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Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial
YIJOM-4304; No of Pages 7
Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx https://doi.org/10.1016/j.ijom.2019.10.006, available online at https://www.sciencedirect.com
Clinical Paper Oral Surgery
Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial
S. Kaewkumnert1, K. Phithaksinsuk1, C. Changpoo2, N. Nochit2, Y. Muensaiyat2, S. Wilaipornsawai2, U. Piriyaphokai2, W. Powcharoen1 1
Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand; 2Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
S. Kaewkumnert, K. Phithaksinsuk, C. Changpoo, N. Nochit, Y. Muensaiyat, S. Wilaipornsawai, U. Piriyaphokai, W. Powcharoen: Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial. Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx. ã 2019 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Abstract. The objective of this study was to compare the effect of intraosseous dexamethasone injection and submucosal dexamethasone injection on postoperative sequelae after mandibular third molar surgery. This was a randomized, triple-blind, split-mouth clinical trial. Fifty-four mandibular third molars (27 patients) were subdivided according to the side (right and left); intraosseous injection of dexamethasone (4 mg) was randomly assigned to one side and submucosal injection to the other. All surgeries were performed by one surgeon. Postoperative pain was evaluated by visual analogue scale score immediately after surgery and on postoperative days 1, 3, and 7. Postoperative swelling (determined using two linear measurements) and mouth opening (determined by measurement of the inter-incisal distance) were assessed on postoperative days 3 and 7. The number of analgesics consumed was recorded. No significant difference in pain or swelling was found between the two injection techniques. However, there was significant difference in trismus on postoperative day 3, with submucosal injection showing a better outcome (P < 0.001). Both techniques of dexamethasone injection were effective in controlling pain and swelling after mandibular third molar surgery, but submucosal injection was superior for the control of trismus.
0901-5027/000001+07
Key words: dexamethasone; submucosal injection; intraosseous injection; mandibular third molar. Accepted for publication 7 October 2019
ã 2019 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kaewkumnert S, et al. Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.
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Mandibular third molar (MTM) surgery is one of the most common procedures in oral surgery and results in pain, swelling, and other disorders that may be transitory or permanent, including trismus and paresthesia1. These sequelae are triggered by an inflammatory response, leading to vasodilation and the arrival of strong proinflammatory mediators2,3. Moreover, these sequelae can affect oral health-related quality of life in the postoperative period following third molar surgery4. In the past, various interventions have been used to minimize these inflammatory responses. The administration of corticosteroids is one of the most commonly used of these interventions, due to their strong antiinflammatory activity. Dexamethasone is one of the corticosteroid medications that has been used in oral and maxillofacial surgery to relieve the postoperative inflammation associated with surgical trauma. Different routes of dexamethasone administration after MTM surgery have been reported in the past, including intramuscular, submucosal, intravenous, intra-pterygomandibular space, and sublingual injection, oral medication, and intra-alveolar powders. These various routes of administration have their pros and cons, but submucosal injection (SM) is commonly mentioned and is simpler for dentists in the clinical setting5. A recent meta-analysis suggested that SM injection of dexamethasone reduces early and late swelling, as well as early trismus6. However, when treated participants were compared with control participants, this route of administration was not found to significantly relieve pain. Intraosseous injection (IO) refers to injection directly into the marrow of a bone. This route was first reported in 1922 by Drinker and colleagues7, and has been used as an alternative to peripheral intravenous injection since the 1980s. In recent decades, paediatricians have used this technique in emergency situations to establish an access for the rapid infusion of fluids, drugs, and blood products. In dentistry, IO injection has been used for the application of local anaesthetic (intraosseous anaesthesia technique). Two studies have reported the use of IO dexamethasone to reduce the pain in irreversible pulpitis8,9. However, it appears that there have been no studies on the use of IO dexamethasone after MTM surgery. This route of administration may enable dexamethasone to directly inhibit the inflammatory response at the surgical extraction wound site and therefore become one of the solutions to decrease pain, swelling, and trismus following MTM surgery.
The aim of this study was to compare the efficacy of IO versus SM dexamethasone administration on the sequelae after MTM surgery, i.e. pain, swelling, and trismus.
The minimum sample size for each group in this study was calculated statistically according to the Rosner formula10. In a previous study by Majid11, the mean trismus in the control group was 12.5 mm (standard deviation 10 mm), while that in the treatment group (submucosal injection of dexamethasone) was 5.5 mm (standard deviation 7.5 mm). Considering a power of 80% (Zb = 0.84) and a 95% confidence interval (Za/2 = 1.96), a sample size of 28 in each group was calculated, allowing for a 10% dropout rate. Therefore, the total number of samples required for the study was 56.
left), and IO or SM injection of dexamethasone (4 mg) was assigned to one side randomly by draw; the other mode of injection was assigned to the remaining side. The patient, surgeon, and outcome assessors were blinded to the result of this allocation. The time interval between the surgeries on the two sides was at least 4 weeks. Two syringes, one containing dexamethasone and one containing normal saline (placebo), were needed for each side undergoing MTM surgery. Preoperatively, the research assistant prepared two syringes of solutions, labelling them ‘for IO’ and ‘for SM’. If the first side for MTM surgery was assigned randomly to the IO group, the syringe labelled ‘for IO’ would contain 1 ml of dexamethasone (4 mg) and the other syringe labelled ‘for SM’ would contain 1 ml of normal saline. Accordingly, at the same patient’s next MTM surgery, with the MTM assigned to the SM group, the syringe labelled ‘for IO’ would contain 1 ml of normal saline and the other labelled ‘for SM’ would contain 1 ml of dexamethasone (4 mg). The patient and the surgeon were also blinded to this preparation. The surgical procedures were performed by the same surgeon using the standard technique. After local anaesthesia, a flap was raised and tooth sectioning with removal of the bone was done in all cases. After the MTM had been removed, IO injection was performed by drilling (using a 0.8 mm diameter fissure bur) through the cortex at the middle point of the buccolingual plane, located about 5 mm distal to the socket wound (Fig. 1). A dental probe was used to explore the communication between the drill hole and the socket wound. If any communication was detected, drilling would be performed again at a more distal location. Then, injection with the syringe labelled ‘for IO’ was done through the drill hole using a 20-gauge needle, penetrating the cortical bone to the medullary bone, at least 2 mm away from the inferior alveolar canal. Closure of the wound was done with 3–0 silk suture. Finally, SM injection with the syringe labelled ‘for SM’ was done at the mucobuccal fold. The total operative time, from incision to the last suture, was recorded. The participant was prescribed amoxicillin (500 mg) to be taken three times per day for 7 days, and paracetamol (500 mg) for pain every 6 hours as needed.
Randomization and interventions
Efficacy assessment
The two MTM in each participant were subdivided according to the side (right and
For the assessment of facial swelling and mouth opening, preoperative evaluations
Materials and methods Study design
This study was registered in the Thai Clinical Trials Registry (TCTR20180524001) and was approved by the Ethics Committee of the Faculty of Dentistry, Chiang Mai University, Thailand (protocol No. 031/2018). The study design was a triple-blind, splitmouth, randomized clinical trial. Participants
Participants were patients who attended the Faculty of Dentistry, Chiang Mai University for the elective surgical removal of bilateral impacted MTM. The inclusion criteria were healthy subjects (American Society of Anesthesiologists class I status), 18–30 years of age, presenting the same angulated bilateral impacted MTM (mesioangular or horizontal, according to the Pell and Gregory classification) without any local inflammation or pathology. The exclusion criteria were pregnant or breast-feeding women, patients who had taken anti-inflammatory drugs within 2 weeks before the procedure, history of peptic ulcer, and history of allergy or adverse reaction to the drugs used in this study. All participants were asked to provide signed informed consent to participate in the trial. Sample size
Please cite this article in press as: Kaewkumnert S, et al. Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.
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value between 0.5 and 0.75 indicates moderate reliability, a value between 0.75 and 0.9 indicates good reliability, and a value greater than 0.90 indicates excellent reliability12. All data analyses were done using IBM SPSS Statistics for Windows, version 24 (IBM Corp., Armonk, NY, USA). A Pvalue of less than 0.05 was considered to be statistically significant. Results
Fig. 1. Anatomical landmark for intraosseous injection in the mandible.
were performed on the day of surgery. Facial swelling was assessed by measuring two linear references with silk thread: (1) between the corner of the mouth and tragus; (2) between the lateral canthus and the angle of the mandible. This outcome was calculated as the sum of the two linear references. For the mouth opening outcome, the maximum distance between the upper and lower incisors was measured using a digital Vernier caliper. Subsequently, both mouth opening and facial swelling were evaluated on postoperative days 3 and 7 using the same methods as described above. These measurements were performed by two outcome assessors who were blinded to the group allocations. For the determination of the standard and individual reliability of the outcome assessors, the intra-rater reliability and interrater reliability were calculated. Postoperative pain was evaluated with a 10-cm visual analogue scale (VAS) anchored
with a three-point descriptive scale: score = 0, ‘no pain at all’; score = 5, ‘moderate pain’; score = 10, ‘unbearable pain’. The participant was asked to mark the VAS immediately after surgery and on postoperative days 1, 3, and 7; the scores were recorded. The participant was also asked to record the total number of rescue analgesics (paracetamol 500 mg) taken during the 7 days postoperative. Statistical analysis
Data were recorded as the mean and standard deviation, for comparison between the two groups at the different time points. The Wilcoxon signed rank test was used to determine the statistical significance of the results in the comparison between groups. The intra-class correlation coefficient (ICC) was used to determine intra-rater reliability and inter-rater reliability among the outcome assessors. An ICC value of less than 0.5 is indicative of poor reliability, a
Table 1. Demographic data of the patients included in the study. Demographic data Sex Male Female Age (years), mean SD Angulation Mesioangular Horizontal Total operative time (min) SM group IO group Postoperative complication SM group IO group
P-value 13 14 21.70 2.43 30 24 0.82 18.85 18.78 0 1
SD, standard deviation; SM, submucosal injection; IO, intraosseous injection.
Of the 28 patients screened, 27 (54 MTM) were included in the study; one patient was excluded because of unknown hypertension. All of the 27 patients agreed to participate in the study. The 54 MTM of these 27 patients were subdivided according to the side (left or right) and assigned to the IO or SM group randomly. No patients were lost to follow-up. Thirteen patients were male and 14 patients were female. Their mean age was 21.70 2.43 years. There was no significant difference in total operative time between the IO and SM groups (P = 0.82). One patient, in the IO group, presented prolonged paresthesia. The demographic data of the patients are presented in Table 1. The individual reliability of the two outcome assessors was excellent (ICC for mouth opening measurement = 0.93 and 0.97; ICC for swelling measurement = 0.94 and 0.91) and the reliability between them was good for the measurement of facial swelling (ICC = 0.82) and mouth opening (ICC = 0.87). The mean VAS pain score immediately after surgery was 3.38 2.56 in the IO group and 2.93 2.75 in the SM group. On postoperative day 1, the mean VAS score was 1.81 1.56 in the IO group and 1.45 1.34 in the SM group. On postoperative day 3, the mean VAS score was 1.16 1.33 in the IO group and 1.29 1.34 in the SM group. On postoperative day 7, the mean VAS score was 0.72 1.12 in the IO group and 0.84 1.18 in the SM group. There was no significant difference between the groups immediately after surgery (P = 0.42), or on postoperative day 1 (P = 0.33), postoperative day 3 (P = 0.62), or postoperative day 7 (P = 0.86) (Fig. 2). However, the total number of rescue analgesics taken was significantly higher in the IO group compared to the SM group (P = 0.03) (Fig. 3). With regard to facial swelling, there was no significant difference between the groups at the time before surgery (P = 0.48). On postoperative day 3, the mean facial swelling was 23.75 1.48 mm in the IO group and
Please cite this article in press as: Kaewkumnert S, et al. Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.
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sequelae, although these conditions originate from the same inflammatory process initiated by the surgical trauma15. Following surgical trauma, there is a subsequent release of mediators from inflammatory cells and the vasculature. The presence of bradykinin and prostaglandin leads to postoperative pain and hyperalgesia. The accumulation of exudate in the surrounding tissue results in swelling. Trismus is associated with inflammation of the surrounding muscles and the collection of exudate within the nearby fascia. It should be stressed that greater surgical difficulty also increases the inflammatory process, resulting in a potentially greater extent of the postoperative sequelae and morbidity16. Most surgeons attempt to control and reduce pain, swelling, and trismus after MTM surgery using both pharmacologiand non-pharmacological methods. cal Fig. 2. Comparison of VAS pain scores between the intraosseous injection group and the Corticosteroids have been utilized to submucosal injection group. control the postoperative inflammatory response in various surgical procedures. Dexamethasone, one of the most common corticosteroids used in dentistry, is a long-acting and highly potent steroid with no mineralocorticoid activity17. Over the past decades, the use of different routes of dexamethasone administration after MTM surgery have been reported. However, there are no definite protocols relative to the different molecules or regimens, and the time and route of administration18. Currently, there is no consensus about the optimal route of administration for the control of postoperative pain, swelling, and trismus. The mandible has a cortical rim with a large medullary core, and hematopoietic marrow remains in the ramus and condyle, even at the age of 25 years19. This type of bone marrow presents capillaries and veins with a discontinuous endothelium that allows fluids and other subFig. 3. Comparison of the number of rescue analgesics taken between the intraosseous injection stances in the surrounding stroma to be group and the submucosal injection group. readily exchanged with the blood current. The medullary cavity is composed of a network of venous sinusoids that are 24.78 5.11 mm in the SM group. On er, there was no significant difference drained by a single central venous canal. postoperative day 7, the mean facial swelling between the IO group (42.69 7.48 Substances injected into the venous was 23.35 1.34 mm in the IO group and mm) and SM group (43.9 8.58 mm) sinusoids ultimately drain via the med24.33 5.44 mm in the SM group. There on postoperative day 7 (P = 0.52) (Fig. 5). ullary veins into the central medullary was no significant difference between the sinus, which acts as a reservoir for subgroups on postoperative day 3 (P = 0.86) or stances collected within the intraosseous Discussion postoperative day 7 (P = 0.95) (Fig. 4). space20. In the case of the mandible, the Regarding mouth opening, no signifi- MTM surgery usually results in postoper- intramedullary vessel may empty directcant difference was observed at the time ative sequelae, like pain, swelling, and ly into the inferior alveolar vein or corbefore surgery (P = 0.34). On postopera- trismus. These conditions deteriorate qual- tical perforating veins. Dexamethasone tive day 3, mean mouth opening in the SM ity of life or compromise the patient’s has been reported to be safe for IO group (40.03 9.73 mm) was significant- daily activity, especially during the first injection in the human21. However only ly greater than that in the IO group 3 days following surgery13,14. There are two studies have reported the application (31.73 11.1 mm) (P < 0.001). Howev- many factors associated with these of this technique in dentistry8,9.
Please cite this article in press as: Kaewkumnert S, et al. Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.
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Fig. 4. Comparison of facial swelling between the intraosseous injection group and the submucosal injection group.
Fig. 5. Comparison of mouth opening between the intraosseous injection group and the submucosal injection group.
The IO technique was selected for administration so that the site where dexamethasone was deposited was adjacent to the surgical extraction wound of the MTM. After administration, dexamethasone collects within the medullary sinus to locally inhibit the inflammatory process from the medullary bone surrounding the surgical extraction wound. Moreover, some dexamethasone is directly absorbed into the inferior alveolar vein or cortical perforating veins and may therefore act systemically. In the present study, swelling was evaluated by measuring linear facial distances. This is a non-invasive, simple, cost-effective, and time-saving method, which
provides numerical data for the determination of soft-tissue changes22. Trismus was measured using a digital Vernier caliper, which eliminates the bias from subjectively reading a scale. The VAS score used to measure pain is also universally accepted. To validate these outcome measurements, calibration was performed among the outcome assessors in this study, which showed excellent intra-observer reliability and good inter-observer reliability. Two meta-analyses on the SM injection of dexamethasone have reported significantly reduced postoperative pain after MTM surgery23,24. SM injection has also shown similar efficacy to intramuscular injection of dexamethasone in the control
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of postoperative pain25. In the present study, postoperative pain was comparable between IO and SM injection of dexamethasone 4 mg, immediately after surgery and on postoperative days 1, 3, and 7. Nevertheless, the total number of recue analgesics taken was significantly greater in the IO group, implying that IO injection may be associated with more pain. Dexamethasone administered via intraosseous route can be absorbed more rapidly through the medullary vein and the analgesic effect of dexamethasone is dosedependent11. This may explain the lower efficacy of dexamethasone administered via intraosseous route compared to the SM route in minimizing postoperative pain. However, the significant difference in total number of rescue analgesics taken may or may not be clinically relevant, due to the lack of data on the minimum clinically important difference in this endpoint. Occasionally, IO will increase the pressure within the medullary cavity, resulting in pain and discomfort at the injection site. The present study found comparable pain in the two groups immediately after surgery and no participant reported pain during IO. This may imply that IO in the mandible rarely triggers pain at the injection site. The effect on swelling was comparable in the two groups on postoperative days 1, 3, and 7. This finding may have resulted from dexamethasone suppressing the production of vasoactive substances, thereby reducing the tissue exudate and consequently the swelling. Moraschini et al.23 reported that SM injection of dexamethasone resulted in a statistically significant effect on the control of swelling, due to the direct action of the drug at the surgical site. However, compared to intramuscular injection, there was no statistically significant difference at any follow-up point or overall25. No statistically significant difference in trismus was observed on postoperative day 1 or 7. However, on postoperative day 3, trismus was significantly greater in the IO group. Postoperative trismus is associated with inflammation and the accumulation of exudate in the surrounding muscles, e.g. buccinator muscle and masseter muscle. Dexamethasone deposited in the medullary bone may improve trismus by reducing the exudate surrounding the muscle, but may not directly inhibit the inflammation of those muscles. Moreover, dexamethasone can be removed rapidly from the surgical site. The present study included both horizontal and mesioangular MTM, and the removal of horizontal MTM would be traumatic and might result
Please cite this article in press as: Kaewkumnert S, et al. Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.
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in more trismus and pain, although there was a comparable total operative time in the two groups. Previous studies have reported that SM injection of dexamethasone can significantly reduce postoperative trismus, like intramuscular injection11,26. In contrast, Majid and Mahmood reported a significant effect on trismus in the SM injection group27. This study was designed as a randomized controlled clinical trial to compare the effect of dexamethasone delivered by SM or IO injection on postoperative pain, swelling, and trismus. The risk factors for pain, swelling, and trismus after MTM surgery have been reported in many studies. The bias due to these factors was minimized by the randomization of the treatment allocation in a split-mouth design and the comparable operative times for both groups. The present study also blinded the patients, surgeon, and outcome assessors, which fundamentally reduced the effect of their bias. This split-mouth design has the advantage of eliminating inter-subject variability28; however only two groups of intervention can be compared. Regarding the IO technique, a small amount of leakage of the solution from the distal wall of the surgical extraction wound was observed at the end of administration in a few cases. This event may represent a confounder if that solution was dexamethasone. This study is novel in reporting the administration of dexamethasone by IO injection following MTM surgery. The process by which the IO injection of dexamethasone reduces the inflammatory sequelae after MTM surgery, whether systemically or locally, becomes interesting. In medical practice, the intraosseous route aims to access the systemic venous circulation via the marrow or medullary cavity, and the onset of drugs administered via this route is similar to that of drugs administered via intravenous route29–31. There may be a somewhat prolonged duration of action of various drugs with intraosseous administration, suggesting that the marrow cavity may act as a depot31. Currently, the physiology of the IO route in the jawbone is unclear. It was hypothesized in this study that dexamethasone administration via IO may, locally and systemically, act to reduce inflammation following MTM surgery. Moreover, the dosage of dexamethasone used in the IO technique remains uncertain for MTM surgery. This study utilized a dose that was comparable to that used in the SM technique to overcome the bias of different doses. Higher doses may be needed for the IO administration of dexamethasone21,
hence further research is needed to determine the optimal dosing. Overall, the IO technique in the mandible is simple and accessible for the dentist to practice in the clinical setting. Moreover, this technique may be feasible for the dentist to access and administer medication to the systemic circulation. The IO injection of dexamethasone in the mandible produced a beneficial effect in reducing pain and swelling following MTM surgery, relatively comparable to that of SM injection. However, the efficacy of IO injection for the control of trismus was significantly lower than that of SM injection on postoperative day 3. Moreover, IO injection presented the possibility of leakage of the dexamethasone and a relatively more complicated injection technique. These indicate that the SM injection technique may still be preferable.
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Funding
None.
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Competing interests
None.
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Ethical approval
This study was approved by Ethics Committee of Faculty of Dentistry, Chiang Mai University, Thailand (protocol No.031/ 2018).
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Patient consent
Patient consent was not required. Acknowledgements. We would like to express our gratitude to Ms Atchara Wongla for assistance with the methodology and to all of the dental assistants of the Oral and Maxillofacial Surgery Clinic for their kind support of this study.
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Address: Warit Powcharoen Oral and Maxillofacial Surgery Faculty of Dentistry Chiang Mai University Suthep Street Chiang Mai 50200 Thailand Tel.: +66 53 944456 E-mail: [email protected]
Please cite this article in press as: Kaewkumnert S, et al. Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.
Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx https://doi.org/10.1016/j.ijom.2019.10.006, available online at https://www.sciencedirect.com
Clinical Paper Oral Surgery
Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial
S. Kaewkumnert1, K. Phithaksinsuk1, C. Changpoo2, N. Nochit2, Y. Muensaiyat2, S. Wilaipornsawai2, U. Piriyaphokai2, W. Powcharoen1 1
Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand; 2Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
S. Kaewkumnert, K. Phithaksinsuk, C. Changpoo, N. Nochit, Y. Muensaiyat, S. Wilaipornsawai, U. Piriyaphokai, W. Powcharoen: Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial. Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx. ã 2019 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Abstract. The objective of this study was to compare the effect of intraosseous dexamethasone injection and submucosal dexamethasone injection on postoperative sequelae after mandibular third molar surgery. This was a randomized, triple-blind, split-mouth clinical trial. Fifty-four mandibular third molars (27 patients) were subdivided according to the side (right and left); intraosseous injection of dexamethasone (4 mg) was randomly assigned to one side and submucosal injection to the other. All surgeries were performed by one surgeon. Postoperative pain was evaluated by visual analogue scale score immediately after surgery and on postoperative days 1, 3, and 7. Postoperative swelling (determined using two linear measurements) and mouth opening (determined by measurement of the inter-incisal distance) were assessed on postoperative days 3 and 7. The number of analgesics consumed was recorded. No significant difference in pain or swelling was found between the two injection techniques. However, there was significant difference in trismus on postoperative day 3, with submucosal injection showing a better outcome (P < 0.001). Both techniques of dexamethasone injection were effective in controlling pain and swelling after mandibular third molar surgery, but submucosal injection was superior for the control of trismus.
0901-5027/000001+07
Key words: dexamethasone; submucosal injection; intraosseous injection; mandibular third molar. Accepted for publication 7 October 2019
ã 2019 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kaewkumnert S, et al. Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.
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Mandibular third molar (MTM) surgery is one of the most common procedures in oral surgery and results in pain, swelling, and other disorders that may be transitory or permanent, including trismus and paresthesia1. These sequelae are triggered by an inflammatory response, leading to vasodilation and the arrival of strong proinflammatory mediators2,3. Moreover, these sequelae can affect oral health-related quality of life in the postoperative period following third molar surgery4. In the past, various interventions have been used to minimize these inflammatory responses. The administration of corticosteroids is one of the most commonly used of these interventions, due to their strong antiinflammatory activity. Dexamethasone is one of the corticosteroid medications that has been used in oral and maxillofacial surgery to relieve the postoperative inflammation associated with surgical trauma. Different routes of dexamethasone administration after MTM surgery have been reported in the past, including intramuscular, submucosal, intravenous, intra-pterygomandibular space, and sublingual injection, oral medication, and intra-alveolar powders. These various routes of administration have their pros and cons, but submucosal injection (SM) is commonly mentioned and is simpler for dentists in the clinical setting5. A recent meta-analysis suggested that SM injection of dexamethasone reduces early and late swelling, as well as early trismus6. However, when treated participants were compared with control participants, this route of administration was not found to significantly relieve pain. Intraosseous injection (IO) refers to injection directly into the marrow of a bone. This route was first reported in 1922 by Drinker and colleagues7, and has been used as an alternative to peripheral intravenous injection since the 1980s. In recent decades, paediatricians have used this technique in emergency situations to establish an access for the rapid infusion of fluids, drugs, and blood products. In dentistry, IO injection has been used for the application of local anaesthetic (intraosseous anaesthesia technique). Two studies have reported the use of IO dexamethasone to reduce the pain in irreversible pulpitis8,9. However, it appears that there have been no studies on the use of IO dexamethasone after MTM surgery. This route of administration may enable dexamethasone to directly inhibit the inflammatory response at the surgical extraction wound site and therefore become one of the solutions to decrease pain, swelling, and trismus following MTM surgery.
The aim of this study was to compare the efficacy of IO versus SM dexamethasone administration on the sequelae after MTM surgery, i.e. pain, swelling, and trismus.
The minimum sample size for each group in this study was calculated statistically according to the Rosner formula10. In a previous study by Majid11, the mean trismus in the control group was 12.5 mm (standard deviation 10 mm), while that in the treatment group (submucosal injection of dexamethasone) was 5.5 mm (standard deviation 7.5 mm). Considering a power of 80% (Zb = 0.84) and a 95% confidence interval (Za/2 = 1.96), a sample size of 28 in each group was calculated, allowing for a 10% dropout rate. Therefore, the total number of samples required for the study was 56.
left), and IO or SM injection of dexamethasone (4 mg) was assigned to one side randomly by draw; the other mode of injection was assigned to the remaining side. The patient, surgeon, and outcome assessors were blinded to the result of this allocation. The time interval between the surgeries on the two sides was at least 4 weeks. Two syringes, one containing dexamethasone and one containing normal saline (placebo), were needed for each side undergoing MTM surgery. Preoperatively, the research assistant prepared two syringes of solutions, labelling them ‘for IO’ and ‘for SM’. If the first side for MTM surgery was assigned randomly to the IO group, the syringe labelled ‘for IO’ would contain 1 ml of dexamethasone (4 mg) and the other syringe labelled ‘for SM’ would contain 1 ml of normal saline. Accordingly, at the same patient’s next MTM surgery, with the MTM assigned to the SM group, the syringe labelled ‘for IO’ would contain 1 ml of normal saline and the other labelled ‘for SM’ would contain 1 ml of dexamethasone (4 mg). The patient and the surgeon were also blinded to this preparation. The surgical procedures were performed by the same surgeon using the standard technique. After local anaesthesia, a flap was raised and tooth sectioning with removal of the bone was done in all cases. After the MTM had been removed, IO injection was performed by drilling (using a 0.8 mm diameter fissure bur) through the cortex at the middle point of the buccolingual plane, located about 5 mm distal to the socket wound (Fig. 1). A dental probe was used to explore the communication between the drill hole and the socket wound. If any communication was detected, drilling would be performed again at a more distal location. Then, injection with the syringe labelled ‘for IO’ was done through the drill hole using a 20-gauge needle, penetrating the cortical bone to the medullary bone, at least 2 mm away from the inferior alveolar canal. Closure of the wound was done with 3–0 silk suture. Finally, SM injection with the syringe labelled ‘for SM’ was done at the mucobuccal fold. The total operative time, from incision to the last suture, was recorded. The participant was prescribed amoxicillin (500 mg) to be taken three times per day for 7 days, and paracetamol (500 mg) for pain every 6 hours as needed.
Randomization and interventions
Efficacy assessment
The two MTM in each participant were subdivided according to the side (right and
For the assessment of facial swelling and mouth opening, preoperative evaluations
Materials and methods Study design
This study was registered in the Thai Clinical Trials Registry (TCTR20180524001) and was approved by the Ethics Committee of the Faculty of Dentistry, Chiang Mai University, Thailand (protocol No. 031/2018). The study design was a triple-blind, splitmouth, randomized clinical trial. Participants
Participants were patients who attended the Faculty of Dentistry, Chiang Mai University for the elective surgical removal of bilateral impacted MTM. The inclusion criteria were healthy subjects (American Society of Anesthesiologists class I status), 18–30 years of age, presenting the same angulated bilateral impacted MTM (mesioangular or horizontal, according to the Pell and Gregory classification) without any local inflammation or pathology. The exclusion criteria were pregnant or breast-feeding women, patients who had taken anti-inflammatory drugs within 2 weeks before the procedure, history of peptic ulcer, and history of allergy or adverse reaction to the drugs used in this study. All participants were asked to provide signed informed consent to participate in the trial. Sample size
Please cite this article in press as: Kaewkumnert S, et al. Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.
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value between 0.5 and 0.75 indicates moderate reliability, a value between 0.75 and 0.9 indicates good reliability, and a value greater than 0.90 indicates excellent reliability12. All data analyses were done using IBM SPSS Statistics for Windows, version 24 (IBM Corp., Armonk, NY, USA). A Pvalue of less than 0.05 was considered to be statistically significant. Results
Fig. 1. Anatomical landmark for intraosseous injection in the mandible.
were performed on the day of surgery. Facial swelling was assessed by measuring two linear references with silk thread: (1) between the corner of the mouth and tragus; (2) between the lateral canthus and the angle of the mandible. This outcome was calculated as the sum of the two linear references. For the mouth opening outcome, the maximum distance between the upper and lower incisors was measured using a digital Vernier caliper. Subsequently, both mouth opening and facial swelling were evaluated on postoperative days 3 and 7 using the same methods as described above. These measurements were performed by two outcome assessors who were blinded to the group allocations. For the determination of the standard and individual reliability of the outcome assessors, the intra-rater reliability and interrater reliability were calculated. Postoperative pain was evaluated with a 10-cm visual analogue scale (VAS) anchored
with a three-point descriptive scale: score = 0, ‘no pain at all’; score = 5, ‘moderate pain’; score = 10, ‘unbearable pain’. The participant was asked to mark the VAS immediately after surgery and on postoperative days 1, 3, and 7; the scores were recorded. The participant was also asked to record the total number of rescue analgesics (paracetamol 500 mg) taken during the 7 days postoperative. Statistical analysis
Data were recorded as the mean and standard deviation, for comparison between the two groups at the different time points. The Wilcoxon signed rank test was used to determine the statistical significance of the results in the comparison between groups. The intra-class correlation coefficient (ICC) was used to determine intra-rater reliability and inter-rater reliability among the outcome assessors. An ICC value of less than 0.5 is indicative of poor reliability, a
Table 1. Demographic data of the patients included in the study. Demographic data Sex Male Female Age (years), mean SD Angulation Mesioangular Horizontal Total operative time (min) SM group IO group Postoperative complication SM group IO group
P-value 13 14 21.70 2.43 30 24 0.82 18.85 18.78 0 1
SD, standard deviation; SM, submucosal injection; IO, intraosseous injection.
Of the 28 patients screened, 27 (54 MTM) were included in the study; one patient was excluded because of unknown hypertension. All of the 27 patients agreed to participate in the study. The 54 MTM of these 27 patients were subdivided according to the side (left or right) and assigned to the IO or SM group randomly. No patients were lost to follow-up. Thirteen patients were male and 14 patients were female. Their mean age was 21.70 2.43 years. There was no significant difference in total operative time between the IO and SM groups (P = 0.82). One patient, in the IO group, presented prolonged paresthesia. The demographic data of the patients are presented in Table 1. The individual reliability of the two outcome assessors was excellent (ICC for mouth opening measurement = 0.93 and 0.97; ICC for swelling measurement = 0.94 and 0.91) and the reliability between them was good for the measurement of facial swelling (ICC = 0.82) and mouth opening (ICC = 0.87). The mean VAS pain score immediately after surgery was 3.38 2.56 in the IO group and 2.93 2.75 in the SM group. On postoperative day 1, the mean VAS score was 1.81 1.56 in the IO group and 1.45 1.34 in the SM group. On postoperative day 3, the mean VAS score was 1.16 1.33 in the IO group and 1.29 1.34 in the SM group. On postoperative day 7, the mean VAS score was 0.72 1.12 in the IO group and 0.84 1.18 in the SM group. There was no significant difference between the groups immediately after surgery (P = 0.42), or on postoperative day 1 (P = 0.33), postoperative day 3 (P = 0.62), or postoperative day 7 (P = 0.86) (Fig. 2). However, the total number of rescue analgesics taken was significantly higher in the IO group compared to the SM group (P = 0.03) (Fig. 3). With regard to facial swelling, there was no significant difference between the groups at the time before surgery (P = 0.48). On postoperative day 3, the mean facial swelling was 23.75 1.48 mm in the IO group and
Please cite this article in press as: Kaewkumnert S, et al. Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.
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sequelae, although these conditions originate from the same inflammatory process initiated by the surgical trauma15. Following surgical trauma, there is a subsequent release of mediators from inflammatory cells and the vasculature. The presence of bradykinin and prostaglandin leads to postoperative pain and hyperalgesia. The accumulation of exudate in the surrounding tissue results in swelling. Trismus is associated with inflammation of the surrounding muscles and the collection of exudate within the nearby fascia. It should be stressed that greater surgical difficulty also increases the inflammatory process, resulting in a potentially greater extent of the postoperative sequelae and morbidity16. Most surgeons attempt to control and reduce pain, swelling, and trismus after MTM surgery using both pharmacologiand non-pharmacological methods. cal Fig. 2. Comparison of VAS pain scores between the intraosseous injection group and the Corticosteroids have been utilized to submucosal injection group. control the postoperative inflammatory response in various surgical procedures. Dexamethasone, one of the most common corticosteroids used in dentistry, is a long-acting and highly potent steroid with no mineralocorticoid activity17. Over the past decades, the use of different routes of dexamethasone administration after MTM surgery have been reported. However, there are no definite protocols relative to the different molecules or regimens, and the time and route of administration18. Currently, there is no consensus about the optimal route of administration for the control of postoperative pain, swelling, and trismus. The mandible has a cortical rim with a large medullary core, and hematopoietic marrow remains in the ramus and condyle, even at the age of 25 years19. This type of bone marrow presents capillaries and veins with a discontinuous endothelium that allows fluids and other subFig. 3. Comparison of the number of rescue analgesics taken between the intraosseous injection stances in the surrounding stroma to be group and the submucosal injection group. readily exchanged with the blood current. The medullary cavity is composed of a network of venous sinusoids that are 24.78 5.11 mm in the SM group. On er, there was no significant difference drained by a single central venous canal. postoperative day 7, the mean facial swelling between the IO group (42.69 7.48 Substances injected into the venous was 23.35 1.34 mm in the IO group and mm) and SM group (43.9 8.58 mm) sinusoids ultimately drain via the med24.33 5.44 mm in the SM group. There on postoperative day 7 (P = 0.52) (Fig. 5). ullary veins into the central medullary was no significant difference between the sinus, which acts as a reservoir for subgroups on postoperative day 3 (P = 0.86) or stances collected within the intraosseous Discussion postoperative day 7 (P = 0.95) (Fig. 4). space20. In the case of the mandible, the Regarding mouth opening, no signifi- MTM surgery usually results in postoper- intramedullary vessel may empty directcant difference was observed at the time ative sequelae, like pain, swelling, and ly into the inferior alveolar vein or corbefore surgery (P = 0.34). On postopera- trismus. These conditions deteriorate qual- tical perforating veins. Dexamethasone tive day 3, mean mouth opening in the SM ity of life or compromise the patient’s has been reported to be safe for IO group (40.03 9.73 mm) was significant- daily activity, especially during the first injection in the human21. However only ly greater than that in the IO group 3 days following surgery13,14. There are two studies have reported the application (31.73 11.1 mm) (P < 0.001). Howev- many factors associated with these of this technique in dentistry8,9.
Please cite this article in press as: Kaewkumnert S, et al. Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.
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Fig. 4. Comparison of facial swelling between the intraosseous injection group and the submucosal injection group.
Fig. 5. Comparison of mouth opening between the intraosseous injection group and the submucosal injection group.
The IO technique was selected for administration so that the site where dexamethasone was deposited was adjacent to the surgical extraction wound of the MTM. After administration, dexamethasone collects within the medullary sinus to locally inhibit the inflammatory process from the medullary bone surrounding the surgical extraction wound. Moreover, some dexamethasone is directly absorbed into the inferior alveolar vein or cortical perforating veins and may therefore act systemically. In the present study, swelling was evaluated by measuring linear facial distances. This is a non-invasive, simple, cost-effective, and time-saving method, which
provides numerical data for the determination of soft-tissue changes22. Trismus was measured using a digital Vernier caliper, which eliminates the bias from subjectively reading a scale. The VAS score used to measure pain is also universally accepted. To validate these outcome measurements, calibration was performed among the outcome assessors in this study, which showed excellent intra-observer reliability and good inter-observer reliability. Two meta-analyses on the SM injection of dexamethasone have reported significantly reduced postoperative pain after MTM surgery23,24. SM injection has also shown similar efficacy to intramuscular injection of dexamethasone in the control
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of postoperative pain25. In the present study, postoperative pain was comparable between IO and SM injection of dexamethasone 4 mg, immediately after surgery and on postoperative days 1, 3, and 7. Nevertheless, the total number of recue analgesics taken was significantly greater in the IO group, implying that IO injection may be associated with more pain. Dexamethasone administered via intraosseous route can be absorbed more rapidly through the medullary vein and the analgesic effect of dexamethasone is dosedependent11. This may explain the lower efficacy of dexamethasone administered via intraosseous route compared to the SM route in minimizing postoperative pain. However, the significant difference in total number of rescue analgesics taken may or may not be clinically relevant, due to the lack of data on the minimum clinically important difference in this endpoint. Occasionally, IO will increase the pressure within the medullary cavity, resulting in pain and discomfort at the injection site. The present study found comparable pain in the two groups immediately after surgery and no participant reported pain during IO. This may imply that IO in the mandible rarely triggers pain at the injection site. The effect on swelling was comparable in the two groups on postoperative days 1, 3, and 7. This finding may have resulted from dexamethasone suppressing the production of vasoactive substances, thereby reducing the tissue exudate and consequently the swelling. Moraschini et al.23 reported that SM injection of dexamethasone resulted in a statistically significant effect on the control of swelling, due to the direct action of the drug at the surgical site. However, compared to intramuscular injection, there was no statistically significant difference at any follow-up point or overall25. No statistically significant difference in trismus was observed on postoperative day 1 or 7. However, on postoperative day 3, trismus was significantly greater in the IO group. Postoperative trismus is associated with inflammation and the accumulation of exudate in the surrounding muscles, e.g. buccinator muscle and masseter muscle. Dexamethasone deposited in the medullary bone may improve trismus by reducing the exudate surrounding the muscle, but may not directly inhibit the inflammation of those muscles. Moreover, dexamethasone can be removed rapidly from the surgical site. The present study included both horizontal and mesioangular MTM, and the removal of horizontal MTM would be traumatic and might result
Please cite this article in press as: Kaewkumnert S, et al. Comparison of intraosseous and submucosal dexamethasone injection in mandibular third molar surgery: a split-mouth randomized clinical trial, Int J Oral Maxillofac Surg (2019), https://doi.org/10.1016/j.
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in more trismus and pain, although there was a comparable total operative time in the two groups. Previous studies have reported that SM injection of dexamethasone can significantly reduce postoperative trismus, like intramuscular injection11,26. In contrast, Majid and Mahmood reported a significant effect on trismus in the SM injection group27. This study was designed as a randomized controlled clinical trial to compare the effect of dexamethasone delivered by SM or IO injection on postoperative pain, swelling, and trismus. The risk factors for pain, swelling, and trismus after MTM surgery have been reported in many studies. The bias due to these factors was minimized by the randomization of the treatment allocation in a split-mouth design and the comparable operative times for both groups. The present study also blinded the patients, surgeon, and outcome assessors, which fundamentally reduced the effect of their bias. This split-mouth design has the advantage of eliminating inter-subject variability28; however only two groups of intervention can be compared. Regarding the IO technique, a small amount of leakage of the solution from the distal wall of the surgical extraction wound was observed at the end of administration in a few cases. This event may represent a confounder if that solution was dexamethasone. This study is novel in reporting the administration of dexamethasone by IO injection following MTM surgery. The process by which the IO injection of dexamethasone reduces the inflammatory sequelae after MTM surgery, whether systemically or locally, becomes interesting. In medical practice, the intraosseous route aims to access the systemic venous circulation via the marrow or medullary cavity, and the onset of drugs administered via this route is similar to that of drugs administered via intravenous route29–31. There may be a somewhat prolonged duration of action of various drugs with intraosseous administration, suggesting that the marrow cavity may act as a depot31. Currently, the physiology of the IO route in the jawbone is unclear. It was hypothesized in this study that dexamethasone administration via IO may, locally and systemically, act to reduce inflammation following MTM surgery. Moreover, the dosage of dexamethasone used in the IO technique remains uncertain for MTM surgery. This study utilized a dose that was comparable to that used in the SM technique to overcome the bias of different doses. Higher doses may be needed for the IO administration of dexamethasone21,
hence further research is needed to determine the optimal dosing. Overall, the IO technique in the mandible is simple and accessible for the dentist to practice in the clinical setting. Moreover, this technique may be feasible for the dentist to access and administer medication to the systemic circulation. The IO injection of dexamethasone in the mandible produced a beneficial effect in reducing pain and swelling following MTM surgery, relatively comparable to that of SM injection. However, the efficacy of IO injection for the control of trismus was significantly lower than that of SM injection on postoperative day 3. Moreover, IO injection presented the possibility of leakage of the dexamethasone and a relatively more complicated injection technique. These indicate that the SM injection technique may still be preferable.
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Funding
None.
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Competing interests
None.
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Ethical approval
This study was approved by Ethics Committee of Faculty of Dentistry, Chiang Mai University, Thailand (protocol No.031/ 2018).
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Patient consent
Patient consent was not required. Acknowledgements. We would like to express our gratitude to Ms Atchara Wongla for assistance with the methodology and to all of the dental assistants of the Oral and Maxillofacial Surgery Clinic for their kind support of this study.
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Address: Warit Powcharoen Oral and Maxillofacial Surgery Faculty of Dentistry Chiang Mai University Suthep Street Chiang Mai 50200 Thailand Tel.: +66 53 944456 E-mail: [email protected]
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