scored on a scale
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0-5 (0 = completely healed wound, 5 = not healed wound) evaluated at 7th, 10th and 14th
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postoperative days.
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Figure Legends
Figure 1A. Mean patient pain scores in hyaluronic acid and control sides in the mornings. Figure 1B: Mean patient pain scores in hyaluronic acid and control sides in the afternoons.
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Figure 2. Mean wound healing scores of control (non-treated) and hyaluronic acid sides evaluated at 7th, 10th and 14th postoperative days. Vertical error bars represent standard
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deviation.
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Table 1
Table 1: Scoring system for tonsillar fossa wound healing. Absence 0 0 0 1
Presence 1 1 1 0
Severe 2
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Feature Erythema Oedema Fossa whitening Wound Healing
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Table(s) 2
Control side Time of
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Table II.
Hyaluronic acid side
Mornings(n=50)
Afternoons(n=50)
Mornings(n=50)
(A)
(B)
(C)
(D)
1th day
6±0.84
6±0.48
5±0.40
2nd day
6±0.40
6±0.49
3th day
6±0.00
5±0.50
4th day
6±0.00
5±0.14
5th day
5±0.40
6th day
5±0.39
7th day
5±0.39
8th day
5±0.00
9th day
p values
Afternoons(n=50) (C) vs. (D)
(A) vs. (C)
(B) vs. (D)
5±0.39
0.003
0.821
<0.001
<0.001
6±0.50
5±0.24
<0.001
<0.001
<0.001
<0.001
5±0.00
5±0.59
<0.001
0.472
<0.001
<0.001
5±0.00
4±0.49
<0.001
<0.001
<0.001
<0.001
5±0.49
5±0.50
4±0.40
0.003
<0.001
<0.001
<0.001
5±0.72
5±0.49
4±0.39
1.000
<0.001
<0.001
<0.001
5±0.75
4±0.49
4±0.27
<0.001
<0.001
<0.001
<0.001
4±0.00
4±0.40
4±0.46
<0.001
<0.001
<0.001
<0.001
5±0.39
4±0.78
4±0.39
4±0.48
<0.001
<0.001
<0.001
<0.001
10th day
5±0.50
4±0.39
4±0.46
3±0.24
<0.001
<0.001
<0.001
<0.001
11th day
4±0.00
4±0.49
3±0.50
3±0.33
<0.001
<0.001
<0.001
<0.001
12th day
4±0.00
4±0.49
3±0.00
3±0.33
<0.001
0.013
<0.001
<0.001
13th day
3±0.50
3±0.50
3±0.00
2±0.14
1.000
<0.001
<0.001
<0.001
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(A) vs. (B)
pain score
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2±0.50
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14th day
2±0.00
0.003
0.001
<0.001
<0.001
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Data given as mean±SD.
2±0.40
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Table(s) 3
Table III. Time of wound healing
Control side
Hyaluronic acid side p value
(n=50)
(n=50)
7th day
5±0.50
3±0.50
<0.001
10th day
5±0.49
3±0.49
<0.001
14th day
2±0.37
1±0.30
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<0.001
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Data given as mean±SD.
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Figure IA
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Figure IB
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Figure 2
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