Accepted Manuscript Effects of perioperatively administered dexamethasone on surgical wound healing in patients undergoing surgery for zygomatic fracture: a prospective study Johanna Snäll, MD, DDS Eeva Kormi, MD, DDS Anna-Maria Koivusalo, MD, PhD Christian Lindqvist, MD, DDS, PhD Anna Liisa Suominen, DDS, PhD, MSc Jyrki Törnwall, MD, DDS, PhD Hanna Thorén, MD, DDS, PhD PII:
S2212-4403(14)00324-1
DOI:
10.1016/j.oooo.2014.02.033
Reference:
OOOO 875
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 4 February 2014 Revised Date:
22 February 2014
Accepted Date: 28 February 2014
Please cite this article as: Snäll J, Kormi E, Koivusalo A-M, Lindqvist C, Suominen AL, Törnwall J, Thorén H, Effects of perioperatively administered dexamethasone on surgical wound healing in patients undergoing surgery for zygomatic fracture: a prospective study, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2014), doi: 10.1016/j.oooo.2014.02.033. 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.
ACCEPTED MANUSCRIPT Effects of perioperatively administered dexamethasone on surgical wound healing in patients undergoing surgery for zygomatic fracture: a prospective
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study
Snäll, Johanna, MD, DDS1; Kormi, Eeva, MD, DDS1; Koivusalo, Anna-Maria, MD, PhD2; Lindqvist, Christian, MD, DDS, PhD, Professor1; Suominen, Anna Liisa, DDS,
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PhD, MSc3,4,5; Törnwall, Jyrki, MD, DDS, PhD1; Thorén, Hanna, MD, DDS, PhD1
1 Department of Oral and Maxillofacial Surgery, Helsinki University Central Hospital
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and University of Helsinki, Helsinki, Finland
2 Department of Anesthesia and Intensive Care Unit, Helsinki University Central Hospital, Helsinki, Finland
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3 University of Eastern Finland, Institute of Dentistry, Kuopio, Finland 4 Department of Oral and Maxillofacial Surgery, Kuopio University Hospital, Kuopio, Finland
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Kuopio, Finland
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5 Department of Environmental Health, National Institute for Health and Welfare,
Corresponding author Johanna Snäll, Department of Oral and Maxillofacial Surgery, Helsinki University Central Hospital, P.O. Box 293, HUCH, Finland e-mail: [email protected] Authors declare no conflict of interest. Words (Abstract): 151; Words (Manuscript): 2408; Tables: 3; Figures: 1
1
ACCEPTED MANUSCRIPT ABSTRACT Objective Aims of the study were to clarify the occurrence of disturbance in surgical wound
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healing (DSWH) after surgery of zygomatic complex (ZC) fractures and to determine whether perioperatively applied dexamethasone increases the risk for DSWH. Study Design
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Sixty-four patients were included in a single-blinded prospective trial. Of these, 33
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perioperatively received a total dose of 10 mg or 30 mg of dexamethasone. The remaining 31 patients served as controls. Results
DSWH occurred in 9 patients (14.1%). Occurrence of DSWH was 24.4% in patients
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who received dexamethasone and 3.2% in controls. The association between DSWH and dexamethasone was significant (P=.016). Intraoral approach associated also with DSWH significantly (P=.042). No association emerged between DSWH and age,
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Conclusions
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gender, timespan from accident to surgery, or duration of surgery.
DSWH occurred significantly more frequently in patients who received perioperative dexamethasone. Because of increased risk of DSWH, perioperative dexamethasone cannot be recommended in open reduction and fixation of ZC fractures. INTRODUCTION A questionnaire to North American members of the American Society of Maxillofacial Surgeons revealed that close to half of the respondents use perioperative glucocorticoids (GCs) to control postoperative edema.1 A recently published meta-
2
ACCEPTED MANUSCRIPT analysis concluded that the administration of GCs in oral surgery does, indeed, significantly decrease edemas as well as pain.2 Another meta-analysis showed that dexamethasone significantly also reduces the incidence of postoperative nausea.3
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As with any medication, adverse effects may follow GC use, and a common reason reported by maxillofacial surgeons for not using perioperative GCs is fear of complications.1 Due to the various effects of GCs on human immunology, one possible
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side-effect of GCs is disturbance in surgical wound healing (DSWH).
A study focusing on DSWH and perioperatively administered dexamethasone in
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patients undergoing surgical treatment for facial fractures could not show a significant correlation between dexamethasone and DSWH.4 In that study, an intraoral approach remained the only significant predictor for DSWH. Yet, a tendency towards more infections was observed in patients who received the GC (6.0%) relative to those who did not (2.8%). The study was retrospective, however, comprising patients with various
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types of fractures undergoing different procedures and receiving variable GC regimens. The safety of perioperative dexamethasone in association with treatment of facial fracture should be investigated more rigorously.
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A fracture of the zygomatic complex (ZC) is commonly observed in patients with facial
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injuries, this fracture being the second most common after mandibular fractures.5 Surgical site infections have been shown to occur in some 5% of patients undergoing open reduction and fixation of ZC fractures, and 89% of these infections occur at the intraoral surgical site.6
This study aimed to clarify the occurrence of DSWH after reduction and osteosynthesis of a ZC fracture and to determine whether dexamethasone increases the risk for DSWH. The hypothesis was that dexamethasone does not significantly increase the risk for DSWH, but the intraoral approach does.
3
ACCEPTED MANUSCRIPT PATIENTS AND METHODS Study design The patients of this study were drawn from a larger cohort of patients who had
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participated in a single-blinded randomized study aiming to clarify the benefits of perioperative dexamethasone after operative treatment of a facial fracture. The patients were randomly assigned either to serve as a control, receiving no GC, or to receive
SC
dexamethasone (Oradexon®) to a total dose of 10 mg or 30 mg. Administration of 10 mg of dexamethasone was performed intravenously during anesthesia induction. In the
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30-mg study group, additional 10-mg doses were given intramuscularly every 8 hours over 16 hours, to a total dose of 30 mg (of dexamethasone). All patients received antibiotics until the seventh to tenth postoperative day, starting with three 1.5-g doses of cefuroxime given intravenously at the ward during the first 24 hours postoperatively,
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followed by three oral doses of 500 mg of cephalexin.
One blinded author (J.S. or E.K.) examined the patients one day, two days, one week, one month, three months, and six months postoperatively. Patients received a longer follow-up for surgical reasons as needed. A postoperative follow-up of at least 30 days
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was required for the patient to be included in the present analysis.
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Patients in this study were at least 18 years of age, had sustained a fracture of the ZC, and were to undergo surgical reduction and fixation with the aid of one or more titanium miniplates. We excluded patients with closed reduction of ZC, who had any other facial fracture requiring surgery, also those who had an ipsilateral orbital floor fracture requiring reconstruction. Other exclusion criteria were infected fractures, a history of liver or kidney dysfunction, peptic ulcer, psychosis due to steroid use, pregnancy, breastfeeding, or allergy to any constituent of the dexamethasone preparation used. Study variables
4
ACCEPTED MANUSCRIPT The outcome variable was DSWH, the presence of which was established when any aberrant wound healing and/or sign of infection in the surgical site occurred. The primary predictor variable was the perioperative use of dexamethasone. Other
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predictor variables included in the analysis were age, gender, duration of surgery, timespan from accident to surgery, total dose of dexamethasone, and surgical approach to the fracture line. Surgical approach was classified as extraoral (i.e., skin
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and transconjunctival incisions) or intraoral (i.e. vestibular incision). Statistical analysis
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The statistical significance of associations between occurrence of DSWH and perioperative use of dexamethasone, gender, age group (classified as 60 years), timespan from accident to surgery (classified as 1-2 days, 3-6 days, or 7+ days), duration of surgery (classified as ≤ 30 min, 31-59 min, or ≥ 60 min),
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total dose of dexamethasone, and surgical approach to the fracture line were evaluated with Chi-square tests and Fisher´s exact test. Ethical approval
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The Ethics Committee of the Department of Surgery and the Internal Review Board of the Division of Musculoskeletal Surgery, Helsinki University Central Hospital, Finland,
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approved the study protocol (Dno 33/E6/06). Informed written consent was obtained from all patients. RESULTS
Seventy-three patients fulfilled the inclusion criteria. Of these, eight patients were excluded because they were lost to follow-up before the 30th postoperative day and one because the patient required further surgery due to an unsatisfactory fracture
5
ACCEPTED MANUSCRIPT reduction. Thus, a total of 64 patients were included in the analysis. The follow-up period ranged from 1 to 34 months, average 8 months. Of the 64 patients, 46 (71.9%) were male. Their ages ranged from 20.2 to 83.8 years,
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average 42.6 years. The timespan from accident to surgery ranged from 1 to 18 days, average 5 days. Duration of surgery ranged from 16 to 140 min, average 48 min. Thirty-three patients (51.6%) received dexamethasone. Of these patients, 11 received a single dose (10 mg) of dexamethasone and the remaining 22 a total dose of 30 mg of
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dexamethasone.
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A total of 85 surgical approaches to the fracture line were used, through which 85 miniplates were inserted. The number of approaches ranged from 1 to 3 and the number of plates from 1 to 4 per patient. Table 1 shows the surgical approaches to the fracture line and also the techniques chosen for fracture reduction. Of the total of 85 approaches to the fracture line, 50 (58.8%) were extraoral and 35 (41.2%) intraoral. In
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most patients (51.6%), the fracture was reduced with the aid of a hook inserted under the zygomatic arch through a small buccal skin incision. This approach was combined with temporal reduction (Gillies approach) in one patient. Overall temporal reduction
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was used in five patients. An exclusively intraoral approach was used as a reduction
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route in 26 patients (40.6%).
DSWH occurred in nine patients (14.1%). Only one DSWH occurred per patient. The details of these patients are shown in Table 2. In four patients with DSWH, an intraoral wound dehiscence with plate exposure was established on average 6 weeks after surgery. Three patients with plate exposure had wound dehiscence without infection signs. Plate removal was arranged for these patients at 4 months after surgery. The third patient did not come to the arranged plate removal. The fourth DSWH with plate exposure associated with local infection (Figure 1), which healed with antibiotic
6
ACCEPTED MANUSCRIPT treatment and local anti-infective mouth-rinse. In three patients, swelling and redness of the cheek and the intraoral sulcus in the region of the intraoral approach were observed at 15, 28, and 31 days after surgery, respectively. One of these patients was first treated with antibiotics, and 3 months after surgery the intraoral plate was
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removed. In the other two patients, the infection resolved after treatment with antibiotics. The remaining two patients with DSWH were treated with extraoral approaches exclusively. One patient had increased swelling, redness, and pain in the
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buccal region of the zygomatic bone on the 28th day after surgery. The other patient had increased swelling, pain, and redness in the region of the upper eyelid after
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blepharoplasty on the 14th day. The local infections in both of these patients resolved with antibiotic treatment. None of the nine patients with DSWH were diabetic and none received immunosuppressive medication.
Table 3 shows the association between predictor variables and DSWH. Eight patients
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with DSWH had received dexamethasone. The DSWH rate among patients who received dexamethasone was 24.2%, whereas the corresponding rate among patients not receiving dexamethasone was 3.2%. DSWHs occurred most often in the intraoral
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region (71.4%, 5 of 7). One-fifth (20.6%) of intraorally operated patients were found to have DSWH in the intraoral region. In exclusively extraorally operated patients, the
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DSWH rate was 3.4%.
The Chi-square test revealed a significant association between dexamethasone and DSWH (P=.016). The association between intraoral approach and DSWH was also significant (P=.042). No significant association existed between DSWH and gender, age group, timespan from accident to surgery, total dose of dexamethasone, or duration of surgery.
7
ACCEPTED MANUSCRIPT One patient with a total dose of 30 mg of dexamethasone needed hospitalization for hematemesis and esophageal ulceration two months after surgery. No other GCrelated side-effects were observed in the 33 patients who received dexamethasone.
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DISCUSSION We aimed to clarify the occurrence of DSWH after reduction and osteosynthesis of a ZC fracture and to determine whether dexamethasone increases the risk for DSWH.
DSWH, but that the intraoral approach does.
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The hypothesis was that dexamethasone does not significantly increase the risk for
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The overall DSWH rate was 14.1%. Dexamethasone eight-folded the occurrence of DSWH, which occurred significantly more often in patients receiving dexamethasone (P=.016). However, a dose-dependent effect of dexamethasone (total dose 10 mg or 30 mg) could not be shown in this study.
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Forounzafar et al.6 analyzed retrospectively 210 patients with ZC fractures, and 177 of these had undergone open reduction and fixation with miniplates. According to the treatment protocol, none of the patients had received GC. Nine of the 177 operated
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patients (5.1%) developed surgical site infection despite antibiotic prophylaxis. In the present study, all patients received antibiotic prophylaxis; however, six of the 64
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patients (9.4%) needed antibiotic treatment due to DSWH. Interestingly, all of these patients received dexamethasone. Of the 31 patients not receiving dexamethasone, only one had DSWH. In this patient, an exposed plate was observed, but there was no need for antibiotic treatment. Accordingly, perioperative high-dose dexamethasone appears to predispose to postoperative infectious complications in the surgical site in ZC fracture patients. During the follow-up one patient needed hospitalization for acute esophageal ulceration and bleeding two months after surgery. The patient had no previous history of ulcers,
8
ACCEPTED MANUSCRIPT but was diagnosed as having chronic esophagitis with acute bleeding of the lower part of the esophagus. Although the connection between dexamethasone administration and bleeding remains uncertain, the influence of high-dose dexamethasone cannot be
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ruled out. The statistically significant difference was observed between occurrence of DSWH and perioperative use of dexamethasone. Because a small sample size can be considered as one of the weaknesses of the present study, we did a power analysis to evaluate the
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statistical reliability of the present study. Technically, the power of a statistical test is the probability of detecting a "true" effect when it exists. We used a two-sided Fisher's
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exact test with a significance level of 0.05 for retrospective power analysis for a test of the two independent proportions, i.e., occurrence of DSWH and perioperative use of dexamethasone. With the slightly unbalanced design (n=33 in the dexamethasone group and n=31 in the control group) and the rates observed (3.2%/24.4%), we
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estimated a power of 0.61, which is somewhat below the commonly used standard (0.80≤1-β≤0.95). To get the recommended level, a sample size of n=46 per group would have been needed.
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To our knowledge, only a few studies have been published focusing on the use of GCs in facial trauma patients. Flood et al.
7
published a trial of blow-out fractures; however,
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the authors stated no complications. Two other studies of maxillofacial fractures have shown higher rates of DSWHs in patients with perioperative dexamethasone, 4 and 8 but the difference was not statistically significant. In this study, the association between dexamethasone and DSWH was significant and the difference between groups was marked (24.2%/3.2%). Therefore, a perioperative dose of dexamethasone of 10 mg or more cannot be recommended for ZC fracture patients needing open surgery.
9
ACCEPTED MANUSCRIPT An interesting finding here was the significant delay between surgery and establishment of DSWH. The biological half-life of dexamethasone is long, up to 36-54 hours. Thus, its effects on the surgical wound continue far beyond the period of primary healing. As we observed, DSWH was diagnosed on average 30 days after surgery, one
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case being established as late as 3 months after the procedure. This finding may explain why a recently published meta-analysis could not prove an increased risk for infections after third molar removal when perioperative GC was used.2 Because third
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molar studies have mainly focused on the effects of GC on pain, swelling, and trismus during the immediate postoperative recovery, the follow-ups have been quite short,
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only about one week.9,10,11,12 and 13 Considering the fact that infections after third molar surgery may become evident weeks after the procedure,14 a one-week follow-up will not permit any conclusions to be drawn regarding the incidence of postoperative infections in general or infections associated with GC use in particular. Thus, indications for further studies focusing on surgical site infections seem to also exist in
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the field of oral surgery. In addition to the short follow-ups in studies focusing on third molar surgery, the doses used were smaller than in the present study.2,9,10,11,12 and 13
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Because of increased risk of DSWH, perioperative dexamethasone cannot be recommended in open reduction and fixations of ZC fractures.
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CONFLICT OF INTEREST
None of the authors have a financial interest in any of the products, devices, or drugs mentioned in this manuscript.
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ACCEPTED MANUSCRIPT
REFERENCES 1. Assimes TL, Lessard ML. The use of perioperative corticosteroids in
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craniomaxillofacial surgery. Plast Reconstr Surg 1999;103:313-21; quiz 322.
2. Dan AE, Thygesen TH, Pinholt EM. Corticosteroid administration in oral and
orthognathic surgery: a systematic review of the literature and meta-analysis. J Oral
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Maxillofac Surg 2010;68:2207-2220.
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3. Hirayama T, Ishii F, Yago K, Ogata H. Evaluation of the effective drugs for the prevention of nausea and vomiting induced by morphine used for postoperative pain: a quantitative systematic review. Yakugaku Zasshi 2001;121:179-185.
4. Thoren H, Snall J, Kormi E, Numminen L, Fah R, Iizuka T, Lindqvist C, Tornwall J.
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Does perioperative glucocorticosteroid treatment correlate with disturbance in surgical wound healing after treatment of facial fractures? A retrospective study. J Oral Maxillofac Surg 2009;67:1884-1888.
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5. Thoren H, Snall J, Salo J, Suominen-Taipale L, Kormi E, Lindqvist C, Tornwall J. Occurrence and types of associated injuries in patients with fractures of the facial
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bones. J Oral Maxillofac Surg 2010;68:805-810.
6. Forouzanfar T, Salentijn E, Peng G, van den Bergh B. A 10-year analysis of the "Amsterdam" protocol in the treatment of zygomatic complex fractures. J Craniomaxillofac Surg 2013.
7. Flood TR, McManners J, el-Attar A, Moos KF. Randomized prospective study of the influence of steroids on postoperative eye-opening after exploration of the orbital floor. Br J Oral Maxillofac Surg 1999;37:312-315.
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ACCEPTED MANUSCRIPT 8. Snall J, Kormi E, Lindqvist C, Suominen AL, Mesimaki K, Tornwall J, Thoren H. Impairment of wound healing after operative treatment of mandibular fractures, and the influence of dexamethasone. Br J Oral Maxillofac Surg 2013;51:808-812.
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9. Esen E, Tasar F, Akhan O. Determination of the anti-inflammatory effects of methylprednisolone on the sequelae of third molar surgery. J Oral Maxillofac Surg 1999;57:1201-6; discussion 1206-8.
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10. Bamgbose BO, Akinwande JA, Adeyemo WL, Ladeinde AL, Arotiba GT, Ogunlewe MO. Effects of co-administered dexamethasone and diclofenac potassium on pain,
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swelling and trismus following third molar surgery. Head Face Med 2005;1:11.
11. Buyukkurt MC, Gungormus M, Kaya O. The effect of a single dose prednisolone with and without diclofenac on pain, trismus, and swelling after removal of mandibular
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third molars. J Oral Maxillofac Surg 2006;64:1761-1766.
12. Graziani F, D'Aiuto F, Arduino PG, Tonelli M, Gabriele M. Perioperative dexamethasone reduces post-surgical sequelae of wisdom tooth removal. A split-
246.
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mouth randomized double-masked clinical trial. Int J Oral Maxillofac Surg 2006;35:241-
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13. Grossi GB, Maiorana C, Garramone RA, Borgonovo A, Beretta M, Farronato D, Santoro F. Effect of submucosal injection of dexamethasone on postoperative discomfort after third molar surgery: a prospective study. J Oral Maxillofac Surg 2007;65:2218-2226.
14. Monaco G, Tavernese L, Agostini R, Marchetti C. Evaluation of antibiotic prophylaxis in reducing postoperative infection after mandibular third molar extraction in young patients. J Oral Maxillofac Surg 2009;67:1467-1472.
12
ACCEPTED MANUSCRIPT Table 1. Surgical approaches to the fracture line and techniques for zygomatic fracture reduction in 64 patients
No. of approaches
% of n
intraoral (zygomaticoalveolar region)
35
41.2
upper eyelid blepharoplasty (lateral orbital rim)
23
eyebrow (lateral orbital rim)
18
lower eyelid blepharoplasty (inferior orbital rim)
8
transconjunctival (inferior orbital rim)
1
transbuccal hook reduction
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Techniques for zygomatic fracture reduction
5
26
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transoral reduction (exclusively)
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No. of reduction sites 33
temporal reduction (Gillies approach)
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Surgical approaches to the fracture line (n=85)
27.1
21.2 9.4
1.2
ACCEPTED MANUSCRIPT Table 2. Data on patients with DSWH
3
man
4 woman
5 woman
man
7 woman 8 woman 9
intraoral wound and soft tissue of cheek soft tissue of cheek area
upper eyelid
x
x
x
x
swelling, redness, and pain swelling, redness, and pain, increasing limitation in mouth opening
swelling, redness, and pain
x
x
swelling, redness, and pain
man intraoral * Patient failed to appear to plate removal.
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6
intraoral and soft tissue of cheek area
x
30 mg
31
30 mg
92
30 mg
28
x
30 mg
15
x
30 mg
28
x
10 mg
7
x
10 mg
28
x
10 mg
14
no
27
swelling, redness
x
x*
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man
Dexamethasone
DSWH / days after surgery
SC
2
Need for antibiotic treatment due to DSWH
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man
Need for plate removal due to DSWH
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1
intraoral wound and soft tissue of cheek area intraoral wound intraoral wound intraoral wound and soft tissue of cheek area
Other symptoms
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Localization of DSWH
Wound dehiscence with plate exposure
ACCEPTED MANUSCRIPT
Table 3. Association between predictor variables and DSWH
DSWH present
% of n
male (n=46)
5
10.9
female (n=18)
4
22.2
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Gender
Surgical approach intraoral (n=34) *
7* 1
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exclusively extraoral (n=29)
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P=.240
P=.042 Dexamethasone yes (n=33)
20.6 3.5
8
24.2
1
3.2
Group of dexamethasone 30 mg (n=22)
5
22.7
Group of dexamethasone 10 mg (n=11)
3
27.2
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no (n=31)
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P=.016
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P=.774
*One patient with a combination of intra-extraoral approaches is omitted because DSWH appeared in the upper eyelid.
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EP
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ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT In this study dexamethasone eight-folded the occurence of DSWH after osteosynthesis of ZC fracture. When regarding to DSWH, high-dose perioperative dexamethasone cannot be
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recommended in patients undergoing reduction and osteosynthesis for ZC fracture.
S2212-4403(14)00324-1
DOI:
10.1016/j.oooo.2014.02.033
Reference:
OOOO 875
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 4 February 2014 Revised Date:
22 February 2014
Accepted Date: 28 February 2014
Please cite this article as: Snäll J, Kormi E, Koivusalo A-M, Lindqvist C, Suominen AL, Törnwall J, Thorén H, Effects of perioperatively administered dexamethasone on surgical wound healing in patients undergoing surgery for zygomatic fracture: a prospective study, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2014), doi: 10.1016/j.oooo.2014.02.033. 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.
ACCEPTED MANUSCRIPT Effects of perioperatively administered dexamethasone on surgical wound healing in patients undergoing surgery for zygomatic fracture: a prospective
RI PT
study
Snäll, Johanna, MD, DDS1; Kormi, Eeva, MD, DDS1; Koivusalo, Anna-Maria, MD, PhD2; Lindqvist, Christian, MD, DDS, PhD, Professor1; Suominen, Anna Liisa, DDS,
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PhD, MSc3,4,5; Törnwall, Jyrki, MD, DDS, PhD1; Thorén, Hanna, MD, DDS, PhD1
1 Department of Oral and Maxillofacial Surgery, Helsinki University Central Hospital
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and University of Helsinki, Helsinki, Finland
2 Department of Anesthesia and Intensive Care Unit, Helsinki University Central Hospital, Helsinki, Finland
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3 University of Eastern Finland, Institute of Dentistry, Kuopio, Finland 4 Department of Oral and Maxillofacial Surgery, Kuopio University Hospital, Kuopio, Finland
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Kuopio, Finland
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5 Department of Environmental Health, National Institute for Health and Welfare,
Corresponding author Johanna Snäll, Department of Oral and Maxillofacial Surgery, Helsinki University Central Hospital, P.O. Box 293, HUCH, Finland e-mail: [email protected] Authors declare no conflict of interest. Words (Abstract): 151; Words (Manuscript): 2408; Tables: 3; Figures: 1
1
ACCEPTED MANUSCRIPT ABSTRACT Objective Aims of the study were to clarify the occurrence of disturbance in surgical wound
RI PT
healing (DSWH) after surgery of zygomatic complex (ZC) fractures and to determine whether perioperatively applied dexamethasone increases the risk for DSWH. Study Design
SC
Sixty-four patients were included in a single-blinded prospective trial. Of these, 33
M AN U
perioperatively received a total dose of 10 mg or 30 mg of dexamethasone. The remaining 31 patients served as controls. Results
DSWH occurred in 9 patients (14.1%). Occurrence of DSWH was 24.4% in patients
TE D
who received dexamethasone and 3.2% in controls. The association between DSWH and dexamethasone was significant (P=.016). Intraoral approach associated also with DSWH significantly (P=.042). No association emerged between DSWH and age,
AC C
Conclusions
EP
gender, timespan from accident to surgery, or duration of surgery.
DSWH occurred significantly more frequently in patients who received perioperative dexamethasone. Because of increased risk of DSWH, perioperative dexamethasone cannot be recommended in open reduction and fixation of ZC fractures. INTRODUCTION A questionnaire to North American members of the American Society of Maxillofacial Surgeons revealed that close to half of the respondents use perioperative glucocorticoids (GCs) to control postoperative edema.1 A recently published meta-
2
ACCEPTED MANUSCRIPT analysis concluded that the administration of GCs in oral surgery does, indeed, significantly decrease edemas as well as pain.2 Another meta-analysis showed that dexamethasone significantly also reduces the incidence of postoperative nausea.3
RI PT
As with any medication, adverse effects may follow GC use, and a common reason reported by maxillofacial surgeons for not using perioperative GCs is fear of complications.1 Due to the various effects of GCs on human immunology, one possible
SC
side-effect of GCs is disturbance in surgical wound healing (DSWH).
A study focusing on DSWH and perioperatively administered dexamethasone in
M AN U
patients undergoing surgical treatment for facial fractures could not show a significant correlation between dexamethasone and DSWH.4 In that study, an intraoral approach remained the only significant predictor for DSWH. Yet, a tendency towards more infections was observed in patients who received the GC (6.0%) relative to those who did not (2.8%). The study was retrospective, however, comprising patients with various
TE D
types of fractures undergoing different procedures and receiving variable GC regimens. The safety of perioperative dexamethasone in association with treatment of facial fracture should be investigated more rigorously.
EP
A fracture of the zygomatic complex (ZC) is commonly observed in patients with facial
AC C
injuries, this fracture being the second most common after mandibular fractures.5 Surgical site infections have been shown to occur in some 5% of patients undergoing open reduction and fixation of ZC fractures, and 89% of these infections occur at the intraoral surgical site.6
This study aimed to clarify the occurrence of DSWH after reduction and osteosynthesis of a ZC fracture and to determine whether dexamethasone increases the risk for DSWH. The hypothesis was that dexamethasone does not significantly increase the risk for DSWH, but the intraoral approach does.
3
ACCEPTED MANUSCRIPT PATIENTS AND METHODS Study design The patients of this study were drawn from a larger cohort of patients who had
RI PT
participated in a single-blinded randomized study aiming to clarify the benefits of perioperative dexamethasone after operative treatment of a facial fracture. The patients were randomly assigned either to serve as a control, receiving no GC, or to receive
SC
dexamethasone (Oradexon®) to a total dose of 10 mg or 30 mg. Administration of 10 mg of dexamethasone was performed intravenously during anesthesia induction. In the
M AN U
30-mg study group, additional 10-mg doses were given intramuscularly every 8 hours over 16 hours, to a total dose of 30 mg (of dexamethasone). All patients received antibiotics until the seventh to tenth postoperative day, starting with three 1.5-g doses of cefuroxime given intravenously at the ward during the first 24 hours postoperatively,
TE D
followed by three oral doses of 500 mg of cephalexin.
One blinded author (J.S. or E.K.) examined the patients one day, two days, one week, one month, three months, and six months postoperatively. Patients received a longer follow-up for surgical reasons as needed. A postoperative follow-up of at least 30 days
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was required for the patient to be included in the present analysis.
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Patients in this study were at least 18 years of age, had sustained a fracture of the ZC, and were to undergo surgical reduction and fixation with the aid of one or more titanium miniplates. We excluded patients with closed reduction of ZC, who had any other facial fracture requiring surgery, also those who had an ipsilateral orbital floor fracture requiring reconstruction. Other exclusion criteria were infected fractures, a history of liver or kidney dysfunction, peptic ulcer, psychosis due to steroid use, pregnancy, breastfeeding, or allergy to any constituent of the dexamethasone preparation used. Study variables
4
ACCEPTED MANUSCRIPT The outcome variable was DSWH, the presence of which was established when any aberrant wound healing and/or sign of infection in the surgical site occurred. The primary predictor variable was the perioperative use of dexamethasone. Other
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predictor variables included in the analysis were age, gender, duration of surgery, timespan from accident to surgery, total dose of dexamethasone, and surgical approach to the fracture line. Surgical approach was classified as extraoral (i.e., skin
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and transconjunctival incisions) or intraoral (i.e. vestibular incision). Statistical analysis
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The statistical significance of associations between occurrence of DSWH and perioperative use of dexamethasone, gender, age group (classified as 60 years), timespan from accident to surgery (classified as 1-2 days, 3-6 days, or 7+ days), duration of surgery (classified as ≤ 30 min, 31-59 min, or ≥ 60 min),
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total dose of dexamethasone, and surgical approach to the fracture line were evaluated with Chi-square tests and Fisher´s exact test. Ethical approval
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The Ethics Committee of the Department of Surgery and the Internal Review Board of the Division of Musculoskeletal Surgery, Helsinki University Central Hospital, Finland,
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approved the study protocol (Dno 33/E6/06). Informed written consent was obtained from all patients. RESULTS
Seventy-three patients fulfilled the inclusion criteria. Of these, eight patients were excluded because they were lost to follow-up before the 30th postoperative day and one because the patient required further surgery due to an unsatisfactory fracture
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ACCEPTED MANUSCRIPT reduction. Thus, a total of 64 patients were included in the analysis. The follow-up period ranged from 1 to 34 months, average 8 months. Of the 64 patients, 46 (71.9%) were male. Their ages ranged from 20.2 to 83.8 years,
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average 42.6 years. The timespan from accident to surgery ranged from 1 to 18 days, average 5 days. Duration of surgery ranged from 16 to 140 min, average 48 min. Thirty-three patients (51.6%) received dexamethasone. Of these patients, 11 received a single dose (10 mg) of dexamethasone and the remaining 22 a total dose of 30 mg of
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dexamethasone.
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A total of 85 surgical approaches to the fracture line were used, through which 85 miniplates were inserted. The number of approaches ranged from 1 to 3 and the number of plates from 1 to 4 per patient. Table 1 shows the surgical approaches to the fracture line and also the techniques chosen for fracture reduction. Of the total of 85 approaches to the fracture line, 50 (58.8%) were extraoral and 35 (41.2%) intraoral. In
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most patients (51.6%), the fracture was reduced with the aid of a hook inserted under the zygomatic arch through a small buccal skin incision. This approach was combined with temporal reduction (Gillies approach) in one patient. Overall temporal reduction
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was used in five patients. An exclusively intraoral approach was used as a reduction
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route in 26 patients (40.6%).
DSWH occurred in nine patients (14.1%). Only one DSWH occurred per patient. The details of these patients are shown in Table 2. In four patients with DSWH, an intraoral wound dehiscence with plate exposure was established on average 6 weeks after surgery. Three patients with plate exposure had wound dehiscence without infection signs. Plate removal was arranged for these patients at 4 months after surgery. The third patient did not come to the arranged plate removal. The fourth DSWH with plate exposure associated with local infection (Figure 1), which healed with antibiotic
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ACCEPTED MANUSCRIPT treatment and local anti-infective mouth-rinse. In three patients, swelling and redness of the cheek and the intraoral sulcus in the region of the intraoral approach were observed at 15, 28, and 31 days after surgery, respectively. One of these patients was first treated with antibiotics, and 3 months after surgery the intraoral plate was
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removed. In the other two patients, the infection resolved after treatment with antibiotics. The remaining two patients with DSWH were treated with extraoral approaches exclusively. One patient had increased swelling, redness, and pain in the
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buccal region of the zygomatic bone on the 28th day after surgery. The other patient had increased swelling, pain, and redness in the region of the upper eyelid after
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blepharoplasty on the 14th day. The local infections in both of these patients resolved with antibiotic treatment. None of the nine patients with DSWH were diabetic and none received immunosuppressive medication.
Table 3 shows the association between predictor variables and DSWH. Eight patients
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with DSWH had received dexamethasone. The DSWH rate among patients who received dexamethasone was 24.2%, whereas the corresponding rate among patients not receiving dexamethasone was 3.2%. DSWHs occurred most often in the intraoral
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region (71.4%, 5 of 7). One-fifth (20.6%) of intraorally operated patients were found to have DSWH in the intraoral region. In exclusively extraorally operated patients, the
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DSWH rate was 3.4%.
The Chi-square test revealed a significant association between dexamethasone and DSWH (P=.016). The association between intraoral approach and DSWH was also significant (P=.042). No significant association existed between DSWH and gender, age group, timespan from accident to surgery, total dose of dexamethasone, or duration of surgery.
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ACCEPTED MANUSCRIPT One patient with a total dose of 30 mg of dexamethasone needed hospitalization for hematemesis and esophageal ulceration two months after surgery. No other GCrelated side-effects were observed in the 33 patients who received dexamethasone.
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DISCUSSION We aimed to clarify the occurrence of DSWH after reduction and osteosynthesis of a ZC fracture and to determine whether dexamethasone increases the risk for DSWH.
DSWH, but that the intraoral approach does.
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The hypothesis was that dexamethasone does not significantly increase the risk for
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The overall DSWH rate was 14.1%. Dexamethasone eight-folded the occurrence of DSWH, which occurred significantly more often in patients receiving dexamethasone (P=.016). However, a dose-dependent effect of dexamethasone (total dose 10 mg or 30 mg) could not be shown in this study.
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Forounzafar et al.6 analyzed retrospectively 210 patients with ZC fractures, and 177 of these had undergone open reduction and fixation with miniplates. According to the treatment protocol, none of the patients had received GC. Nine of the 177 operated
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patients (5.1%) developed surgical site infection despite antibiotic prophylaxis. In the present study, all patients received antibiotic prophylaxis; however, six of the 64
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patients (9.4%) needed antibiotic treatment due to DSWH. Interestingly, all of these patients received dexamethasone. Of the 31 patients not receiving dexamethasone, only one had DSWH. In this patient, an exposed plate was observed, but there was no need for antibiotic treatment. Accordingly, perioperative high-dose dexamethasone appears to predispose to postoperative infectious complications in the surgical site in ZC fracture patients. During the follow-up one patient needed hospitalization for acute esophageal ulceration and bleeding two months after surgery. The patient had no previous history of ulcers,
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ACCEPTED MANUSCRIPT but was diagnosed as having chronic esophagitis with acute bleeding of the lower part of the esophagus. Although the connection between dexamethasone administration and bleeding remains uncertain, the influence of high-dose dexamethasone cannot be
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ruled out. The statistically significant difference was observed between occurrence of DSWH and perioperative use of dexamethasone. Because a small sample size can be considered as one of the weaknesses of the present study, we did a power analysis to evaluate the
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statistical reliability of the present study. Technically, the power of a statistical test is the probability of detecting a "true" effect when it exists. We used a two-sided Fisher's
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exact test with a significance level of 0.05 for retrospective power analysis for a test of the two independent proportions, i.e., occurrence of DSWH and perioperative use of dexamethasone. With the slightly unbalanced design (n=33 in the dexamethasone group and n=31 in the control group) and the rates observed (3.2%/24.4%), we
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estimated a power of 0.61, which is somewhat below the commonly used standard (0.80≤1-β≤0.95). To get the recommended level, a sample size of n=46 per group would have been needed.
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To our knowledge, only a few studies have been published focusing on the use of GCs in facial trauma patients. Flood et al.
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published a trial of blow-out fractures; however,
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the authors stated no complications. Two other studies of maxillofacial fractures have shown higher rates of DSWHs in patients with perioperative dexamethasone, 4 and 8 but the difference was not statistically significant. In this study, the association between dexamethasone and DSWH was significant and the difference between groups was marked (24.2%/3.2%). Therefore, a perioperative dose of dexamethasone of 10 mg or more cannot be recommended for ZC fracture patients needing open surgery.
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ACCEPTED MANUSCRIPT An interesting finding here was the significant delay between surgery and establishment of DSWH. The biological half-life of dexamethasone is long, up to 36-54 hours. Thus, its effects on the surgical wound continue far beyond the period of primary healing. As we observed, DSWH was diagnosed on average 30 days after surgery, one
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case being established as late as 3 months after the procedure. This finding may explain why a recently published meta-analysis could not prove an increased risk for infections after third molar removal when perioperative GC was used.2 Because third
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molar studies have mainly focused on the effects of GC on pain, swelling, and trismus during the immediate postoperative recovery, the follow-ups have been quite short,
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only about one week.9,10,11,12 and 13 Considering the fact that infections after third molar surgery may become evident weeks after the procedure,14 a one-week follow-up will not permit any conclusions to be drawn regarding the incidence of postoperative infections in general or infections associated with GC use in particular. Thus, indications for further studies focusing on surgical site infections seem to also exist in
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the field of oral surgery. In addition to the short follow-ups in studies focusing on third molar surgery, the doses used were smaller than in the present study.2,9,10,11,12 and 13
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Because of increased risk of DSWH, perioperative dexamethasone cannot be recommended in open reduction and fixations of ZC fractures.
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CONFLICT OF INTEREST
None of the authors have a financial interest in any of the products, devices, or drugs mentioned in this manuscript.
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REFERENCES 1. Assimes TL, Lessard ML. The use of perioperative corticosteroids in
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craniomaxillofacial surgery. Plast Reconstr Surg 1999;103:313-21; quiz 322.
2. Dan AE, Thygesen TH, Pinholt EM. Corticosteroid administration in oral and
orthognathic surgery: a systematic review of the literature and meta-analysis. J Oral
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Maxillofac Surg 2010;68:2207-2220.
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3. Hirayama T, Ishii F, Yago K, Ogata H. Evaluation of the effective drugs for the prevention of nausea and vomiting induced by morphine used for postoperative pain: a quantitative systematic review. Yakugaku Zasshi 2001;121:179-185.
4. Thoren H, Snall J, Kormi E, Numminen L, Fah R, Iizuka T, Lindqvist C, Tornwall J.
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Does perioperative glucocorticosteroid treatment correlate with disturbance in surgical wound healing after treatment of facial fractures? A retrospective study. J Oral Maxillofac Surg 2009;67:1884-1888.
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5. Thoren H, Snall J, Salo J, Suominen-Taipale L, Kormi E, Lindqvist C, Tornwall J. Occurrence and types of associated injuries in patients with fractures of the facial
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bones. J Oral Maxillofac Surg 2010;68:805-810.
6. Forouzanfar T, Salentijn E, Peng G, van den Bergh B. A 10-year analysis of the "Amsterdam" protocol in the treatment of zygomatic complex fractures. J Craniomaxillofac Surg 2013.
7. Flood TR, McManners J, el-Attar A, Moos KF. Randomized prospective study of the influence of steroids on postoperative eye-opening after exploration of the orbital floor. Br J Oral Maxillofac Surg 1999;37:312-315.
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ACCEPTED MANUSCRIPT 8. Snall J, Kormi E, Lindqvist C, Suominen AL, Mesimaki K, Tornwall J, Thoren H. Impairment of wound healing after operative treatment of mandibular fractures, and the influence of dexamethasone. Br J Oral Maxillofac Surg 2013;51:808-812.
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9. Esen E, Tasar F, Akhan O. Determination of the anti-inflammatory effects of methylprednisolone on the sequelae of third molar surgery. J Oral Maxillofac Surg 1999;57:1201-6; discussion 1206-8.
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10. Bamgbose BO, Akinwande JA, Adeyemo WL, Ladeinde AL, Arotiba GT, Ogunlewe MO. Effects of co-administered dexamethasone and diclofenac potassium on pain,
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swelling and trismus following third molar surgery. Head Face Med 2005;1:11.
11. Buyukkurt MC, Gungormus M, Kaya O. The effect of a single dose prednisolone with and without diclofenac on pain, trismus, and swelling after removal of mandibular
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third molars. J Oral Maxillofac Surg 2006;64:1761-1766.
12. Graziani F, D'Aiuto F, Arduino PG, Tonelli M, Gabriele M. Perioperative dexamethasone reduces post-surgical sequelae of wisdom tooth removal. A split-
246.
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mouth randomized double-masked clinical trial. Int J Oral Maxillofac Surg 2006;35:241-
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13. Grossi GB, Maiorana C, Garramone RA, Borgonovo A, Beretta M, Farronato D, Santoro F. Effect of submucosal injection of dexamethasone on postoperative discomfort after third molar surgery: a prospective study. J Oral Maxillofac Surg 2007;65:2218-2226.
14. Monaco G, Tavernese L, Agostini R, Marchetti C. Evaluation of antibiotic prophylaxis in reducing postoperative infection after mandibular third molar extraction in young patients. J Oral Maxillofac Surg 2009;67:1467-1472.
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ACCEPTED MANUSCRIPT Table 1. Surgical approaches to the fracture line and techniques for zygomatic fracture reduction in 64 patients
No. of approaches
% of n
intraoral (zygomaticoalveolar region)
35
41.2
upper eyelid blepharoplasty (lateral orbital rim)
23
eyebrow (lateral orbital rim)
18
lower eyelid blepharoplasty (inferior orbital rim)
8
transconjunctival (inferior orbital rim)
1
transbuccal hook reduction
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Techniques for zygomatic fracture reduction
5
26
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transoral reduction (exclusively)
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No. of reduction sites 33
temporal reduction (Gillies approach)
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Surgical approaches to the fracture line (n=85)
27.1
21.2 9.4
1.2
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3
man
4 woman
5 woman
man
7 woman 8 woman 9
intraoral wound and soft tissue of cheek soft tissue of cheek area
upper eyelid
x
x
x
x
swelling, redness, and pain swelling, redness, and pain, increasing limitation in mouth opening
swelling, redness, and pain
x
x
swelling, redness, and pain
man intraoral * Patient failed to appear to plate removal.
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intraoral and soft tissue of cheek area
x
30 mg
31
30 mg
92
30 mg
28
x
30 mg
15
x
30 mg
28
x
10 mg
7
x
10 mg
28
x
10 mg
14
no
27
swelling, redness
x
x*
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man
Dexamethasone
DSWH / days after surgery
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2
Need for antibiotic treatment due to DSWH
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man
Need for plate removal due to DSWH
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1
intraoral wound and soft tissue of cheek area intraoral wound intraoral wound intraoral wound and soft tissue of cheek area
Other symptoms
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Localization of DSWH
Wound dehiscence with plate exposure
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Table 3. Association between predictor variables and DSWH
DSWH present
% of n
male (n=46)
5
10.9
female (n=18)
4
22.2
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Gender
Surgical approach intraoral (n=34) *
7* 1
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exclusively extraoral (n=29)
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P=.240
P=.042 Dexamethasone yes (n=33)
20.6 3.5
8
24.2
1
3.2
Group of dexamethasone 30 mg (n=22)
5
22.7
Group of dexamethasone 10 mg (n=11)
3
27.2
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no (n=31)
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P=.016
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P=.774
*One patient with a combination of intra-extraoral approaches is omitted because DSWH appeared in the upper eyelid.
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ACCEPTED MANUSCRIPT In this study dexamethasone eight-folded the occurence of DSWH after osteosynthesis of ZC fracture. When regarding to DSWH, high-dose perioperative dexamethasone cannot be
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recommended in patients undergoing reduction and osteosynthesis for ZC fracture.
