Introduction
The aims of this 2-arm parallel pilot randomized controlled trial were to investigate the influence of antibiotic prophylaxis on the stability of orthodontic microimplants and to evaluate the efficacy of systemic inflammatory marker measurements in detecting infections in tissues surrounding microscrews.
Methods
Orthodontic patients requiring en-masse distalization in the maxilla received antibiotics or a placebo before microimplant placement. Eligibility criteria included 13 years of age, and good general and oral health. Exclusion criteria comprised allergy to antibiotics, severe systemic allergy, heart and kidney diseases, and recent antibiotic treatment. Stability of the microimplants was the primary outcome; inflammation of the tissues surrounding the microscrews, pain related to the microimplantation, and serum levels of inflammatory markers were the secondary outcomes. Randomization in a 1:1 ratio was performed by auxilliary staff via a flip of a coin between 2 participants of the same sex and developmental stage, and the “winner” was allocated to the intervention group. Pharmaceutically prepared identical capsules with either amoxicillin (intervention) or glucose (control) given 1 hour before microimplant placement according to the allocation provided blinding of the participants. Subsequently, 1 clinician unaware of the allocation inserted the microimplants and assessed the outcomes, which simultaneously blinded the operator-assessor. Blood samples for laboratory analysis of inflammatory markers were collected a day before and 1, 3, and 7 days postoperatively.
Results
Out of 80 participants initially assessed for eligibility, 41 received the randomized allocation. Three patients were lost to follow-up. Eventually, data of 18 and 20 participants (mean age, 20.4 ± 5.9 years) were available for analysis in the intervention and control groups, in which 1 and 2 patients lost a microimplant, respectively, resulting in odds ratio of 0.53 (95% confidence interval [CI], 0.0084-11.23; P = 1.0). The odds ratio for inflammation development was 1.22 (95% CI, 0.34-4.38), and the odds ratio for feeling milder pain was 1.174 (95% CI, 0.350-3.941) in the intervention compared with the control group, but the result was not statistically significant ( P = 0.758; P = 0.795, respectively). The inflammatory marker levels did not increase due to either microimplantation (procalcitonin, P = 0.445; C-reactive protein, P = 0.4) or peri-implantitis. Antibiotic prophylaxis slightly decreased the levels of the biomarkers in the intervention group; however, the results were not statistically significant ( P = 0.68; P = 0.908, respectively). No harms caused by the microimplantation procedure or drug intake were noted.
Conclusions
Antibiotics provided no benefit in terms of microimplant stability, inflammation of soft tissues, or postoperative pain in our pilot sample. Measurements of serum levels of inflammatory markers were inefficient in detecting soft tissue inflammations. These initial results should be interpreted with caution until validated by a large multicenter definitive trial.
Registration
This trial was not registered.
Protocol
The protocol was not published before trial commencement.
Funding
The trial was funded by Wroclaw Medical University; grant number pbmn91 and supported by Diagnostyka.
Highlights
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The influence of antibiotic prophylaxis on stability of microimplants was investigated.
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Serial inflammatory markers were measured.
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Soft tissue inflammation is a major risk factor of microimplant failure.
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Antibiotic prophylaxis did not improve stability and survival of microimplants.
Temporary intraoral skeletal anchorage devices (TISADs) have become a vital tool in modern orthodontics due to their remarkable capabilities. Improvement of treatment efficiency, redundancy of the patient’s compliance, and performance of complex tooth movements previously unobtainable without apparent side effects are some paramount advantages of TISAD use. However, we must recognize the most significant factor limiting their efficacy: premature loss of stability. The reported microscrew success rates range from 75.4% to 94.4%, indicating that approximately 1 of 10 devices becomes mobile and cannot serve as the anchorage enabling achievement of the treatment goal. Failure of a TISAD requires at best its reinsertion resulting in additional surgery and increases treatment cost and duration; in complex cases, microimplant instability may imply more severe consequences: eg, inability to intrude molars and need for referral for orthognathic surgery.
Investigation of both the patient’s characteristics and the design and management of the microimplants in terms of their impact on TISAD stability showed various failure risk factors such as hyperdivergent skeletal relationship, small diameter or length of the screw, improper insertion torque, and placement in free mucosa or thin cortical bone. Nevertheless, most researchers unanimously stated that inflammation of soft tissues surrounding the microimplant is the predominant factor jeopardizing TISAD stability, which is fully confirmed by the most recent meta-analysis of the factors related to microimplant failures. The authors concluded that variables such as age, sex, and type of loading of the screw have some mild impact on the stability of the microimplant, whereas inflammation of soft tissues results in as high as a 9-fold increase of the risk of microimplant failure. This conclusion corresponds well with the results of experimental studies showing that the inflammatory process spreading from the soft tissues causes degeneration of the bone surrounding the implant, which then loses stability and needs replacement. Taking these phenomena into account, prevention of soft tissue inflammations seems to be a crucial measure for improvement of microimplant stability.
Infectious inflammation develops when oral bacteria penetrate the areas surrounding the TISAD; this is likely to happen at 2 times: (1) during and shortly after implantation, when tissue continuity is broken; and (2) during the whole period of microimplant loading, via the fissure between the microimplant head and the soft tissues. The reported microimplant survival analyses show that most failures take place within the first few weeks after TISAD insertion, indicating that factors acting during and immediately after implantation are crucial for stability: ie, host and operative factors. On the other hand, considering the long-term issues, the meta-analysis by Papageorgiou et al showed no influence of oral hygiene on the stability of microimplants; this significantly undermines the importance of long-term hygiene maintenance aspects. Thus, according to the evidence, operative-related factors and not maintenance ones should be screened for refinements to improve microscrew survival rates.
In general, development of infections in the surgical site depends on patient-host and surgery-related factors. Taking into account that most of a patient’s characteristics (age and bone quality) cannot be modified, prevention of infections should focus on the surgical aspects of the insertion procedure, which include (1) localization and preparation of the operative area; (2) invasiveness, technique, and duration of the procedure; and (3) use of antimicrobial agents. When performed properly, microimplantation is a quick and minimally invasive procedure leaving few possibilities for technical improvement. On the other hand, use of antimicrobial agents may exert a favorable effect on prevention of infections during microimplantation. The literature provides scarce data on the use of antimicrobials related to microimplants; a few authors have barely mentioned administration of antibiotics in their descriptions of the surgical protocol ( Table I ). Various regimens ranging from 1 dose before implantation up to 7 days postoperatively were applied, but no author provided any rationale supporting use of the antibiotics in conjunction with the microimplants. Therefore, up to now, no studies have directly investigated the impact of antibiotics on the stability of orthodontic microimplants. However, taking into account a similar model, a meta-analysis evaluating the influence of antibiotic prophylaxis on the survival of dental implants showed that a single dose of preoperative prophylaxis improved the success rates from 92% to 96%, which was statistically and clinically significant. Thus, the question arises whether a similar effect could be obtained for orthodontic microimplants. On the other hand, we must not forget that administration of antibiotics has some significant drawbacks: risk of adverse reactions and promotion of antibiotic-resistant species of bacteria that counterweigh the positive effects.
| Group | Drug and timing of delivery | Type of microimplants | Location of microimplants | Number and average age (y) of male participants | Number and average age (y) of female participants |
|---|---|---|---|---|---|
| Intervention | Amoxicillin with clavulanic acid 875 + 125 mg 1 hour preop |
Absoanchor 13-12 08 SH (1.3 × 8 mm, self tapered) | Maxilla, buccally between first molar and second premolar, attached gingiva | n = 5 24.2 ± 6.5 |
n = 13 20.8 ± 5.8 |
| Control | Glucose 1.0 g 1 hour preop |
Absoanchor 13-12 08 SH (1.3 × 8 mm, self tapered) |
Maxilla, buccally between first molar and second premolar, attached gingiva | n = 4 17.5 ± 5.8 |
n = 16 19.7 ± 5.7 |
Specific objectives of the pilot trial
The aim of this pilot trial was to investigate whether administration of antibiotic prophylaxis before the microimplantation procedure improves the stability of the microimplants, reduces the soft tissue inflammation rate, and alleves the pain after microimplant insertion. On the other hand, to evaluate the intensity of the general immunologic response to the tissue trauma from microimplantation and, in particular, to the inflammation of the tissues surrounding the microimplant, we included measurements of systemic inflammatory biomarker levels.
Material and methods
Trial design and any changes after trial commencement
This was a parallel-group pilot randomized controlled trial with a 1:1 allocation ratio.
Participants, eligibility criteria, settings
This pilot randomized trial was conducted at the Department of Dentofacial Orthopedics and Orthodontics of the Wroclaw Medical University in Poland, and the participants were recruited from November 2013 to August 2015. The inclusion criteria comprised age, 13 years; good general, dental, and oral health; and malocclusion requiring en-masse distalization of the entire maxillary arch with absolute anchorage. The exclusion criteria were allergic reaction to penicillin or any other drug in the medical statement, severe systemic allergy, immune system disorders, endoprosthesis, heart defects, past incidents of endocarditis and glomerulonephritis, and antibiotic treatment in the 2 months before our study. The ethical committee of Wroclaw Medical University approved the study design (380/2012), and informed written consent was obtained from each participant. No changes to methods were introduced after commencement of the trial.
Intervention
In orthodontic terms, the participants were planned for microimplant-supported distalization of the maxillary dental arch. From the methodologic perspective, the division of intervention and control groups relied on different pharmaceutical substances before microimplantation. In the intervention group, the subjects were given 1.0 g of amoxicillin with clavulanic acid (875 + 125 mg); the subjects in the control group received glucose (1.0 g) as a placebo. To prevent the patients from recognizing the type of drug they were given, identical antibiotic and placebo capsules were manufactured by a pharmacist. The capsules were taken by the subjects 1 hour before microimplantation.
Microimplantation procedure
Two Absoanchor microimplants 1312-08 SH (tapered from 1.3 to 1.2 mm; 8 mm long; Dentos, Daegu, Korea) were placed buccally between the roots of the maxillary second premolar and first molar (1 on the left and 1 on the right sides) according to a previously described protocol. The procedure started with local anesthesia followed by vertical indentation of the alveolar mucosa with a dental probe to mark the mesiodistal position of the microscrew. A limited 0.4 mL volume of anesthetic per side was used to preserve the periodontal ligament sensation and prevent potential implant-root contact or proximity. Subsequently, a small 2-to-3 mm vertical stab incision provided access to the surface of the alveolar bone, and the microimplant bed was performed with a 0.9-mm pilot drill at 500 rpm under ample saline solution irrigation. The microimplants were placed with a hand screwdriver by an experienced operator (J.A-S.) at an angle of 30° to 40° to the long axes of adjacent teeth. After a solid fixation of the microscrews was confirmed with cotton tweezers, the patient was given postoperative instructions. Low or medium locations were used to maintain the heads of the microscrews in the alveolar gingiva.
Outcomes and any changes after trial commencement
The primary outcome was the stability of the microimplants. The assessment was performed 1 week postoperatively, after the healing of the soft tissue around the head of the microimplant. At first, the microscrews were checked for any clinical signs of mobility with cotton tweezers. Subsequently, they were loaded with nickel-titanium springs with a force of 200 g. If the screw remained steady after loading, the microimplant was considered successful. One millimeter of the microimplant head displacement was also considered to be stable if no pain was associated with the loading. The secondary outcomes were inflammation of the soft tissues around the head of a microimplant and postoperative pain. The inflammation of the soft tissues was screened 1 week postoperatively on a scale: 0, no inflammation; 1, redness; 2, redness and swelling; and 3, redness, swelling, and exudate. Postoperative pain was measured by the patients 1 day after the microimplantation on a visual analog scale (VAS) ranging from 0 mm (no pain) to 100 mm (excruciating pain). To evaluate the general immunologic response to microimplantation and peri-implantitis, measurements of procalcitonin (PCT) and C-reactive protein (CRP) serum concentrations were also included. Consecutive blood samples for inflammatory marker measurements were collected and analyzed at the same laboratory (Diagnostyka, Opolska Str. 131A, 52-013, Wroclaw) before (control sample) and 1, 3, and 7 days after microimplantation. One diagnostic laboratory tested all blood samples. Highly sensitive electro-chemiluminescent method and the Elecsys Brahms PCT immunoassays and Cobas Integra 411 (assay reference 05056888 200; Roche, Basel, Switzerland) analyzes enabled assessment of the PCT with a detection threshold of 0.02 ng per milliliter. The CRP analysis involved the highly sensitivity immunoturbidimetric method with the use of Cobas CRPHS assay and analyzed with Cobas Integra 400 plus (assay ref 04628918 190; Roche), with a detection threshold of 0.1 mg per liter.
Sample size estimation
Taking into account as high as 90% success rates of microimplants in the maxilla, we deemed that improvement up to 95% would be clinically significant. The calculation of the sample size for the definitive trial with alfa = 0.05 and power of 0.85% yielded a result of 403 participants per group. Considering the preliminary character of our investigation and the significant invasiveness of quadruple blood testing, we decided to include 50 patients per group in this pilot trial. Because of the high number of participants needed to test the null hypothesis in the definitive trial, a multicenter one will probably be necessary to recruit enough patients.
Interim analyses and stopping guidelines
To allow early discovery of any trends or aberrations in the levels of inflammatory markers, all data were evaluated after every 10 patients completed the trial. In case of adverse reactions from drug delivery, a patient would immediately be excluded from further participation in the trial. In case of severe or life-threatening adverse reactions from the pharmaceuticals, the entire trial would be terminated. The pilot trial would also be stopped if any significant problem with completion of the study occurred, especially in terms of participant recruitment.
Randomization
Randomization stratified to skeletal maturity and sex was applied to ensure equal distribution of these characteristics in both groups and to prevent their influence on the results. The cutoff skeletal developmental stage was CS6 according to most recent modification of cervical vertebral assessment method. Participants in CS1 to CS5 were considered growing patients, and those in CS6 were nongrowing patients. The allocation to groups was performed when 2 participants of the same sex and developmental stage were ready to enter the trial. Auxiliary staff unaware of the purpose of the study executed randomization between the patients with a flip of a coin in a separate room. The winning participant was admitted as number 1 and allocated to the intervention group, and the other one was number 2 and allocated to the control group. Before the trial, a pharmacist prepared 1.0 g of amoxicillin with clavulanic acid (875 + 125 mg) and glucose as the placebo in identical capsules and placed them in containers labeled 1 and 2, respectively. According to the allocations, the patients were given capsules from the respective containers and took them 1 hour before the microimplantation. This procedure ensured blinding of the patients from the administered drug. Thereafter, the 2 participants moved to the clinical room to undergo the microimplantation procedure carried out by a clinician (J.A-S.) who was unaware of the drugs taken by each patient. Since both the microimplantation and outcome assessment were performed by the same clinician, blinding of the operator and the assessor was instantly achieved.
Statistical analysis
Data analysis started with assessment of the groups’ homogeneity in terms of sex and developmental stage, followed by analysis of the outcome measures. A sum of the outcomes of the 2 evaluated microimplant sites was used to account for the clustering effect from insertion of 2 microimplants in 1 subject. In terms of microimplant failures, loss of at least 1 microscrew was regarded as a failure. Subsequently, the Fisher exact test and the odds ratio of microimplant failure between groups with 95% confidence intervals (CI) were calculated. The cumulative microimplant success rate reflecting overall survival of the microimplants was also calculated and compared between groups with the Fisher exact test. For the soft tissue conditions, the more intense inflammation noted on either the left or right side was taken into account, and the differences in the proportions of the subjects with specific levels of inflammation with 95% confidence intervals were estimated. Second, binary logistic regression analysis was used to estimate the odds ratio of developing any inflammation around either microimplant. Since The VAS is ordinal, an ordinal logistic regression under the assumption of a proportional odds model was used to determine the odds ratio for pain. The generalized estimating equation method was used for analysis of the influence of antibiotics on PCT and CRP serum concentrations in the blood samples. We used Statistica software (version 12 with medical bundle; StatSoft, Krakow, Poland) for all calculations, with the level of significance set at P <0.05. General estimating equations analysis was performed with the Geepack:Generalized Estimating Equation Package, R Package (version 1.2-1).
Material and methods
Trial design and any changes after trial commencement
This was a parallel-group pilot randomized controlled trial with a 1:1 allocation ratio.
Participants, eligibility criteria, settings
This pilot randomized trial was conducted at the Department of Dentofacial Orthopedics and Orthodontics of the Wroclaw Medical University in Poland, and the participants were recruited from November 2013 to August 2015. The inclusion criteria comprised age, 13 years; good general, dental, and oral health; and malocclusion requiring en-masse distalization of the entire maxillary arch with absolute anchorage. The exclusion criteria were allergic reaction to penicillin or any other drug in the medical statement, severe systemic allergy, immune system disorders, endoprosthesis, heart defects, past incidents of endocarditis and glomerulonephritis, and antibiotic treatment in the 2 months before our study. The ethical committee of Wroclaw Medical University approved the study design (380/2012), and informed written consent was obtained from each participant. No changes to methods were introduced after commencement of the trial.
Intervention
In orthodontic terms, the participants were planned for microimplant-supported distalization of the maxillary dental arch. From the methodologic perspective, the division of intervention and control groups relied on different pharmaceutical substances before microimplantation. In the intervention group, the subjects were given 1.0 g of amoxicillin with clavulanic acid (875 + 125 mg); the subjects in the control group received glucose (1.0 g) as a placebo. To prevent the patients from recognizing the type of drug they were given, identical antibiotic and placebo capsules were manufactured by a pharmacist. The capsules were taken by the subjects 1 hour before microimplantation.
Microimplantation procedure
Two Absoanchor microimplants 1312-08 SH (tapered from 1.3 to 1.2 mm; 8 mm long; Dentos, Daegu, Korea) were placed buccally between the roots of the maxillary second premolar and first molar (1 on the left and 1 on the right sides) according to a previously described protocol. The procedure started with local anesthesia followed by vertical indentation of the alveolar mucosa with a dental probe to mark the mesiodistal position of the microscrew. A limited 0.4 mL volume of anesthetic per side was used to preserve the periodontal ligament sensation and prevent potential implant-root contact or proximity. Subsequently, a small 2-to-3 mm vertical stab incision provided access to the surface of the alveolar bone, and the microimplant bed was performed with a 0.9-mm pilot drill at 500 rpm under ample saline solution irrigation. The microimplants were placed with a hand screwdriver by an experienced operator (J.A-S.) at an angle of 30° to 40° to the long axes of adjacent teeth. After a solid fixation of the microscrews was confirmed with cotton tweezers, the patient was given postoperative instructions. Low or medium locations were used to maintain the heads of the microscrews in the alveolar gingiva.
Outcomes and any changes after trial commencement
The primary outcome was the stability of the microimplants. The assessment was performed 1 week postoperatively, after the healing of the soft tissue around the head of the microimplant. At first, the microscrews were checked for any clinical signs of mobility with cotton tweezers. Subsequently, they were loaded with nickel-titanium springs with a force of 200 g. If the screw remained steady after loading, the microimplant was considered successful. One millimeter of the microimplant head displacement was also considered to be stable if no pain was associated with the loading. The secondary outcomes were inflammation of the soft tissues around the head of a microimplant and postoperative pain. The inflammation of the soft tissues was screened 1 week postoperatively on a scale: 0, no inflammation; 1, redness; 2, redness and swelling; and 3, redness, swelling, and exudate. Postoperative pain was measured by the patients 1 day after the microimplantation on a visual analog scale (VAS) ranging from 0 mm (no pain) to 100 mm (excruciating pain). To evaluate the general immunologic response to microimplantation and peri-implantitis, measurements of procalcitonin (PCT) and C-reactive protein (CRP) serum concentrations were also included. Consecutive blood samples for inflammatory marker measurements were collected and analyzed at the same laboratory (Diagnostyka, Opolska Str. 131A, 52-013, Wroclaw) before (control sample) and 1, 3, and 7 days after microimplantation. One diagnostic laboratory tested all blood samples. Highly sensitive electro-chemiluminescent method and the Elecsys Brahms PCT immunoassays and Cobas Integra 411 (assay reference 05056888 200; Roche, Basel, Switzerland) analyzes enabled assessment of the PCT with a detection threshold of 0.02 ng per milliliter. The CRP analysis involved the highly sensitivity immunoturbidimetric method with the use of Cobas CRPHS assay and analyzed with Cobas Integra 400 plus (assay ref 04628918 190; Roche), with a detection threshold of 0.1 mg per liter.
Sample size estimation
Taking into account as high as 90% success rates of microimplants in the maxilla, we deemed that improvement up to 95% would be clinically significant. The calculation of the sample size for the definitive trial with alfa = 0.05 and power of 0.85% yielded a result of 403 participants per group. Considering the preliminary character of our investigation and the significant invasiveness of quadruple blood testing, we decided to include 50 patients per group in this pilot trial. Because of the high number of participants needed to test the null hypothesis in the definitive trial, a multicenter one will probably be necessary to recruit enough patients.
Interim analyses and stopping guidelines
To allow early discovery of any trends or aberrations in the levels of inflammatory markers, all data were evaluated after every 10 patients completed the trial. In case of adverse reactions from drug delivery, a patient would immediately be excluded from further participation in the trial. In case of severe or life-threatening adverse reactions from the pharmaceuticals, the entire trial would be terminated. The pilot trial would also be stopped if any significant problem with completion of the study occurred, especially in terms of participant recruitment.
Randomization
Randomization stratified to skeletal maturity and sex was applied to ensure equal distribution of these characteristics in both groups and to prevent their influence on the results. The cutoff skeletal developmental stage was CS6 according to most recent modification of cervical vertebral assessment method. Participants in CS1 to CS5 were considered growing patients, and those in CS6 were nongrowing patients. The allocation to groups was performed when 2 participants of the same sex and developmental stage were ready to enter the trial. Auxiliary staff unaware of the purpose of the study executed randomization between the patients with a flip of a coin in a separate room. The winning participant was admitted as number 1 and allocated to the intervention group, and the other one was number 2 and allocated to the control group. Before the trial, a pharmacist prepared 1.0 g of amoxicillin with clavulanic acid (875 + 125 mg) and glucose as the placebo in identical capsules and placed them in containers labeled 1 and 2, respectively. According to the allocations, the patients were given capsules from the respective containers and took them 1 hour before the microimplantation. This procedure ensured blinding of the patients from the administered drug. Thereafter, the 2 participants moved to the clinical room to undergo the microimplantation procedure carried out by a clinician (J.A-S.) who was unaware of the drugs taken by each patient. Since both the microimplantation and outcome assessment were performed by the same clinician, blinding of the operator and the assessor was instantly achieved.
Statistical analysis
Data analysis started with assessment of the groups’ homogeneity in terms of sex and developmental stage, followed by analysis of the outcome measures. A sum of the outcomes of the 2 evaluated microimplant sites was used to account for the clustering effect from insertion of 2 microimplants in 1 subject. In terms of microimplant failures, loss of at least 1 microscrew was regarded as a failure. Subsequently, the Fisher exact test and the odds ratio of microimplant failure between groups with 95% confidence intervals (CI) were calculated. The cumulative microimplant success rate reflecting overall survival of the microimplants was also calculated and compared between groups with the Fisher exact test. For the soft tissue conditions, the more intense inflammation noted on either the left or right side was taken into account, and the differences in the proportions of the subjects with specific levels of inflammation with 95% confidence intervals were estimated. Second, binary logistic regression analysis was used to estimate the odds ratio of developing any inflammation around either microimplant. Since The VAS is ordinal, an ordinal logistic regression under the assumption of a proportional odds model was used to determine the odds ratio for pain. The generalized estimating equation method was used for analysis of the influence of antibiotics on PCT and CRP serum concentrations in the blood samples. We used Statistica software (version 12 with medical bundle; StatSoft, Krakow, Poland) for all calculations, with the level of significance set at P <0.05. General estimating equations analysis was performed with the Geepack:Generalized Estimating Equation Package, R Package (version 1.2-1).
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