Title

Perioperative antibiotic prophylaxis in orthognathic surgery

Author(s)

Tan, Su-keng; sS

Citation

Issue Date

2010

URL

http://hdl.handle.net/10722/130873

Rights

unrestricted

Perioperative Antibiotic Prophylaxis in Orthognathic Surgery

A thesis submitted In fulfillment for the degree of

Master of Dental Surgery

Oral & Maxillofacial Surgery
by

Tan Su Keng
The University of Hong Kong July 2010

Principal Supervisor PD Dr.Dr.med Roger Arthur Zwahlen

MD, DMD, Priv.-Doz., FEBOMFS

Co-Supervisor Dr John Lo
BDS, MDS, FCDSHK, FHKAM

Preface

Prophylactic antibiotic regimen in orthognathic surgery is still a controversial issue. To date a high variability exists in literature regarding the type of prophylactic antibiotic drug of choice, their dosage, and the period of administration. An evidence based research was performed regarding the choice of postoperative prophylactic antibiotic

administration in orthognathic surgery. This thesis is divided into two parts. While in Part I, current literature was reviewed systematically to scrutinize in a meta-analysis the most appropriate postoperative prophylactic antibiotic regimen in orthognathic surgery, in Part II the results of a prospective, randomized, double-blind, placebo-controlled clinical trial tackling the question whether postoperative oral is as effective as intravenous prophylactic antibiotic administration in bimaxillary orthognathic surgery, are elaborated and discussed.

Declaration

I declare that this thesis represents my own work, except where due acknowledgement is made, and that is has not been previously included in a thesis, dissertation or report submitted to this University or to any other institution for a degree, diploma or other qualification.

______________________ Tan Su Keng

Acknowledgements
I would like to express the deepest appreciation to my supervisor, PD Dr.Dr.med Roger Arthur Zwahlen for his enormous support, advice and guidance during my research and study at The University of Hong Kong. His perpetual energy, enthusiasm and patience in teaching are highly appreciated. He showed me different ways to approach a research problem and the need to be persistent to accomplish any goal. He has advocated a huge amount of time in correcting and revising this manuscript. In addition, he was always accessible and willing to help me with my research. He was always there to meet and talk about my ideas. Without his dedicated guidance and persistent help, this thesis would not have been possible. I am heartily thankful to my co-supervisor, Dr John Lo, whose encouragement, guidance and support from the preliminary to the concluding level enabled me to develop an understanding of the subject. Above all and the most needed, he provided me unflinching encouragement and support in various ways. He was always there to listen and to give advice. Without his encouragement and constant guidance, I could not have finished this thesis.

It is difficult to overstate my gratitude to Professor Nabil Samman, Post-graduate Programme Director, for his kindness, support, sound advice and encouragement throughout this 3 years course. I am indebted to him more than he knows. My special thanks go to our Chair Professor, Professor Cheung Lim Kwong for his advice, encouragement and guidance during my training period. During the course of this work, he has offered much advice and insight throughout the work. The assistance received from all the residents and nursing staffs in E1 ward in Queen Mary Hospital during the course of this work is greatly appreciated. The support and advice from my colleagues and nursing staffs of The Prince Philip Dental Hospital is highly appreciated too. Without the generous help of these individuals, the clinical study would not have been possible. I must thank Mr. Yeung, for his patience in guiding me through the doubts related to statistics. I would also like to show my gratitude to my family, especially my parents for supporting and encouraging me to pursue this degree. I would like to thank my parents for their unending love, understanding and support.

Above all, my utmost appreciation, dedicates to the Almighty God for the divine intervention in this academic endeavour.

Table of contents
Page Preface Declaration Acknowledgments Table of contents 1 2 3-5 6-7

Part I: Perioperative Antibiotic Prophylaxis in Orthognathic Surgery: A Systematic Review and Meta-analysis of Clinical Trials Abstract Introduction Methods Results Discussion Conclusion References Figures and tables 9-10 11-12 13-17 18-21 22-28 29 30-35 36-41

Part II: Oral versus Intravenous Antibiotic Treatment after Bimaxillary Orthognathic Surgery - A Prospective, Randomized, Double Blind & Placebo-Controlled Clinical Trial Abstract Introduction Methods Results Discussion Conclusion References Figures and tables 43-44 45-47 48-54 55-57 58-61 62 63-69 70-74

Appendix I - PRISMA checklist Appendix II - CONSORT checklist

75-76 77-78

Part I

Perioperative Antibiotic Prophylaxis in Orthognathic Surgery: A Systematic Review and Meta-analysis of Clinical Trials

Abstract
Background: The need and the appropriate administration of

prophylactic antibiotics in orthognathic surgery remain a controversial issue. Objective: To investigate whether the use of antibiotic prophylaxis in orthognathic surgery can effectively reduce the postoperative infection rate. Methods: PubMed, Ovid, Cochrane library, EMBASE, ISI Web of Science and MD Consult were searched for potentially eligible prospective clinical studies using a set of predetermined keywords. Full articles meeting the inclusion criteria were retrieved and their references were searched manually for additional relevant articles. Study details and outcome data of these reports were extracted using spreadsheets for comparison. No language limitation set. Results: Five randomized clinical trials were included in the final review process; four articles compared the period of prophylactic antibiotic usage,

whereas the fifth trial compared the infection prevention effect of different types of antibiotics with placebo. Although a significantly higher infection rate was found in the placebo group, no significant difference could be found related to infection prevention between short and long term antibiotic regimen. Conclusion: Prophylactic antibiotic regimen is considered to be useful for infection prevention in orthognathic surgery. A single-dose regimen is recommended; application for extended postoperative period is not advocated.

10

Introduction
Rationale Since the dawn of bimaxillary orthognathic surgery more than 40 years ago, it has become a well-established elective procedure to correct any jaw discrepancy in patients with dentofacial deformity1. The perioperative morbidity can be kept minimal with judicious general surgical principles2-7. Orthognathic surgery was classified as to commit a clean-contaminated wound according to the categories of contaminated wounds by Alherabi et al8. Peterson in 19909, estimated the postoperative infection rate for orthognathic surgery to be between 10% to 15%, being reduced to about 1% under concomitant antibiotic treatment. Others stated the prevalence of infection after maxillary and mandibular osteotomies to be higher, ranging from 1.4% to 33.4%4, 5, 10-12. Clinically, postoperative infection may be associated with patients discomfort, prolonged hospital stay, and an increased in both postoperative morbidity and cost of medical care. Therefore, the minimization of postoperative infection should be of utmost interest, especially in respect of the elective character of orthognathic surgery5, 13. The usage of prophylactic antibiotics still remains somewhat controversial in orthognathic surgery, which is demonstrated in a high

11

variability of recommendations within the literature5, 10, 11, 14, 15. Nowadays, the need of prophylactic antibiotics and their appropriate regimen in orthognathic surgery is still heatedly debated. Up to date, there is still no consensus regarding the type and duration of postoperative antibiotic regimen. Only very few randomized clinical trials have been carried out so far, yielding evidence based results related to these questions. Objective The purpose of this study was to systematically review the current literature and to perform a comprehensive meta-analysis of these literatures to investigate whether the use of antibiotic prophylaxis in orthognathic surgery can effectively reduce the postoperative infection rate. The primary objective of this study is to scrutinize the best prophylactic antibiotic regimen for orthognathic surgery.

12

Methods
A protocol has been composed prior to the commencement of the study regarding the methods and eligible criteria for this study. Electronic databases search The electronic databases including PubMed, Ovid, Cochrane library, EMBASE, ISI Web of Science and MD Consult were searched using the following keywords from the earliest year available to February 2010: (#1) AND (#2) OR (#3) #1- (orthognathic*) OR (bimaxillary osteotomies) OR (jaw surgery) #2- (antibiotic*) OR (antibiotic treatment) OR (antibiotic agent) OR (antimicrobial agent) #3- (infection*) A combination of free text terms with Boolean operators and truncation were used. No restrictions were placed on the year or language of publication. The search strategy was designed in consultation with a senior librarian. The citations retrieved from each database were exported to the EndNote X3 (Thomson Reuters; Carlsbad, CA) bibliographic

management software. Duplicates were removed. The abstracts of all

13

articles related to perioperative antibiotic prophylaxis in orthognathic surgery were screened and their full texts were obtained. Manual search The reference lists of all selected articles in first round were manually searched for any related articles. All the selected articles from electronic and manual search were independently assessed by the authors (SKT, RAZ) according the inclusion criteria, i.e. clinical studies related to perioperative antibiotic prophylaxis in orthognathic surgery including randomized clinical trials, case controlled studies and prospective clinical studies. Besides, postoperative infection had to be one of the primary outcome measures in the study. Guidelines, review articles, expert opinions and case reports as well as trials with less than ten subjects in either intervention group were excluded. Furthermore, articles related to temporomandibular joint surgery, distraction osteogenesis, trauma, bone grafting (autologous bone and/or grafting materials), bioresorbable fixation devices, endoscopic assisted surgery, dental implants and surgically assisted rapid palatal expansion were excluded from this review. Studies involving either syndromic or medically compromised patients, especially in regard of a compromised immune system were also excluded.

14

Primary assessment The articles that fulfilled all inclusion criteria were assessed accordingly. The study details and outcome data related to perioperative antibiotic prophylaxis in orthognathic surgery were collected using a prefabricated data extraction sheet. Data extraction (general demographic data, sample size, trials inclusion and exclusion criteria, type of intervention i.e. different treatment regimens, infection rate and follow up period) were performed by two authors (TSK, RAZ) independently regarding following criteria. The completeness of the methodological reporting of each study was checked according to the following criteria: 1. Complete description of patients demographic profile, i.e. age and gender 2. Clear inclusion/exclusion criteria 3. Statement about patients medical conditions 4. Indication of type, dose, and duration of antibiotic agents being used 5. Indication of criteria used to define infection The reporting of the first three criteria is important for the authors to include only medically fit and healthy individuals (aged in this 15) review; while the forth criterion is important for the data analysis. The last

15

criterion was set to check for any significant heterogeneity in the outcome measures in these prospective studies. Articles which met all the above mentioned criteria were appraised critically in the final review. In case of any disagreements between the review authors (TSK and RAZ), it was resolved by consensus or consulted a third party (JL). Final review The articles included in this stage were studied in detail and critically appraised; the risk of bias was analyzed based on The Cochrane Collaborations tool for assessing risk of bias16. The primary outcome measure was the infection rate in orthognathic surgery with the relative risk (RR) of infection rate of different treatment effects; while the secondary outcome measure was the adverse events in different treatment regimens.

Data analysis and statistical methods

The primary measure of treatment effect was the relative risk (RR) of infection rate reduction. Relative risks with 95% confidence intervals (CIs) for the trial results were calculated using Review Manager (RevMan version 5.0; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008). The heterogeneity of trial results was assessed with

16

a 2 test for heterogeneity (P=0.1) and the I2 measure of inconsistency. A significant heterogeneity was considered when P value <0.1 for 2 test or an I2 measure >50%. Treatment effects across the studies were combined using the fixed effect model when there was no heterogeneity observed (P>0.1); in case of heterogeneity was observed, the random effect model was applied. Publication bias was assessed by the funnel plot method using Eggers test. Number needed to treat (NNT) was calculated as the inverse of the absolute risk reduction; it was used to assess the number of patients who need to be treated in order to prevent one infection in orthognathic surgery.

17

Results
The sequence of selecting studies and the number of articles remaining at each stage is illustrated in figure 1. Ten articles were included in primary assessment but only five studies17-21 met the selection criteria being thereafter included in the final review. Table 1 highlights the reasons for the exclusion of five articles12, 22-25 from the final review. Generally, these articles were excluded due to insufficient data provided to fulfill our inclusion criteria, i.e. medically fit individuals (aged 15). Characteristics of included studies Study design and demographics All articles that met the inclusion criteria were randomized clinical studies and published in English (Two articles from the Netherlands, and one each from Korea, India and Thailand). While four of the articles17-20 have compared the period of antibiotic prophylaxis in orthognathic surgery, the fifth21 has investigated the effect of antibiotic prophylaxis in comparison with placebo. A total of 452 patients were included in these five studies. Their age ranged from 15 to 54 years (mean age: 25.8 years). The female to male ratio was 2:1. Demographic data of all articles are highlighted in Table 2.

18

Intervention Lindeboom et al20 only focused on bilateral sagittal ramus osteotomy while Jansisyanont et al19 and Danda et al17 included both single and double jaw surgeries in their study. On the other hand, the remaining two studies18,
21

performed a Le Fort I in combination with

different mandibular osteotomies. The study of Jansisyanont et al19 reported a wide range of operation time (1.25-8.45 hour), whereas the other three studies18, 20, 21 presented an operation time of less than five hours. Danda et al17 reported a comparable operation time across the study groups but did not report their operation time. The detail of the type, dosage and duration of the antibiotics used in each study group and the associated infection rate are shown in Table 3. The infection criteria defined in each study were not completely identical (Table 4), but in general, the criteria being used to define infection within these five studies including: purulent or a positive-cultured

serosanguineous drainage from the surgical site; pain or tenderness, localized swelling and redness of the wound margin and surrounding tissue; and an elevation of body temperature to more than 38.5C after more than 48 hours; clinician diagnosis of infection.

19

Follow-up period Kang et al18 had the shortest follow-up period (two weeks). This was followed by Danda et al17 and Zijderveld et al21 who evaluate their patients up to one month. The other studies19, 20 examined the participants for a longer duration (three months). Primary outcome The primary outcome assessed in all studies was postoperative infection rate across different intervention groups (Table 3). All five studies found no statistically significant differences between different prophylactic antibiotic regimens they administered. However, Zijderveld et al21 successfully demonstrated the importance of prophylactic antibiotic in orthognathic surgery by detecting a significantly increased risk of infectious complications (52.63%) after bimaxillary orthognathic surgery without antibiotic prophylaxis. Based on this study, the number needed to treat (NNT) to prevent one infection in orthognathic surgery is 2.61; this means one in every 2.61 patients who has received antibiotic prophylaxis will benefit from the treatment when compared with controls. Single dose versus placebo. (One trial21) There was only one trial comparing the infection rate between two types of antibiotics with placebo. The two antibiotic groups were pooled to detect statistical

20

different with placebo. As a result, there was a statistically significant fewer infection rate found in the antibiotic group [RR 0.27 (0.11-0.68); 95%CI] (Figure 2). Single-dose versus single-day. (Two trials17, 20) There was no different in infection rate in patients who have been administered single-dose antibiotic or single-day antibiotic regimen [RR 3.00 (0.83-10.79); 95%CI] (Figure 3). Short term versus long term. (Two trials18,
19

) Short term antibiotic

regimen did not show statistically significant different infection rate compared with long term antibiotic regimen [RR 1.33 (0.31-5.67); 95% CI] (Figure 3). Secondary outcome There was only one research20 out of five articles that study regarding the adverse event associated with the antibiotic treatment, which they reported none observed in their study. Risk of bias The outcome of the quality appraisal which based on The Cochrane Collaborations tool for assessing risk of bias16 is highlighted in Table 5.

21

Discussion
The basic idea of antibiotic prophylaxis is twofold: to provide an adequate drug level in the tissues prior to and during any procedure, as well as the shortest entire administration period possible26. The initial dose should be administered parenterally prior to the operation; other than this is considered to be associated with an increased wound infection rate2. In a prospective study, Classen et al27 found that the administration of prophylactic antibiotics within 2 hours prior to the operation was associated with the lowest rate of wound infection. Furthermore, they detected that the infection rate was increasing with each hour of surgery after the incision. Burke28 showed in animals that delayed antibiotic administration exceeding a period of longer than 3 hours after bacterial inoculation consistently failed to reduce the infection rate. Therefore, he emphasized that maximum infection suppression can be achieved only if antibiotics were administered before bacteria had gained tissue access. The development of wound infection is a complex interaction between intraoperative bacterial inoculation and various factors of the hosts local and systemic resistance to infection2. The decision to administer prophylactic antibiotics is based on various reasons, including patients general state of health, the surgical site and extension, the

22

preoperative diagnosis and/or even the surgeons preference. Extended antibiotic regimens may predispose to the development of resistant bacterial strains, changes in physiological host flora, secondary infection and increased health care costs2, 4, 7, 9, 14, 29. Besides, antibiotic application bears the risk of adverse reaction which range from simple skin rash to severe anaphylactic shock4,
21, 29-31

. Therefore, one should consider

administering prophylactic antibiotic regimen when its benefit outweighs its risk4, 7, 19, 21, 29. Majority (80%) of the included articles did not report on the adverse events associated with the antibiotic usage and this is a severe flaw in the clinical studies on antibiotics. Although some authors3,
6, 32

doubt about the importance of

prophylactic antibiotics in orthognathic surgery, Peterson9 advocated that short-term perioperative antibiotic regimen should be recommended; this recommendation was supported by the finding of Conover et al33 who demonstrated its effectiveness in preventing postoperative wound infection. Other recommendations for the usage of prophylactic antibiotic regimen include medically compromised patients or surgery requiring sizable bone grafts3, 6. Patients age, operation time and the hospitalization postoperatively, i.e. in a large ward, were considered to be factors affecting wound

23

infection in the past4,

6, 7, 11, 14, 34, 35

. Although oral and maxillofacial

operations that last longer than 3 hours have been suggested to be associated with increased infection rate since 19909, later studies5, 20, 21 have failed to identify such relationship. Yet, Zijderveld et al21 detected no significant correlation between infection and both patients gender and age. The selection of the appropriate antimicrobial agent depends on the identification of the pathogens being most likely associated with particular surgical procedure2, 4, 7, 14, 30. Penicillin with its broad spectrum is effective against most oral pathogens4, 10, 14. It is considered to be the antibiotic of first choice in preventing infection during intraoral procedures7, 9, 14, 19, 36, whereas first generation cephalosporin was preferably administered during interventions involving transcutaneous surgery7, 9, 14, 30. Lindeboom et al20 investigated the efficacy of clindamycin in preventing perioperative infections: However, all of the three infection cases were found to be caused by penicillin-sensitive streptococci. Therefore, penicillin may suffice for prophylaxis in orthognathic surgery. Among the four articles17-19,
21

where orthognathic surgery was

performed in both jaws, the majority of infection (77.42%) occurred in the mandible. Two reasons for this finding might be presumed: first, a poorer

24

blood supply of the mandible when compared to the maxilla; second, a gravity pooling effect probably causing stagnation of the bacteria rich saliva in the lower jaw area10, 35. Koole and Egyedi37 detected the presence of saliva in the mandibular osteotomy site for at least 3 days postoperatively. According to this finding, they considered the saliva entering the surgical wound might cause infection of the osteotomy site. The administration of local antimicrobial agent might have played a role in reducing postoperative wound infection rate2. Lindeboom et al20 in their study prescribed chlorhexidine 0.12% for two weeks postoperatively for all participants regardless of their allocation. This antimicrobial mouth wash might be important for their decreased infection rate when compared with other studies. Future randomized controlled trials should consider local antimicrobial agents as a potential confounding factor in their study. Clinical studies not mentioning anything about the hosts defense state have been excluded in this systematic review. Immuno-compromised patients states will inevitably affect the infection rate3, 7, 13. Therefore, it was considered to be crucial for a clinical study to report the medical condition of their study population2 in order to reduce the potential study bias. Although Kang et al18 did not report their exclusion criteria, we have included their study in our final review based on their inclusion of young

25

patients without specific medical history. However, these investigators only assessed the patients for two weeks postoperatively, a period which to the authors opinion is considered to be insufficient to detect all eventual postoperative infections during the wound and bone healing. All five articles12, 22-25 excluded during primary assessment did not report about the criteria being used to define the term of infection. The Committee on Antimicrobial Agents2 declared that written definitions of wound infection as a highly important criteria to design and report results of clinical studies evaluating the efficacy of various prophylactic antimicrobial agents in surgery. The lack of the information regarding the infection criteria was thus considered to be a severe bias of infection studies. Defined infection criteria specifically for oral and maxillofacial area should be compiled for future clinical studies. Many studies10, 12, 17-21, 30, 35 so far have been performed to detect an eventual evidence based need for prophylactic antibiotic regimen in orthognathic surgery. Zijderveld et al21 have successfully demonstrated an unacceptably high infection rate (52.63%) in their placebo group. However, their result was in contrast to many older studies showing no significant different between the infection rates between groups of antibiotic prophylaxis and placebo3, 6, 29. Still most surgeons administer

26

different kinds of prophylactic antibiotics in orthognathic surgery according to their experience11, 36. One might assume that this is based on the concept that orthognathic surgery is performed in clean-contaminated area possibly predisposes significant risk to postoperative infection2, 5, 7, 9,
12, 29, 35

. Direct communication between surgically mobilized bony

segments and the oral or nasal cavity and maxillary sinuses provide a basic rationale for the use of prophylactic antibiotic in orthognathic surgery7, 14. To the authors opinion, a large randomized controlled trial with high power should be performed in the future to yield an evidence based answer to the question regarding the most appropriate antibiotic prophylaxis regimen in orthognathic surgery. The need for multicenter trials with an appropriate sample size calculation is of paramount importance. Future randomized controlled trials regarding antibiotic prophylaxis in orthognathic surgery should report randomization procedures in detail, including sequence generation, allocation concealment and implementation as suggested by The CONSORT Statement38. Moreover, definitions of infection criteria as well as descriptions of the patients medical condition need to be provided2. In addition, surgical procedures should be equally distributed in each arm of the trial and the administration of concomitant perioperative local

27

antimicrobial or antiseptic agents should be controlled2. Yet, the association between infection rate with age, gender, surgical site, operation time, size of the ward and period of hospitalization would be a very interesting field of future research regarding the topic of antibiotic prophylaxis. Besides, the adverse events of the antibiotic treatment must be reported. The main limitation of this meta-analysis is only a small number of randomized controlled trials being available up-to-date related to antibiotic prophylaxis regimen in orthognathic surgery. Besides, in none of the included articles allocation concealment has been mentioned. Related to this study design flaw, an increased potential bias exists in all of the here included studies. Publication bias might account for limitation in this review study. Although we have performed searching using the main electronic databases without limitation of language of publications, however, there are many papers which reported in other language (e.g. Chinese) which were not available in the above mentioned databases.

28

Conclusion
This systematic review with meta-analysis confirmed a significant reduction of infection rate with the application of antibiotic prophylaxis in orthognathic surgery regardless of the regimen used. Orthognathic surgery is mainly performed in young, healthy individuals without significant comorbidities. Thus, a single-dose antibiotic regimen is effective in preventing infection after the orthognathic surgery within this target group. An extended antibiotic regimen needs a clear indication, and the risk and benefit of it to the patients need to be clearly pondered. Future doubleblinded randomized controlled trials with high power need to be performed to yield evidence based answers to the question of the most appropriate antibiotic prophylaxis regimen in orthognathic surgery.

29

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correction of dentofacial deformities: a review of 140 consecutive cases. J Oral Surg 1980 Feb;38(2):117-20. [5] Fridrich KL, Partnoy BE, Zeitler DL. Prospective analysis of

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comparative, randomized study between amoxicillin-clavulanic acid and penicillin. J Med Assoc Thai 2008 Nov;91(11):1726-31. [20] Lindeboom JA, Baas EM, Kroon FH. Prophylactic single-dose administration of 600 mg clindamycin versus 4-time administration of 600 mg clindamycin in orthognathic surgery: A prospective randomized study

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Administration Ad Hoc

Interdisciplinary Advisory Committee on Antimicrobial Drug Usage. JAMA 1977 Mar 7;237(10):1003-8. [27] Classen DC, Evans RS, Pestotnik SL, Horn SD, Menlove RL, Burke JP. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med 1992 Jan 30;326(5):281-6. [28] Burke JF. The effective period of preventive antibiotic action in experimental incisions and dermal lesions. Surgery 1961 Jul;50:161-8. [29] Peterson LJ, Booth DF. Efficacy of antibiotic prophylaxis in intraoral orthognathic surgery. J Oral Surg 1976 Dec;34(12):1088-91. [30] Spaey YJ, Bettens RM, Mommaerts MY, Adriaens J, Van Landuyt HW, Abeloos JV, et al. A prospective study on infectious complications in orthognathic surgery. J Craniomaxillofac Surg 2005 Feb;33(1):24-9. [31] Cunha BA. ANTIBIOTIC SIDE EFFECTS. Medical Clinics of North America 2001;85(1):149-85. [32] Olson RE, Morello JA, Kieff ED. Antibiotic treatment of oral anaerobic infections. J Oral Surg 1975;33:619. [33] Conover MA, Kaban LB, Mulliken JB. Antibiotic prophylaxis for major maxillocraniofacial surgery. J Oral Maxillofac Surg 1985 Nov;43(11):865-9.

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[34] Gallagher DM, Sinn DP. Penicillin-induced anaphylaxis in a patient under hypotensive anesthesia. Oral Surg Oral Med Oral Pathol 1983 Oct;56(4):361-4. [35] Reinhart E, Reuther J, Michel C, Kubler N, Ordung R, Bosebeck H. [Perioperative antibiotic prophylaxis in orthodontic bone operations of the facial skull]. Mund Kiefer Gesichtschir 1998 Jul;2(4):194-201. [36] Heit JM, Farhood VW, Edwards RC. Survey of antibiotic prophylaxis for intraoral orthognathic surgery. J Oral Maxillofac Surg 1991 Apr;49(4):340-2. [37] Koole R, Egyedi P. Postoperative contamination of mandibular osteotomy sites with saliva. Int J Oral Maxillofac Surg 1987 Oct;16(5):554-8. [38] Moher D, Schulz KF, Altman D, Group C. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 2001 Apr 18;285(15):1987-91.

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Figure 1. Flow diagram of articles selection

Electronic literature search
(n = 418) Databases: PubMed, Ovid, Cochrane library, EMBASE, ISI Web of Science, MD Consult Limits: No language limitation Key words: (#1) AND (#2) OR (#3) #1- (orthognathic*) OR (bimaxillary osteotomies) OR (jaw surgery) #2- (antibiotic*) OR (antibiotic treatment) OR (antibiotic agent)

Manual search
(n = 32)

Duplicates removed (n = 218)

Articles screened (n = 232)

Inclusion criteria: 1. Randomized clinical trial/case controlled studies/prospective clinical studies 2. Primary outcome: postoperative infection

Articles excluded (n = 222)

1. 2. 3. 4.

Primary assessment (n = 10) Complete demographic profile Clear inclusion/exclusion criteria Statement of patients medical conditions Indication of antibiotic regimen being used

Articles excluded (n = 5)

Final review (meta-analysis)

(n = 5)

36

Figure 2. Infection rate in orthognathic surgery. Single dose prophylactic antibiotics versus placebo
Single dose Placebo Risk Ratio Events Total Events Total Weight M-H, Fixed, 95% CI 5 35 35 10 0.01 0.1 1 10 100 Favours experimental Favours control 10 19 100.0% 19 100.0% 0.27 [0.11, 0.68] 0.27 [0.11, 0.68] Risk Ratio M-H, Fixed, 95% CI

Study or Subgroup Zijderveld et al, 1999 Total (95% CI)

Total events 5 Heterogeneity: Not applicable Test for overall effect: Z = 2.79 (P = 0.005)

Figure 3. Infection rate in orthognathic surgery. Short term versus long term antibiotic regimen
Short term Long term Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI 1.1.1 Single-dose versus single day regimen Danda, 2010 Lindeboom, 2003 Subtotal (95% CI) 7 2 75 35 110 2 1 75 35 110 33.3% 16.7% 50.0% 3.50 [0.75, 16.30] 2.00 [0.19, 21.06] 3.00 [0.83, 10.79] Risk Ratio M-H, Fixed, 95% CI

9 3 Total events Heterogeneity: Chi = 0.15, df = 1 (P = 0.70); I = 0% Test for overall effect: Z = 1.68 (P = 0.09) 1.1.2 Intraoperative versus >1 day regimen Jansisyanont, 2008 Kang, 2009 Subtotal (95% CI) 1 3 61 28 89 1 2 61 28 89 16.7% 33.3% 50.0% 1.00 [0.06, 15.63] 1.50 [0.27, 8.30] 1.33 [0.31, 5.67]

Total events 3 4 Heterogeneity: Chi = 0.06, df = 1 (P = 0.81); I = 0% Test for overall effect: Z = 0.39 (P = 0.70) Total (95% CI) 199 199 100.0% 2.17 [0.84, 5.56]

Total events 6 13 Heterogeneity: Chi = 0.86, df = 3 (P = 0.84); I = 0% Test for overall effect: Z = 1.61 (P = 0.11) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours experimental Favours control

37

Table 1. Articles excluded from final review

Study Teltzrow et al22, 2005 Title Perioperative complications following sagittal split osteotomy of the mandible Antibiotic prophylaxis for orthognathic surgery: a prospective, randomized clinical trial Perioperative antimicrobial prophylaxis in Obwegeser-Dal Pont surgery for prognathism Reasons for exclusion Article did not report on: 1. Exclusion criteria 2. Medical conditions of patients 3. Criteria used to define infection Article did not report on: 1. Medical conditions of patients 2. Criteria used to define infection Article did not report on: 1. Full description of patients demographic profile 2. Inclusion/exclusion criteria 3. Medical conditions of patients 4. Criteria used to define infection Article did not report on: 1. Inclusion/exclusion criteria 2. Medical conditions of patients 3. Criteria used to define infection Article did not report on: 1. Full description of patients demographic profile 2. Exclusion criteria 3. Medical conditions of patients 4. The dosage of antibiotics used 5. Criteria used to define infection

Baqain et al12, 2004

Liebermann et al23, 1990*

Guernsey and DeChamplain24, 1971

Sequelae and complications of the intraoral sagittal osteotomy in the mandibular rami The use of prophylactic antibiotics in extraoral procedures for mandibular prognathism

Zallen and Strader25, 1971

# All articles were reported in English except (*)

Table 2. Study number and patients demographic profile

Total patients included 150 56 122 70 54 452 Age (mean) 15.0-37.0 (24.0) 17.9-30.6 (23.9) 17.1-47.6 (26.5) 19.0-54.0 (29.9) 18.0-40.0 (25.5) 25.8

Study Danda et al17, 2010 Kang et al18, 2009 Jansisyanont et al19, 2008 Lindeboom et al20, 2003 Zijderveld et al21, 1999 TOTAL

Study no. 150 56 137 70 54

Male 57 30 40 18 13 101

Female 93 26 82 52 41 201

38

Table 3. Prophylactic antibiotic regimen and associated infection rate

Study Danda et al17 Study groups Single-dose group Single-day group Kang et al18 Experimental group Control group Pre-operative antibiotic 1g Ampicillin intravenously at induction 1g Ampicillin intravenously at induction 1.0g Cefpiramide intravenously 30 minutes before surgery 1.0g Cefpiramide given intravenously 30 minutes before surgery 1.2g amoxicillinclavulanic acid given intravenously 30 minutes pre-operatively and every 8 hours during the operation 1.2g amoxicillinclavulanic acid given intravenously 30 minutes pre-operatively and every 8 hours during the operation 2MU penicillin G given intravenously 30 minutes preoperatively and every 4 hours during the operation 2MU penicillin G given intravenously 30 minutes preoperatively and every 4 hours during the operation 600mg Clindamycin given intravenously 15 minutes before the surgical incision 600mg Clindamycin given intravenously 15 minutes before the surgical incision 2200 mg amoxicillinclavulanic acid dissolved in 50mL of 0.9% sodium chloride given intravenously 30 minutes before surgery 1500mg cefuroxime dissolved in 50mL of 0.9% sodium chloride given intravenously 30 minutes before surgery Placebo Post-operative antibiotic Saline solution intravenously every 6 hours for 24 hours 500mg Ampicillin intravenously every 6 hours for 24 hours Infection cases 7/75 Infection rate (%) 9.3

2/75

2.6

3/28

10.71

1.0g Cefpiramide given intravenously twice daily for 3 days after surgery 1.2g amoxicillin-clavulanic acid given intravenously 8 hours after the surgery

2/28*

7.14

Jansisyanont et al19

Short term amoxicillinclavulanic acid

1/33

3.03

Long-term amoxicillinclavulanic acid

625mg amoxicillinclavulanic acid tablet orally every 8 hours after surgery for 5 days

0/28

Short-term penicillin

2MU penicillin G given intravenously 4 hours after the surgery

0/29

Long term penicillin

500mg oral amoxicillin every 8 hours for 5 days

1/32

3.13

Lindeboom et al20

Single dose regimen

Saline solution given intravenously every 6 hours for 24 hours 600mg Clindamycin given intravenously every 6 hours for 24 hours -

2/35

5.71

4-doses regimen

1/35

2.86

Zijderveld et al21

Amoxicillinclavulanic acid

2/18

11.11

Cefuroxime

3/17

17.65

Placebo

10/19

52.63

^ All results found no significant different statistically in their studies. ^^ There was 1 case of wound dehiscence in this group (#) without any sign of infection.

39

Table 4. Infection criteria of the included studies

Study Danda et al
17

Criteria to define postoperative infection 1. Purulent discharge from an incision 2. serosanguineous drainage and a wound culture positive for a known pathogen 3. clinician diagnosis of infection

Kang et al

18

1. Purulent drainage from the surgical site with or without laboratory confirmation 2. At least 1 of the following signs or symptoms of infection: pain or tenderness, localized swelling, redness or heat and a superficial incision deliberately opened by surgeon, unless the incision is culture negative 3. An abscess or other evidence of infection is found on a direct examination, during reoperation, or by the histopathological or radiologic examination 4. Diagnosis of surgical site infection (SSI) by the surgeon or attending physician

Jansisyanont et al19

1. Purulent discharge from the surgical site 2. Serosanguineous drainage and a wound culture proved positive from a known pathogen 3. An elevation of temperature to more than 38.5C after more than 48 hours and the patients had been ruled out from other causes of infection by complete blood count, chest x-ray and urinary analysis 4. Pain or tenderness, localized swelling, and redness of the wound margin and surrounding tissue * The infection had to present at the surgical site within 42 days (6 weeks) of surgery

Lindeboom et al

20

1. Presence of purulent drainage (either spontaneously or by incision), accompanied with pain or tenderness, localized swelling, redness and heat or fever (>38.5C) 2. An increase in localized swelling, after an initial post-operative decrease of edema, together with pain, discomfort, induration and increase in body temperature (>38.5C)

Zijderveld et al21

1. Appearance of the wound on the third and seventh day postoperatively and after 1 month (subdivided into 4 categories: normal, edematous, exudate with drainage of non-purulent material, or an abscess with drainage of purulent material with or without incision * Wound infection was defined as any inflammatory condition previously described that prompted the surgeon to give additional treatment that was not part of the routine postoperative protocol * The presence of wound dehiscence was scored separately

40

Table 5. Quality appraisal of the included studies based on The Cochrane Collaborations tool for assessing risk of bias16
Adequate sequence generation? Unclear Allocation concealment? Unclear Incomplete outcome data addressed? Unclear Free of selective reporting? Unclear Other sources of bias Unclear

Trials Danda et al17 Kang et al18 Jansisyanont et al19 Lindeboom et al20 Zijderveld et al17 Risk of bias

Blinding? Yes (Doubleblinded) Unclear Yes (Doubleblinded) Yes (Assessor) Yes (Doubleblinded) Low risk

Yes Yes

Unclear Unclear

Unclear Unclear

Unclear Unclear

Unclear Unclear

Yes Yes

Unclear Unclear

Unclear Unclear

Unclear Unclear

Unclear Unclear

Low risk

Unclear

Unclear

Unclear

Unclear

41

Part II

42

Oral

versus

Intravenous Orthognathic

Antibiotic Surgery -

Treatment A

after

Bimaxillary

Prospective,

Randomized, Double-Blind & Placebo-Controlled Clinical Trial

Abstract
Background: Postoperative antibiotic prophylaxis is usually administered intravenously, despite of an increased morbidity rate compared with oral application. Objective: To investigate whether prophylactic oral antibiotic regimen is as effective as intravenous in bimaxillary orthognathic surgery. Methods: Between December 2008 and May 2010, forty-two patients who underwent bimaxillary orthognathic surgery were randomly allocated into two placebo-controlled postoperative antibiotic prophylaxis groups. Group 1 received oral amoxicillin 500mg three times daily; group 2 received intravenous ampicillin 1g four times daily for two days. Both groups were subsequently taking oral amoxicillin for three more days. The surgeons, participants and clinical assessors were blinded to the study group. Clinically, the infection rate was assessed in both study groups for a period of six weeks after the surgery.
43

Results: Nine of 42 patients (21.4%) developed infection. No significant difference was detected in the infection rate between oral (3/21) and intravenous (6/21) prophylactic antibiotic regimen (p=0.45). Neither adverse drug events nor relation between age, type of surgical procedures, duration of the operative procedure, surgical procedure-related events, blood lost and blood transfusion with infection were detected (p>0.05). Conclusion: Prophylactic oral antibiotic regimen after bimaxillary orthognathic surgery proves to be as effective and safe as intravenous.

44

Introduction
Dentofacial deformities affect approximately 20% of the population. These people may benefit from a combined treatment of orthodontics and orthognathic surgery1. Peterson (1990) estimated the infection rate for orthognathic surgery to be 10-15%, which was reduced to 1% under perioperative antibiotic regimen2. Others stated a higher prevalence of infection after bimaxillary osteotomies, ranging from 1.4% to 33.4%3-5. Performance of orthognathic surgery is considered to commit cleancontaminated wounds6. The infecting microorganisms are part of the mixed endogenous flora of the oral cavity. Furthermore, when performing extraoral approaches, there is a risk of infection due to skin microorganisms. In cases involving intraoral approaches, mainly streptococci, anaerobic gram-positive cocci and anaerobic gram-negative rods are involved, with staphylococci to be the most important germs to cause transcutaneous infection7. Perioperative antibiotic treatment has been used worldwide prophylactically to reduce the post-operative infection rate without any consensus regarding the regimen. Direct communication of surgically displaced osseous segments with the oral and nasal cavities, or the maxillary sinuses provides the basic rationale to use antibiotic prophylaxis

45

in these procedures8. The controversies regarding the use of prophylactic antibiotics result in a high variability in literature regarding prophylactic antibiotic regimens3,4,8-10. Although some authors11,12 doubt the role of prophylactic antibiotics in intraoral orthognathic surgery, Peterson2 recommended a short-term perioperative antibiotic regimen in intraoral orthognathic surgery, considering it to be effective in preventing postoperative wound infection. This recommendation corresponds to those of later studies13-16. Yrastorza12 suggested that routine prophylactic use of antibiotics in bimaxillary osteotomies should be reserved for specific cases, such as patients with decreased host defense and patients undergoing surgery with sizable bone grafts. However, up to date there is no clinical study comparing the efficacy of oral versus intravenous antibiotic regimen in bimaxillary orthognathic surgery reported in the English literature. There is certain risk of adverse event related to antibiotic usage. Immediate adverse effects such as anaphylactic shock, itching, urticaria, angiooedema, rhinitis, bronchospasm, laryngeal oedema are fortunately very rare. Delayed adverse effects such as serum sickness with urticaria, fever, polyarthralgia, lymphadenopathy and eosinophilia may also be encountered17,18. Appropriate criteria to select the optimal antibiotic

46

regimen for specific purposes include efficacy, risk of adverse advents, contraindications, treatment costs, and details on the clinical condition of the patient16. Most of the previous studies of immediate postoperative antibiotics regimen were given intravenously4. The aim of this study was to investigate whether prophylactic oral antibiotic regimen is as effective as intravenous in bimaxillary orthognathic surgery. The null hypothesis of this study was no significant difference in the prevalence of infection between oral and intravenous antibiotic treatment groups.

47

Methods
This prospective, single center, randomized, double-blinded, placebo-controlled clinical trial was conducted prospectively at Queen Marry Hospital, Hong Kong SAR, PR-China. The study was performed following the principles outlined in the Declaration of Helsinki and was approved by the Human Ethics Committee of Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster. Patients recruitment All patients, male and female, aged 18 to 40 years old, who underwent bimaxillary orthognathic surgery within the Discipline of Oral and Maxillofacial Surgery, The University of Hong Kong, from December 2008 to May 2010 were enrolled in this study. Written informed consent was obtained from all participants. Exclusion criteria The patients were excluded from the study when any of the following criteria was present: (1) History of any type of previous surgery of head and neck area, including previous orthognathic surgery. (2) Patients who were having distraction osteogenesis as part of the
48

orthognathic surgery. (3) History of malignancy of the head and neck region, and/or history of radiation to the head and neck region. (4) Known hypersensitivity to amoxicillin, ampicillin or other -lactam antibiotics; known history of lactose intolerance. (5) (6) Used of any antibiotics within the past 14 days prior to the surgery. All patients with compromised host defenses, e.g. diabetes mellitus, autoimmune disease, end-stage renal disease, severe alcoholic cirrhosis and neutropenia. (7) All patients who were receiving immunosuppressive drugs that interfere with host defenses, e.g. cyclosporine, steroids and cancer chemotherapeutic agents. Randomization All participants were randomly assigned into two groups

corresponding to a list of computer-generated random numbers which was generated and kept by an independent pharmacist. Block randomization with a block size of four was used to ensure approximately equal numbers of subjects in each study group. They remained in the same allocation throughout the post-operative period. The details of the series were unknown to any of the surgeons. The pharmacist prepared the medications

49

and placebo which were identical in size, shape and colour; and dispensed them to the nurses in the ward in a sequentially numbered opaque sealed envelope. The code was revealed to the principal investigator at the end of the trial. Therefore, the patients, surgeons and clinical assessors were blinded to the postoperative prophylactic antibiotic regimen. Antimicrobial prophylaxis Postoperatively, participants in group 1 received oral amoxicillin (Bright Future Pharmaceutical Laboratories Ltd., Hong Kong SAR, PRChina) 500mg three times daily and intravenous placebo (normal saline) injection four times daily in the first two days after orthognathic surgery. Participants in group 2 were administered intravenous ampicillin (Medochemie Ltd., Limassol, Cyprus) 1g four times daily and oral lactose (placebo) three times daily for the first two days after the orthognathic surgery. All participants received oral amoxicillin 500mg three times daily for another three days. All participants received intravenous ampicillin 1g during anesthetic induction at operating theater, and 500mg every 6 hourly during the operation. In case of adverse reaction developed after the administration of amoxicillin, the antibiotic drug was changed to clindamycin (Pfizer PGM, Poc Sur Cisse, France) and the case was withdrawn from the study.

50

Surgical intervention The orthognathic surgeries were performed under induced

hypotensive anaesthesia19-22. Intravenous tranexemic acid19,23 (Daiichi Sankyo Co. Ltd., Tokyo, Japan) 20mg/kg was administered to participants in both groups on anaesthetic induction. All surgeries were performed by senior staffs and residents. The incision sites were infiltrated with lidocaine with 1:80000 epinephrine (Lidocaton 2% 1:80000, Weimer Pharma GmbH, Rastatt, Germany). All osteotomies were performed using bur and saw by Stryker (Michigan, USA). The segments were internally fixed with titanium osteosynthesis plates and screws (Compact MFTM 2.0, Synthes-Stratec, Oberdorf, Switzerland). In cases with vertical

subsigmoid osteotomy (VSO), mandibulomaxillary fixation (MMF) was performed for 6 weeks. All surgical wounds were closed primarily with 40 and 3-0 Vicryl sutures (Ethicon, Somerville NJ, USA), without any drainage. Suture removal was performed one week after the operation. Compression chin dressing was applied after genioplasty for two days. Ice packs were applied for the first two days postoperatively. Additionally, the patients were prescribed mefenamic acid (APT Pharma Ltd., Hong Kong SAR, PR-China) 500mg three times daily, intravenous dexamethasone (Weimer Pharma GmbH, Rastatt, Germany)

51

4mg on induction, then every 12 hours postoperatively for 2 days and 0.2% chlorhexidine gluconate mouthwash (Europharm, Hong Kong SAR, PR-China) for two weeks post-operatively. Outcome measures Primary outcome The blinded clinical assessors evaluated all participants for infection based on the presence of the following clinical criteria, similar to previous studies 7,8,14,16,24: 1. Drainage or purulent exudates from the surgical site. 2. Elevated body temperature (>37.5C) for longer than 72 hours; or a sudden increase of body temperature after showing common temperature postoperatively. 3. Increase in edema, induration and erythema of wound edges and surrounding tissues. 4. Unusual pain associated with the surgical site. 5. Increased leukocyte count (>10.10X109/L) with an associated increase in immature forms of polymorphonuclear neutrophils; an elevated C-reactive protein level (>0.76 mg/dL). 6. Localized, red, tender, overheated swelling, either fluctuating or indurated

52

The patients were evaluated daily during their hospital stay. Subsequently, they were assessed at one, two, four and six weeks after the operation in the outpatient clinic. The overall observation phase was determined to be six weeks after the operation as soft tissue and bone healing is considered to occur during this period7,15,25. The patients temperature was recorded twice daily in the ward and once during each out-patient follow-up review. Pain experience was recorded as visual analogue scale (VAS). Laboratory investigations (leukocyte counts and C-reactive protein) were performed preoperatively as baseline measurement and also on day 3 and day 5 post-operatively. The infection was confirmed by two independent senior consultants for all cases. In case of pus drainage, culture and gram staining were performed to identify the pathogens and determine their sensitivity. All infections were treated by local measures including local incision and drainage and multiple daily wound irrigations using sterile water for irrigation, USP (Baxter Healthcare Corporation, Illinois, USA). Broad spectrum antibiotic therapy was started immediately and modified later according to sensitivity test results7. Secondary outcome Any adverse reactions to the prescribed antibiotics were recorded.

53

Sample size calculation Based on previous studies4,5, the prevalence of infection after bimaxillary osteotomies ranged from 1.4% to 33.4%. For a power of 80% and type I error level of 5% (two tailed), the sample size needed to be 42 patients, with 21 patients in each intervention group to detect a significant difference in two groups (Power and Precision 3.2, Biostat Inc., Nova Jersey, EUA).

Statistical analysis
Variables for the two groups were compared using 2-sided Fishers exact test and 2-sample t-test with a 95% confidence interval. Fisher exact test was also used to assess any significant difference between the infection rates in the two study groups. Furthermore, the infected and the uninfected patients were compared with regard to the white cell count, body temperature and C-reactive protein. Multiple logistic regression was used to adjust for the possible effects of age, type of surgical procedures, duration of the operative procedure, surgical procedure related events, blood lost and blood transfusion to the incidence of infection. All statistical analysis was performed using SPSS 16.0 (SPSS Inc. Chicago, US).

54

Results
Between December 2008 and May 2010, 66 consecutive patients were recruited in Queen Marry Hospital, Hong Kong SAR, PR-China. Based on the exclusion criteria, 24 patients were not included. There was no withdrawal throughout the trial. The flow of the participants was summarized in Figure 1. The primary analysis was intention-to-treat and involved all randomly assigned participants. There were 16 cases of Class II deformity and 26 cases of class III deformity. Out of these, 20 patients were suffering from facial asymmetry. Preoperatively all patients underwent orthodontic treatment to optimize the shape of the dental arches. Orthodontic alignment started only six weeks after the operation. The surgical procedures are summarized in Table 1. The patients age ranged from 18 to 34 years, with a mean age of 26.0 years (SD 4.2 years). 28 patients were female, and 14 patients were male (2:1). The participants were assigned equally in 2 groups, with 21 patients in each group (Table 2). Statistical analysis showed that the study groups were comparable with respect to age (p=1.00), gender (p=0.74), operating time (p=0.99), diagnosis (p>0.05), surgical procedures (p>0.10), intraoperative surgical procedure-related events (p>0.10), blood loss (p=0.76) and blood transfusion (p=1.00). The mean operation time was 452

55

minutes (SD 123 minutes; range 197-660 minutes). No patient developed allergic reaction or adverse events due to the administered antibiotics. A total of nine infections (21.4%) developed postoperatively; three infections (14.3%) in the oral group and six infections (28.6%) in the intravenous group. There was no significant different in the infection rate between the oral and intravenous groups (P=0.45). Five of the infected patients were female. All but one infections were unilateral (5 right; 3 left); and most infections (6/9) occurred in the mandible. However, these differences were not significant statistically (p= 0.73; p=0.51). The infections in the oral group started between 4 to 7 days (mean 6 days) but developed later in the intravenous group between 5 to 42 days (mean 14.5 days). This finding was of clinical interest but not significant statistically (p=0.27). The infection cases were summarized in Table 3. Additionally, no significant difference was found related to the pain score (VAS) either between infected and non-infected participants (p>0.05), or oral and intravenous group (p>0.05). Additionally, multiple logistic regression did not showed any positive relation between age, type of surgical procedures, duration of the operative procedure, surgical procedure related events, blood lost and blood transfusion with infection in orthognathic surgery (p>0.05). Table 4 summarizes the infection rates in both study groups.

56

All but one infection cases were associated with purulent discharge. This exceptional case presented with fever, excessive pain and erythematous wound changes at both sides of the mandible. Pus was sent for culture and sensitivity. The results showed oral commensals only, being sensitive to amoxicillin and ampicillin. All infections subsided after local measures and empirical antibiotic treatment, i.e. amoxicillin and metronidazole (Vickmans Laboratories Ltd., Hong Kong SAR, PR-China). In eleven cases of intraoperatively surgical adverse events (Table 2) occurred, 54.5% of them pertained to accidentally shaved tooth roots during segmentalisation. With an average blood loss of 1112.5mL (SD 482.0mL), blood transfusion became necessary in seven cases.

57

Discussion
No significant difference regarding the infection rate was found between oral and intravenous antibiotic regimen groups. The null hypothesis accepted at a 0.05 level of significance, implied that postoperative oral is as efficient as intravenous prophylactic antibiotic regimen in bimaxillary orthognathic surgery. The here presented overall infection rate of 21.4% is slightly higher than those found in other studies14,26-28. Multiple segmentalisations and extensive blood loss could be the tributary factors to this incidence. Additionally, no adverse drug events were observed in this trial, same as reported elsewhere16,29. Although reporting the adverse events of antibiotics was important, but it was often neglected25. Future trials on antibiotics should document it distinctly. Postoperative infection prevention using oral instead of intravenous antibiotics provides threefold benefit: 1) reduction of postoperative morbidity (e.g. thrombophlebitis, cellulitis, infiltration and compartment syndrome30); 2) cost-effectiveness; 3) and earlier patient mobilization without intravenous drip31. The intravenous antibiotic administration group revealed an infection rate two times higher than the one in the oral group. Furthermore, no significant difference related to the pain score

58

(VAS) was found between the two study groups. Therefore, postoperative prophylactic antibiotics should be given orally based on the drawback of administration of intravenous antibiotics. It was somewhat astonishing that the pain score of infected patients was not significantly higher than the one of non-infected. It may be argued that this finding might be due to surgery related neurapraxia. Mostly infection developed in the mandible, similar to other studies15,24,26,32. The reasons for it may be 1) the poorer blood supply of the mandible when compared to the maxilla; 2) the gravity pooling effect which probably causes stagnation of the bacteria rich saliva in the lower jaw area4,33. As early as in 1987, Koole and Egyedi34 detected the presence of saliva in mandibular osteotomy sites for at least 3 days postoperatively, suggesting that this finding might cause infection of the osteotomy site. Similar with previous studies3,4,24, there was no positive relation found in this trial between age and operation duration with infection in orthognathic surgery. Compared to others
14,15,24

, the here reported mean

operation period of 425 minutes (SD 123.4 minutes) was higher. However, due to the common presence of the clinical finding of dentoalveolar protrusion in local population3, multiple segmental surgeries (e.g. Le Fort I osteotomies with segmentalisation, Wunderer and posterior Le Fort I

59

osteotomies, mandibular subapical osteotomies in combination with ramus surgery and genioplasties), were necessary, leading to considerable extension of the operation duration and increased blood loss and surgery related adverse events such as accidentally shaved tooth roots. In the here presented study, -lactam antibiotics were used due to their known antimicrobial activity against the common oral flora8,13,35,36. The isolates were uniformly sensitive to penicillin, like those observed in other studies8,24. Amoxicillin is a broad spectrum penicillin against grampositive organisms that are susceptible to other penicillins, with a higher activity against some gram-negative bacteria and enterococcal infections than other penicillins37. Therefore, prophylactic antibiotic regimen with amoxicillin in orthognathic surgery is sufficient as already published elsewhere14,15. There were several limitations in this study. Firstly, only healthy adults (18-40 years old) were included in this trial. Thus the findings cannot be applied to younger, immunocompromised or systemically ill patients. Secondly, concomitant procedures such as distraction

osteogenesis, septorhinoplasty and bone grafting3,7,8,38,39 were not assessed in this study. The third limitation was the determination of effective length of hospitalization: in order to ascertain the patients compliance in taking

60

the medication over a period of 5 days postoperatively, all of them were not discharged earlier, than five days after the operation.

61

Conclusion
The results of the present randomized, double-blinded, placebocontrolled study suggest that prophylactic postoperative oral antibiotic regimen is as effective and safe as intravenous in bimaxillary orthognathic surgery. It therefore represents an evidence based alternative to prophylactic intravenous antibiotic regimen.

62

References
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Spaey YJ, Bettens RM, Mommaerts MY, et al. A prospective study on infectious complications in orthognathic surgery. J

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Dec;42(12):797-801. 9. Fridrich KL, Partnoy BE, Zeitler DL. Prospective analysis of antibiotic prophylaxis for orthognathic surgery. Int J Adult Orthodon Orthognath Surg. 1994;9(2):129-31. 10. Schubert J, Schafer R. [Results of perioperative antibiotic prophylaxis in orthognathic surgery]. Dtsch Z Mund Kiefer Gesichtschir. 1990 Mar-Apr;14(2):96-8. 11. Olson RE, Morello JA, Kieff ED. Antibiotic treatment of oral anaerobic infections. J Oral Surg. 1975;33:619. 12. Yrastorza JA. Indications for antibiotics in orthognathic surgery. J Oral Surg. 1976 Jun;34(6):514-6. 13. Laskin DM. The use of prohphylactic antibiotics for the prevention of postoperative infections. Oral Maxillofacial Surg Clin N Am. 2003;15:155-60.

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Baqain ZH, Hyde N, Patrikidou A, Harris M. Antibiotic prophylaxis for orthognathic surgery: a prospective, randomised clinical trial. Br J Oral Maxillofac Surg. 2004 Dec;42(6):506-10.

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Jansisyanont P, Sessirisombat S, Sastravaha P, Bamroong P. Antibiotic prophylaxis for orthognathic surgery: a prospective, comparative, randomized study between amoxicillin-clavulanic acid and penicillin. J Med Assoc Thai. 2008 Nov;91(11):1726-31.

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Lindeboom JA, Baas EM, Kroon FH. Prophylactic single-dose administration of 600 mg clindamycin versus 4-time administration of 600 mg clindamycin in orthognathic surgery: A prospective randomized study in bilateral mandibular sagittal ramus

osteotomies. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003 Feb;95(2):145-9. 17. Katzung BG. Basic & clinical pharmacology. 9th ed. New York; London: Lange Medical Books/McGraw Hill ; McGraw-Hill; 2004. 1088 p. p. 18. Lambert HP, O'Grady F, Garrod LP. Antibiotic and chemotherapy. 6th ed. Edinburgh: Churchill Livingstone; 1992. [10], 561 p. p.

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19.

Zellin G, Rasmusson L, Palsson J, Kahnberg KE. Evaluation of hemorrhage depressors on blood loss during orthognathic surgery: a retrospective study. J Oral Maxillofac Surg. 2004 Jun;62(6):662-6.

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Choi WS, Samman N. Risks and benefits of deliberate hypotension in anaesthesia: a systematic review. Int J Oral Maxillofac Surg. 2008 Aug;37(8):687-703.

21.

Kim SG, Park SS. Incidence of complications and problems related to orthognathic surgery. J Oral Maxillofac Surg. 2007

Dec;65(12):2438-44. 22. Dolman RM, Bentley KC, Head TW, English M. The effect of hypotensive anesthesia on blood loss and operative time during Le Fort I osteotomies. J Oral Maxillofac Surg. 2000 Aug;58(8):834-9; discussion 40. 23. Choi WS, Irwin MG, Samman N. The effect of tranexamic acid on blood loss during orthognathic surgery: a randomized controlled trial. J Oral Maxillofac Surg. 2009 Jan;67(1):125-33. 24. Zijderveld SA, Smeele LE, Kostense PJ, Tuinzing DB. Preoperative antibiotic prophylaxis in orthognathic surgery: a randomized, double-blind, and placebo-controlled clinical study. J Oral Maxillofac Surg. 1999 Dec;57(12):1403-6; discussion 6-7.

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Zallen RD, Strader RJ. The use of prophylactic antibiotics in extraoral procedures for mandibular prognathism. J Oral Surg. 1971 Mar;29(3):178-9.

26.

Kang SH, Yoo JH, Yi CK. The efficacy of postoperative prophylactic antibiotics in orthognathic surgery: a prospective study in Le Fort I osteotomy and bilateral intraoral vertical ramus osteotomy. Yonsei Med J. 2009 Feb 28;50(1):55-9.

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Fridrich KL. Preoperative antibiotic prophylaxis in orthognathic surgery: a randomized, double-blind, and placebo-controlled clinical study. J Oral Maxillofac Surg. 1999;57:1406-7.

28.

Peterson LJ, Booth DF. Efficacy of antibiotic prophylaxis in intraoral orthognathic surgery. J Oral Surg. 1976 Dec;34(12):108891.

29.

Bystedt H, Josefsson K, Nord CE. Ecological effects of penicillin prophylaxis in orthognatic surgery. Int J Oral Maxillofac Surg. 1987 Oct;16(5):559-65.

30.

Kagel EM, Rayan GM. Intravenous catheter complications in the hand and forearm. J Trauma. 2004 Jan;56(1):123-7.

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Adibe OO, Barnaby K, Dobies J, et al. Postoperative antibiotic therapy for children with perforated appendicitis: long course of intravenous antibiotics versus early conversion to an oral regimen. Am J Surg. 2008 Feb;195(2):141-3.

32.

Danda AK, Wahab A, Narayanan V, Siddareddi A. Single-dose versus single-day antibiotic prophylaxis for orthognathic surgery: a prospective, randomized, double-blind clinical study. J Oral Maxillofac Surg. 2010 Feb;68(2):344-6.

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Reinhart E, Reuther J, Michel C, Kubler N, Ordung R, Bosebeck H. [Perioperative antibiotic prophylaxis in orthodontic bone operations of the facial skull]. Mund Kiefer Gesichtschir. 1998 Jul;2(4):194201.

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Koole R, Egyedi P. Postoperative contamination of mandibular osteotomy sites with saliva. Int J Oral Maxillofac Surg. 1987 Oct;16(5):554-8.

35.

Peterson LJ. Antibiotic prophylaxis against wound infections in oral and maxillofacial surgery. J Oral Maxillofac Surg. 1990 Jun;48(6):617-20.

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Hotz G, Novotny-Lenhard J, Kinzig M, Soergel F. Single-dose antibiotic prophylaxis in maxillofacial surgery. Chemotherapy. 1994 Jan-Feb;40(1):65-9.

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Huaman ET, Juvet LM, Nastri A, Denman WT, Kaban LB, Dodson TB. Changing patterns of hospital length of stay after orthognathic surgery. J Oral Maxillofac Surg. 2008 Mar;66(3):492-7.

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Figure 1. Flow diagram of the participants of the trial

Assessed for eligibility, n=66 Excluded (total), n=24

Declined to participate, n=3 Previous surgery of head and neck, n=9 Simultaneous istraction osteogenesis, n=6 Allergic to -lactam antibiotics, n=2 Used of antibiotic with 14 days, n=2 Long term steroid therapy, n=2

Randomized, n=42

Allocated to oral group, n=21

Allocated to intravenous group, n=21

Lost follow up, n=0

Lost follow up, n=0

Analyzed, n=21

Analyzed, n=21

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Table 1. Summary of the surgical procedures performed Intravenous group (n=21)

Surgical procedures

Oral group (n=21)

1. Maxilla surgery (without segmentalisation), ramus surgery + genioplasty 2. Maxilla surgery (without segmentalisation), ramus surgery, anterior mandibular surgery + genioplasty 3. Maxilla surgery (with segmentalisation), ramus surgery + genioplasty 4. Maxilla surgery (with segmentalisation), ramus surgery, anterior mandibular surgery + genioplasty *Maxilla surgery - (without segmentalisation): Le Fort I osteotomy - (with segmentalisation): Le Fort I osteotomy with segmentalisation, Wunderer and posterior Le Fort I # Ramus surgery: bilateral vertical subsigmoid osteotomies or bilateral sagittal split osteotomies ^Anterior mandibular surgery: mandibular anterior subapical osteotomies or step osteotomies 13 15 5 3 2 1 1 2

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Table 2. Baseline demographic and clinical characteristic of participants in oral versus intravenous antibiotic regimen groups Group 1: Participants Oral group (n=21)
Age (years old) Range Mean (SD)

Group 2: Intravenous group (n=21)

18-33 26.3 (4.3)

18-34 mean: 25.7 (4.0)

Gender Female Male 13 8 197-680 (mean: 445.7 + 128.9) Surgical procedure-related events Unfavorable fracture Transected mental nerve Laceration of descending palatine artery Shaved root during segmentalisation 0 0 0 3 1 2 2 3 15 6 240-650 (mean: 454.6 + 123.2)

Operation time (mins)

Blood loss (mL)

400-2300 (mean: 1095.5 + 553.5)

490-2100 (mean: 1129.5 + 411.5) 4 6

Blood transfusion (cases) Infection (cases)

3 3

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Table 3. Summary of infection cases

Study group (Antibiotic regimen) 1. Oral Age (years) 21 Onset of infection (day) 7 Infection site Right anterior mandible

Sex

Surgical procedure

Maxilla surgery (with segmentalisation), ramus surgery, anterior mandibular surgery, genioplasty Maxilla surgery (with segmentalisation), ramus surgery, anterior mandibular surgery, genioplasty Maxilla surgery (with segmentalisation), ramus surgery, anterior mandibular surgery, genioplasty Maxilla surgery (with segmentalisation), ramus surgery, anterior mandibular surgery ,genioplasty Maxilla surgery (with segmentalisation), ramus surgery, anterior mandibular surgery, genioplasty Maxilla surgery (with segmentalisation), ramus surgery, anterior mandibular surgery, genioplasty Maxilla surgery (no segmentalisation), ramus surgery, genioplasty Maxilla surgery (with segmentalisation), ramus surgery

2.

Intravenous

28

Right anterior mandible

3.

Intravenous

30

Right anterior mandible

4.

Oral

18

Both left and right posterior mandible Right anterior maxilla

5.

Intravenous

24

14

6.

Intravenous

24

14

Right posterior mandible

7.

Intravenous

23

Left anterior maxilla Right anterior mandible Right anterior maxilla

8.

Intravenous

27

42

9.

Oral

34

Maxilla surgery (with segmentalisation), ramus surgery, anterior mandibular surgery, genioplasty

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Table 4. Summary of infection rate for prophylactic oral and intravenous antibiotic groups
Study groups Intravenous Primary outcome Oral group group (n=21) (n=21) Infection cases 3 (14.3) (%) 6 (28.6) 0.5 (0.15-1.59) 0.11) -0.14 (-0.39 (95% CI) (95% CI) Risk ratio Risk difference

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Appendix I PRISMA checklist

Section/ topic TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both. 9

# Checklist item

Reported on page #

ABSTRACT
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

9-10

INTRODUCTION
Rationale Objectives 3 4 Describe the rationale for the review in the context of what is already known. Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). 11-12 12

METHODS
Protocol and registration Eligibility criteria Information sources Search Study selection Data collection process Data items 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. State the principal summary measures (e.g., risk ratio, difference in means). 13

13-16

13-14

8 9

13-14

14-16

10

14

11

15

Risk of bias in individual studies Summary measures

12

16

13

16

75

Synthesis of results Risk of bias across studies Additional analyses

14

Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis. Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

17

15

17

16

--

RESULTS
Study selection Study characteristi cs Risk of bias within studies Results of individual studies Synthesis of results Risk of bias across studies Additional analysis 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Present results of each meta-analysis done, including confidence intervals and measures of consistency. Present results of any assessment of risk of bias across studies (see Item 15). Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 18, 36 18-20, 3839 21, 41

18

19

20

20-21, 39

21 22

37 41 --

23

DISCUSSION
Summary of evidence Limitations 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). Provide a general interpretation of the results in the context of other evidence, and implications for future research. 22-28

25

25-26 29

Conclusions

26

FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. 29

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

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Appendix II CONSORT checklist

PAPER SECTION And topic
TITLE & ABSTRACT

Item

Descriptor

Reported on Page #
43-44 45-47 48-49 50-52 47 52-53

How participants were allocated to interventions (e.g., "random allocation", "randomized", or "randomly assigned"). Scientific background and explanation of rationale. Eligibility criteria for participants and the settings and locations where the data were collected. Precise details of the interventions intended for each group and how and when they were actually administered. Specific objectives and hypotheses. Clearly defined primary and secondary outcome measures and, when applicable, any methods used to enhance the quality of measurements (e.g., multiple observations, training of assessors). How sample size was determined and, when applicable, explanation of any interim analyses and stopping rules. Method used to generate the random allocation sequence, including details of any restrictions (e.g., blocking, stratification) Method used to implement the random allocation sequence (e.g., numbered containers or central telephone), clarifying whether the sequence was concealed until interventions were assigned. Who generated the allocation sequence, who enrolled participants, and who assigned participants to their groups. Whether or not participants, those administering the interventions, and those assessing the outcomes were blinded to group assignment. If done, how the success of blinding was evaluated. Statistical methods used to compare groups for primary outcome(s); Methods for additional analyses, such as subgroup analyses and adjusted analyses. Flow of participants through each stage (a diagram is strongly recommended). Specifically, for each group report the numbers of participants randomly assigned, receiving intended treatment, completing the study protocol, and analyzed for the primary outcome. Describe protocol deviations from study as planned, together with reasons. Dates defining the periods of recruitment and follow-up. Baseline demographic and clinical characteristics of each group. Number of participants (denominator) in each group included in each analysis and whether the analysis was

INTRODUCTION Background METHODS Participants Interventions

2 3 4

Objectives Outcomes

5 6

Sample size Randomization -Sequence generation Randomization -Allocation concealment Randomization -Implementation Blinding (masking)

7 8

54 49-50

50

10

49

11

50

Statistical methods

12

54

RESULTS Participant flow

13

55, 70

Recruitment Baseline data Numbers analyzed

14 15 16

48, 53 55-56, 72 55, 70

77

by "intention-to-treat". State the results in absolute numbers when feasible (e.g., 10/20, not 50%). Outcomes and estimation Ancillary analyses 17 For each primary and secondary outcome, a summary of results for each group, and the estimated effect size and its precision (e.g., 95% confidence interval). Address multiplicity by reporting any other analyses performed, including subgroup analyses and adjusted analyses, indicating those pre-specified and those exploratory. All important adverse events or side effects in each intervention group. Interpretation of the results, taking into account study hypotheses, sources of potential bias or imprecision and the dangers associated with multiplicity of analyses and outcomes. Generalizability (external validity) of the trial findings. General interpretation of the results in the context of current evidence. 55-56, 74

18

55-56

Adverse events DISCUSSION Interpretation

19 20

56

58-61 60 62

Generalizability Overall evidence

21 22

From Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001; 357(9263):1191-1194.

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