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J Oral Maxillofac Surg68:2207-2220, 2010

Corticosteroid Administration in Oral andOrthognathic Surgery: A Systematic

Review of the Literatureand Meta-Analysis

Anne E.B. Dan, DDS,* Torben H. Thygesen, DDS, PhD,† and

Else M. Pinholt, DDS, MSc, DrOdont‡

Purpose: This study evaluated the effect of corticosteroid (CS) administration on edema, analgesia, andneuroregeneration in conjunction with surgical dental extraction, orthognathic surgery, and the risk ofdeveloping side effects.

Materials and Methods: A systematic search of the literature was made. The primary predictorvariable was CS administration and the outcome variables were edema, pain, and infection. Ameta-analysis was performed. The risk of other side effects was evaluated through a simple review.

Results: In oral surgery, most clinical trials showed a significant decrease in edema (P � .0001) afterCS, and local injection of methylprednisolone �25 mg was expected to result in a significant decreasein edema. Regarding the analgesic effect, several clinical trials showed a decrease in pain after CS (P �.0001). Further, CS administration resulted in a slightly higher risk of infection (relative risk, 1.0041), butwith a P value of .89. CS could be administered with no increased risk of infection. In orthognathicsurgery, methylprednisolone �85 mg administered intravenously seemed sufficient to produce a signif-icant decrease in edema, and several trials pointed toward a neuroregeneration effect, but no statisticalanalysis could be performed. Regarding the risk of other side effects, in oral surgery, a minimal risk ofchronic adrenal suppression was seen; in orthognathic surgery, an elevated risk of avascular osteone-crosis, steroid-induced psychosis, and adrenal suppression was seen. There were no reports of decreasedhealing.

Conclusion: These findings suggest that the administration of CS in oral surgery decreases edemaand pain significantly, with no higher risk of infection and with a minimum risk of other side effects.© 2010 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 68:2207-2220, 2010
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n the late 1960s and early 1970s, corticosteroid (CS)dministration was advocated in conjunction witharious oral surgical interventions to minimize edemand possibly decrease pain and promote neuroregen-ration.1,2

The most commonly administered types of CSre betamethasone, dexamethasone, and methyl-

*Research Assistant, Department of Oral and Maxillofacial Sur-

ery, School of Dentistry, Faculty of Health Sciences, University of

openhagen, Copenhagen, Denmark.

†Chief Surgeon, Associate Professor, Department of Oral and

axillofacial Surgery, K. Odense University Hospital, Odense, Den-

ark.

‡Professor and Head, Department of Oral and Maxillofacial Sur-

ery, School of Dentistry, Faculty of Health Sciences, University of

openhagen, Copenhagen, Denmark.

2207

rednisolone, administered intravenously, orally ory injection into the masseter muscle.1

The administration of CS is thought to inhibit mastell production and secretion of cytokine, kinin, andistamine.3-5 This should promote an inhibition ofhromboxane6,7 and bradykinin,8 resulting in less bloodessel dilatation and less permeability.

Address correspondence and reprint requests to Dr Dan:

epartment of Oral and Maxillofacial Surgery, Institute of Odontol-

gy, Faculty of Health Science, University of Copenhagen, Bleg-

amsvej 3B, 2200 Copenhagen N, Seeland, Denmark; e-mail:

[email protected]

2010 American Association of Oral and Maxillofacial Surgeons

278-2391/10/6809-0027$36.00/0

oi:10.1016/j.joms.2010.04.019

mailto:[email protected]

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2208 CORTICOSTEROIDS IN ORAL/ORTHOGNATHIC SURGERY

Another edema-decreasing factor, which haseen claimed to be the result of CS administration,

s the inhibition of lysozyme-induced membraneupture, which decreases the local release of pro-eolytic enzymes and hyaluronidase.9

Furthermore, the administration of CS is thought toromote an inhibition of the synthesis of prostaglan-in, thereby facilitating an analgesic effect.10,11

Nerve damage is the result of direct or indirectnjury to the nerves. Compression or trauma results indema in nearby tissues or release of inflammatoryediators that temporarily irritate the nerves.12 Some

nvestigators have suggested that CS promotes theealing of nerves.12,13

However, CS administration has been discouragedecause of the fear of serious side effects,14-16 such asvascular osteonecrosis,17-24 adrenal suppression,25-30

ecreased healing potential, a higher infectionate,30-35 and steroid-induced psychosis.14,36-44

It has been stated that the exogenic CS has a neg-tive feedback effect on the hypothalamus-pituitary-drenal axis, resulting in suppression of the normalndogenic secretion of cortisol. The suppressioneaches its maximum on the third day and normalizesn the seventh day, which seems to be of little or noignificance in the postoperative period, and prob-ems only occur when this temporary suppressionurns into a chronic state of adrenal suppres-ion.28,45-49

In animals, the administration of CS can producehanges in hippocampal structure and function.36 Inumans, it results in euphoria37-39 or, more rarely, inuicidal thoughts due to a lowering of serotonin levelsn the brain.40

Post-traumatic avascular osteonecrosis primarily inhe femur is seen because of various medical conditionsnd after treatment with high-dose (long-duration) pred-isolone, all of which inhibit microvascularity in bonend thereby cause ischemia and necrosis.30,50

Table 1. EQUIVALENT DOSE WITH REGARD TO ANTI-IN

Type* Anti-Inflammatory Potency

ortisol 1rednisolone 3-5ethylprednisolone 3-5riamcinolone 3-5aramethasone 10etamethasone 20-30examethasone 20-30

Equivalent volumes of cortisol, prednisolone, methylpreexamethasone are listed with regard to anti-inflammatoryalf-time.9,79 It should be noted that available studies usingo bioavailability, to a further decrease of 20%.

an, Thygesen, and Pinholt. Corticosteroids in Oral/Orthognathic Surg

Theoretically, the administration of CSs should in-ibit fibroblast function and contribute to a decrease

n the rate of healing and an increase in the rate ofnfection.30-32

Does edema actually require prophylactic CS treat-ent? Rarely, edema can be life-threatening if it re-

ults in airway obstruction, but this is the case only inrthognathic surgery, severe trauma in general, andajor head and neck surgery.51 In oral surgery, indi-

ations for the use of prophylactic CS are functionalnd esthetic.

The purpose of this review and meta-analysis oflinical trials (on the topic of CS use in oral andrthognathic surgery) was to clarify whether CSdministration does indeed significantly decreasedema and pain and promote neuroregeneration.urthermore, we wanted to identify the minimumffective dose of CS in relation to onset, duration,nd route of administration. In addition, we evalu-ted whether CS administration did in fact intro-uce an increased risk of side effects.

aterials and Methods

Articles were located through PubMed (www.ubmed.org) and the Cochrane Database (www.ochrane.org) using the search words corticoste-oid � oral surgery/orthognathic surgery � neu-oregeneration/avascular osteonecrosis/steroid-nduced psychosis/healing/infection.

The articles were evaluated on the presence orbsence of the following parameters:

● Introduction: A clear hypothesis and aim of the studyand the correct use and citation of prior studies.

● Method: A logical coherence between the aim ofthe trial and the choice of method, sufficient num-ber of patients to provide statistical strength, use of

MATORY EFFECT

Half-Life in HoursEquivalent Dose With Regardto Anti-Inflammatory Effect

8-12 20 mg12-36 5 mg12-36 4 mg12-36 4 mg

2 mg36-54 0.6 mg36-54 0.75 mg

one, triamcinolone, paramethasone, betamethasone, andts and respective values of anti-inflammatory potency andadministered dexamethasone were recalculated according

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DAN, THYGESEN, AND PINHOLT 2209

control groups, validity, precision, reliability of themeasurement method, and repeatability of the trial.

● Results and discussion: Coherence between pre-sented results and hypothesis, well-presentedfindings, well-documented conclusions, and nopresence of bias.

The administered doses of CS in the selectedrticles were recalculated to equivalent anti-inflam-atory doses of methylprednisolone, to facilitate

omparison (betamethasone 9 mg � [9 mg/0.6 mg] �� methylprednisolone 60 mg). Further, the doses ofrally administered dexamethasone were decreasedy 20% to adjust the dose according to the bioavail-bility difference between oral and intravenous ad-inistration and local injection (Table 1).Regarding CS administration and decreased edema

n oral surgery, 20 articles2,3,49,52-68 were found, and2,3,55,64-68 were rejected due to the lack of objectivearameters,66 lack of statistical analysis,2,68 not beingouble-blinded64,65 or randomized,65 and use of insuf-cient evaluation methods (Table 2).3,55 The remain-

ng 12 articles49,52,53,56-63,69 showed great diversityegarding the dose, route of administration, and drugf choice. Of the 12 selected articles, only 652,53,56-59

rovided sufficient data to be included in the meta-nalysis.

On the topic of CS administration and decreased pain inral surgery, 13 articles were found,2,49,52,53,56,58-62,63,67,69

nd 2 were excluded because of lack of statistical analy-is,2,67 leaving 11 articles49,52,53,56,58-62,63,69 to be includedn the review (Table 3). Of these 11 articles, only 5 arti-les52,53,56,59,63 provided sufficient data to be included inhe meta-analysis.

Regarding orthognathic surgery, 5 eligible trials wereound1,4,70-72; 2 were rejected due to lack of randomiza-ion and blinding.1,4 The remaining 3 trials were in-luded in the review and no meta-analysis could beerformed on decreased edema after orthognathic sur-ery due to insufficient available data (Table 4).Eleven articles2,3,49,52,53,57-60,63,69 on infection rate

fter oral surgery were available; 2 were excluded dueo lack of statistical analysis2 and insufficient evalua-ion method used.3 The remaining 9 arti-les49,52,53,57-60,63,69 were included in the review (Ta-le 5). Of these 9 articles,49,52,53,57-60,63,69 all providedufficient data to be included in the meta-analysis.

Because of the lack of sufficient numbers of avail-ble double-blinded and randomized studies, other CSffects such as neuroregeneration and the risk of sideffects (avascular osteonecrosis, steroid-induced psy-hosis, adrenal suppression, and decreased healing)ould be reviewed only by including randomized,ontrolled trials and single-case studies. No meta-anal-
sis was performed and, hence, no valid conclusion
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an be made. This section of the report should servenly as a basic guideline for further investigation.Meta-analysis was performed on data in oral surgery

nd evaluated CS compared with placebo, resulting indema/no edema, analgesia/no analgesia, and infec-ion/no infection.

The meta-analysis was performed using an inverseariance method, and results were summarized usingorest plots73 and relative risks (RRs), estimated basedn fixed and random effects models.74

Heterogeneity was quantified (�2, H[ ; ], I2 [% , %])nd tested (Q value, degrees of freedom, P value); andn the Results section, RR with 95% confidence inter-al, P value; and Z value are given.74

Further, a forest plot was done for oral surgicaldema, analgesia, and infection rate using a logarithmiccale for RR to achieve symmetrical confidence inter-als.73

esults

CORTICOSTEROID ADMINISTRATION INORAL SURGERY

EdemaFive reviews on oral surgery and CS administrationere available. The reviews concluded that CS is

ffective in decreasing edema and thus should bedministered, although different dosages, administra-ion routes, times of onset, and durations of treat-

Table 3. SELECTED ARTICLES IN ORAL SURGERY (CORTI

Study

Randomized-Controlled

Trial Jaw Arch

SubjectsUsing

SteroidsControlSubjects

MA

kjelbred andLøkken,52 1982

Yes Max/mand 24 24 2

eirne andHollander,56 1986


sen et al,49 1999 Yes Mand 20 20 2

raziani et al,62 2006 Yes Mand 15 43 2

chmelseizen andFrölich,60 1989


kjelbred andLøkken,53 1982B


axendale et al,59

1993Yes Max/mand 25 25 2

edersen,69 1985 Yes Mand 30 30 2uyukkurt et al,61

2006Yes Mand 15 15 2

illes et al,58 1993 Yes Max/mand 11 11 2eupert et al,63 1992 Yes Max/mand 60 60

bbreviations: IM, intramuscular; IV, intravenous; mand, maemoved; NA, no available data; postop, postoperative; preNOTE. Table lists trials in which corticosteroids were ad

andomized, double-blind studies tested against placebo (saostoperative pain; P values less than .05 indicate significa

an, Thygesen, and Pinholt. Corticosteroids in Oral/Orthognathi

ents were used.37-39,51,75 t

In oral surgery, 12 trials49,52,53,56-63,69 were selected,n which CSs were administered before, during, or afterurgical extraction, and these were divided into 2roups. In group 1, 11 studies reported significantlyecreased edema because of CS administration at vari-us times and doses.49,52,53,56-62,69 In group 2, 1 trial byeupert et al63 did not report decreased edema after CS

dministration. The reasons Neupert et al did not reportignificantly decreased edema were probably due to aack of sensitivity in the method used to measure edema,he possibility that the dose was close to the minimumose threshold, and in the choice of route of adminis-ration. These possibilities are supported by the findingy Pedersen69 of significantly decreased edema whendministering the same dose at the same time and dura-ion as Neupert et al, but by injection into the masseteruscle.Figure 1A shows that most trials resulted in signifi-

antly decreased edema after administration of CSs. Ad-inistration had effect when administered in various

ombinations of dose and time of onset, route, anduration of treatment. Based on Figure 1A, the singlehreshold dose is expected to be methylprednisolone 0o 25 mg, but this should be verified through furtherlinical trials.A forest plot of the selected 6 studies52,53,56-59 wasade. Figure 1B shows the results of 6 randomized

linical trials combined in a collaborative meta-analysisf 232 M3 surgery sites treated with CS or placebo and

ROID ADMINISTRATION AND ANALGESIA)

Original SteroidUsed

OriginalDose(mg)

Method ofDelivery

Time of SteroidDelivery

AnalgesicEffect (PValue)

etamethasone 9 IM Preop �.001

ethylprednisolone 125 IV Preop �.01

ethylprednisolonesodium succinate

125 IV Preop �.0001

examethasone 21.3 Submucosalinjection

Postop .02

examethasone 6 Oral Preop � postop .01

etamethasone 9 IM Postop �.1

examethasone 8 Oral Preop �.005

examethasone 4 IM Preop �.05rednisolone 25 IM Postop �.05

ethylprednisolone 20 IV Preop �.05examethasone 21.3 IV Preop �.0001

ar teeth surgically removed; max, maxillary teeth surgicallyeoperative.ered to evaluate postoperative analgesia. All studies werevalues greater than .05 indicate no significant decrease in

reases in postoperative pain.


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Table 4. SELECTED ARTICLES IN ORTHOGNATHIC SURGERY (CORTICOSTEROID ADMINISTRATION AND EDEMA DECREASE)

Study


Trial Design Type

SubjectsUsing

SteroidsControlSubjects

MeanAge(yr)

Original Type ofSteroid Used Original Dose

Method ofDelivery

Time of SteroidDelivery P Value

Weber and Griffin,70 1994 Yes Sagittal split osteotomy 8 4 NA Dexamethasone 16 mg preop IV Preop �.05Weber and Griffin,70 1994 Yes Sagittal split osteotomy 8 4 NA Dexamethasone 16 mg preop �

8 mg � 3postop

IV Preop � postop �.05

Peillon et al,71 1996 Yes Le Fort I 16 16 NA Methylprednisolone 1.5 mg/kg IV Preop � postop NAMunro et al,72 1986 Yes Le Fort I/II,

hemimandibulectomy,and sagittal splitmandibular osteotomy

17 19 15 Dexamethasone 0.5 mg/kg preopand 0.25 mg/kg for 48 h

IV Preop � postop �.05

Abbreviations: IM, intramuscular; IV, intravenous; mand, mandibular teeth surgically removed; max, maxillary teeth surgically removed; NA, no available data; postop,postoperative; preop, preoperative.

NOTE. Table lists trials in which corticosteroids were administered to evaluate postoperative edema. All studies were randomized, double-blind studies tested against placebo(saline). P values greater than .05 indicate no significant decrease in postoperative edema; P values less than .05 indicate significant decreases in postoperative edema.

Dan, Thygesen, and Pinholt. Corticosteroids in Oral/Orthognathic Surgery. J Oral Maxillofac Surg 2010.

Table 5. SELECTED ARTICLES IN ORAL SURGERY (CORTICOSTEROID ADMINISTRATION AND INFECTION)

Study


Trial Jaw Arch

Infectionsin CSGroup

Subjectsin CSGroup

Infections inControlGroup

Subjectsin

ControlGroup

MeanAge(yr)

Original SteroidUsed

OriginalDose(mg)

Methodof

DeliveryTime of Steroid

Delivery

Esen et al,49 1999 Yes Mand 0 20 0 20 22 Methylprednisolonesodium succinate

125 IV Preop

Holland,57 1987 Yes Mand 0 20 0 20 23.4 Methylprednisolone 40 IV PreopMilles et al,58 1993 Yes Max/mand 0 11 1 11 24 Methylprednisolone 20 IV PreopSkjelbred and Løkken,52 1982 Yes Max/mand 0 24 0 24 24 Betamethasone 9 IM PreopSkjelbred and Løkken,53 1982 Yes Max/mand 0 12 0 12 23 Betamethasone 9 IM PostopNeupert et al,63 1992 Yes Max/mand 2 60 2 60 18-24 Dexamethasone 4 IV PreopBaxendale et al,59 1993 Yes Max/mand 0 25 0 25 22.8 Dexamethasone 8 Oral PreopSchmelseizen and Frölich,60 1989 Yes Max/mand 5 26 3 25 18 Dexamethasone 6 Oral Preop � postopPedersen,69 1985 Yes Mand 0 30 0 30 22 Dexamethasone 4 IM Preop

Abbreviations: CS, corticosteroid; IM, intramuscular; IV, intravenous; mand, mandibular teeth surgically removed; max, maxillary teeth surgically removed; postop,postoperative; preop, preoperative.

NOTE. Table lists the number of infections in the CS versus control groups in various clinical oral surgery trials, in which a CS was administered. All studies were randomized,double-blind studies tested against placebo (saline).

Dan, Thygesen, and Pinholt. Corticosteroids in Oral/Orthognathic Surgery. J Oral Maxillofac Surg 2010.

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r no/mild edema (results from the second and thirdostoperative days). Figure 1B shows the RR of edema

or the CS compared with the placebo group, and indi-

Dose Methylprednisolone (mg)

120

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70

50

60

10

20

30

40

52

56 49

62

60

59

57

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A

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IGURE 1. A, Comparison of administration time (x axis) and dose of meersus nonsignificant (P � .05, red squares) decreases in edema by CSurations of treatment. Studies are cited (within squares) and those connect

imes. B, Forest plot of number of edema events (CS use in oral surgery) shocontrol) has been administered. With each trial, the number of events (sevelected trials according to the combined estimated RR (RR �1 � increas

(random) values are displayed. CI, confidence interval; CS, corticoste

an, Thygesen, and Pinholt. Corticosteroids in Oral/Orthognathic Surg

idual estimates of RR are quite consistently below 1, t

howing a lower risk. The confidence intervals of all 6tudies overlap, and a formal assessment of heterogene-ty using the Cochran �2 test for homogeneity (statistics

Administration time

t-operative

Skjelbred and Løkken, 1982A,Betamethasone, IM, P<0,001

Beirne and Hollander, 1986,Methylprednisolone, IV, P<0,05

Esen et al, 1999, Methylprednisolone-sodium succinate, IV, P<0,005

Buyukkurt et al, 2006, Prednisolone,IM, P = 0,001

Graziani et al, 2006, Dexamethasone,Submucosal injection, P<0,001

Schmelseizen and Frolich, 1989,Dexamethasone, Oral, P<0,056

Skjelbred and Løkken, 1982B, Betamethasone, IM, P=0,006

Baxendale et al, 1993, Dexamethasone,Oral, P<0,05

Holland et al, 1987,Methylprednisolone, IV, P=0,0003

Pedersen et al, 1985, Dexamethasone,IM, P<0,001

Milles et al, 1993, Methylprednisolone,IV, P<0,001

Neupert et al, 1992, Dexamethasone,IV, P = Not significant

52

56

49

61

62

60

53

59

57

69

58

63

Reference number in square.Black = Significant edema reductionRed = No significant edema reduction

61

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dnisolone in milligrams (y axis) shows significant (P � .05, black squares)istration in oral surgery at different doses, times of treatment onset, anda line indicate thatmore than1dosewasgivenat different administrationmparison of 6 selected trials in which a CS (experimental) versus placebooderate edema) has been noted. A schematic graph (center) shows thef postoperative edema). On the right side, RR (95% CI), W (fixed), and, intramuscular; IV, intravenous; RR, relative risk; W, normal distribution.

ral Maxillofac Surg 2010.

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est, Q5 � 15.01, P � .0103, I2 � 66.7% [20.5%, 86%])

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Post-operative

Skjelbred and Løkken, 1982A, Betamethasone, IM, P < 0,001

Beirne and Hollander, 1986, Methylprednisolone, IV, P < 0,01

Esen et al, 1999, Methylprednisolone- sodium succinate, IV, P < 0,0001

Graziani et al, 2006, Dexamethasone, Submucosal injection, P = 0,02

Schmelseizen and Frolich, 1989, Dexamethasone, Oral, P = 0,01

Baxendale et al, 1993, Dexamethasone, Oral, P < 0,005

Neupert et al, 1992, Dexamethasone, IV, P < 0,0001

Pedersen et al, 1985, Dexamethasone, IM, P > 0,05

Milles et al, 1993, Methylprednisolone, IV, P > 0,05

Buyukkurt et al, 2006, Prednisolone, IM, P > 0,05

Skjelbred and Løkken, 1982B, Betamethasone, IM, P > 0,1

52

56

49

62

60

53

59

63

69

58

Reference number in square.Black = Significant post-op pain reductionRed = No significant post-op pain reduction

52

56 49

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60

53

59

69

58

63

6061

A

B

IGURE 2. A, Comparison of administration time (x axis) and dose of methylprednisolone in milligrams (y axis) shows significant (P � .05,lack squares) versus nonsignificant (P � .05, red squares) decreases in pain by CS administration in oral surgery at different doses, timesf treatment onset, and durations of treatment. Studies are cited (within squares) and those connected with a line indicate that more than 1ose was given at different administration times. B, Forest plot of number of analgesia events (CS use in oral surgery) shows a comparisonf 5 selected trials in which a CS (experimental) versus placebo (control) was administered. With each trial, the number of eventspostoperative analgesia) is noted. A schematic graph (center) shows the selected trials according to the combined estimated RR (RR �1 �ncreased chance of postoperative analgesia). On the right side, RR (95% CI), W(fixed), and W(random) values are displayed. CI, confidencenterval; CS, corticosteroid; IM, intramuscular; IV, intravenous; RR, relative risk.

an, Thygesen, and Pinholt. Corticosteroids in Oral/Orthognathic Surgery. J Oral Maxillofac Surg 2010.

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hows a consistency across studies and that the com-ined estimate of RR can be trusted.The �2 test on the selected data52,53,56-59 shows thathen CS has been administered, the estimated RR ofostoperative edema is 0.4065 (0.2917, 0.5666) com-ared with placebo, a highly significant result (P �

0001, Z � �5.3153) allowing the conclusion that CSdministration does decrease the risk of postoperativedema significantly.

AnalgesiaRegarding CS administration and decreased pain in

ral surgery, 11 articles49,52,53,56,58-62,63,69 were se-ected and divided into 2 groups: 7 trials that showedignificantly decreased pain after administration ofS49,52,56,59,60,62,63 and 4 with no significant analgesicffect of CS.53,58,61,69

Figure 2A shows the magnitude of available trialshat have shown the pain-decreasing effect of CS afterral surgery. Four trials showed no significant analge-ic effect of CS,53,58,61,69 with 358,61,69 placed in theower quadrant of Figure 2A, indicating a relation tohe CS dose administered, and 253,69 of the 4 trials in


160

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110

90

100

60

70

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IGURE 3. Comparison of administration time (x axis) and dose ofquares) versus nonsignificant (P � .05, red squares) decreases in eoses, times of treatment onset, and durations of treatment. Studieore than 1 dose was given at different administration times.


he section of postoperative administration time, in- i

icating that this might be too late to facilitate annalgesic effect of CSs.

Six studies49,52,56,59,60,62 reported decreased edemand analgesia, 4 studies53,58,61,69 reported decreaseddema and no analgesia, and 1 study63 reported de-reased edema but no analgesia, indicating a relationetween the dose (and degree of edema) and postop-rative pain. No trial showed an increased need fornalgesic treatment postoperatively after CS adminis-ration.2,49,52,53,56,58-62,63,67,69 Of these available 11 ar-icles, 5 articles52,53,56,59,63 provided sufficient data toe included in the meta-analysis. A forest plot of theelected 5 articles was made.

Figure 2B shows the results from 5 randomizedlinical trials of 269 bilateral M3 surgery sites treatedith CS or placebo with the composite endpointeing postoperative no pain or pain (results from therst postoperative day). Figure 2B shows the RR ofnalgesia for the CS compared with placebo group,nd individual estimates of RR vary quite consider-bly, but are all above 1, showing an increased rate ofostoperative analgesia using CSs. The confidence

Administration time

Weber and Griffin, 1994, Dexamethasone, IV, P < 0,05

Peillon et al, 1996, Methylprednisolone, IV, P = Not available

Munroe et al, 1986, Dexamethasone, IV, P > 0,05

70

71

72

Reference number in square.Black = Significant Edema reductionRed = No significant Edema reduction

2nd post-op day 3rd post-op day

72 72

71

rednisolone in milligrams (y axis) shows significant (P � .05, blackby corticosteroid administration in orthognathic surgery at differentted (within squares) and those connected with a line indicate that


p day

methylpdemas are ci

ntervals of all 5 studies overlap, and a formal assess-

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ent of heterogeneity using the Cochran �2 test foromogeneity shows a consistency across studies (sta-istics test, Q4 � 18.67, P � .0009, I2 � 78.6% [48.8%,1%]) and that the combined estimate of RR can berusted.

The �2 test showed an estimated relative rate ofnalgesia with CS of 2.8824 (1.9579, 4.2437) com-ared with placebo (P � .0001, Z � 5.3644), indicat-

ng that CS administration decreases the risk of post-perative pain significantly.

CORTICOSTEROID ADMINISTRATION INORTHOGNATHIC SURGERY

EdemaTwo reviews concerning orthognathic surgery sup-

orted the administration of CSs when edema or vas-ular problems were to be expected.76,77

Five clinical trials were conducted,1,4,70-72 and 2ere abandoned because they were neither random-

zed nor double-blinded.1,4 This left 3 well-conductedrials,70-72 with 2 showing a significant decrease indema70,71 and 1 that did not.72

In all trials represented in Figure 3, CSs were admin-stered through an intravenous route, but at differentoses, times of onset, and durations of treatment.A trial by Munro et al72 did not show any significant

ecrease in edema but is among the trials in whichhe highest doses and the longest durations of treat-ent were used.1,72 The researchers stated that the

ack of effect was due to hormonal differences be-ause all patients were children. This seems plausibleut was not possible to clarify by the literature re-iewed in the present study. Another problem in thistudy could be the grading of clinical edema on aimple scale from 0 to 4, which is not as accurate ashe objective measurement method used in the othertudies, examples being computed tomographiccans, C-reactive protein values,72 and laser scans.71

A trial by Weber and Griffin70 published in 1994howed significantly decreased edema with 1 singlereoperative dose of dexamethasone and doses admin-

stered before and after surgery and on the first postop-rative day. This trial concluded that, if minimum dosend duration are preferred, administration of methyl-rednisolone 85 mg (intravenously) preoperativelyeems to decrease edema significantly, but more clinicalrials are needed to support this conclusion.

No meta-analysis could be performed in orthog-athic surgery and decreased edema with CSs; furtherlinical trials are needed.

NeuroregenerationA trial by Al-Bishri e al,13 which was based on the

atients’ own evaluation of neurosensory dysfunc-ion, was not included because of the purely subjec-
ive evaluation method. w
Bracken et al78 advocated the use of 24-hour methyl-rednisolone (initially 30 mg/kg before the operationnd thereafter a methylprednisolone infusion of 5.4 mg/g/h) if started sooner than 3 hours after trauma and of8-hour methylprednisolone (2.5-mg/kg bolus infusionf tirilazad mesylate every 6 hours) if longer than 3ours after trauma, and both regimens had significanteuroregeneration effects. Seo et al12 administered axed CS dose (prednisolone 30 mg for 7 days, 15g for 4 days, and 5 mg for 3 days) during 14 days

f treatment with different times for onset of treat-ent (1 week, 3 weeks, or 6 weeks after trauma)

nd found significant neuroregeneration in patientshen treatment onset was later than the first week

fter trauma.A study by Galloway et al79 showed that an initial

euroregeneration effect was not statistically signifi-ant.Combined, these studies show that there might beneuroregeneration effect of CSs, but no meta-analy-

is could be performed, and further clinical studiesre needed.

Side Effects

Adrenal suppression. Several investigators haveoncluded that the administration of CSs results inemporary adrenal suppression.28,45-49

Long-term states of adrenal suppression are claimedo occur at random if the dose administered is hydro-ortisone �20 mg (methylprednisolone �4 mg)25 orrednisolone �50 mg (methylprednisolone �40g)26 and when the dose is higher than physiologic

evels for longer than 5 days27-29 or is administered foronger than 1 to 2 weeks of treatment.30 This indi-ates that an increased risk is to be expected with thedministration of doses, although low, used for oralnd orthognathic surgeries because the administra-ion period is shorter than 5 days. No meta-analysisould be done to verify this, and further studies areeeded.

Steroid-induced psychosis. A trial by Lewis andmith40 concluded that women have an increased riskf steroid-induced psychosis because of hormonal dif-erences. A history of psychotic behavior has alsoeen associated with a higher risk,41 although some

nvestigators could not relate risk to prehistory.14 Sev-ral trials have concluded that the risk of psychosis isignificantly increased when a dose of prednisolone40 mg (methylprednisolone �32 mg) is adminis-

ered.42,43 Galen et al14 showed that higher dosesnduce a higher risk, and Flemming and Flood44

inked an increased risk to the use of a CS with a longalf-life.These findings indicate an increased risk using a CS
ith a long half-life (betamethasone and dexametha-

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one) and with doses of methylprednisolone �32 mg,hich is the case for the dose advocated for orthog-athic surgery. No meta-analysis could be performedn the topic of CS inducing steroid-induced psycho-is, and further clinical studies are needed.

Avascular osteonecrosis. Some investigators haveound that high CS dosages, even for shorter periods,ncrease the risk of avascular osteonecrosis.17-20 Oth-rs have claimed that a dose of dexamethasone �16g daily (methylprednisolone �85 mg)21 or methyl-rednisolone �1,830 mg over the first 30 hours22,23

lso increases the risk.A large study by Precious et al78 with 2,773 patients

howed retrospectively that there were no increasedisk of femoral head necrosis and subsequent need forip replacement in patients who received orthog-athic surgery and were treated with high-dose short-uration CS. Other factors such as smoking, alcoholonsumption, and work are also thought to predis-ose to the development of avascular osteonecrosis.24

These findings indicate that an increased risk iseen with doses of methylprednisolone �85 mg (or-hognathic surgery); no meta-analysis could be per-ormed, and further studies are needed.

Increased infection rate and decreased healing. Innimal studies, decreased healing is associated withS administration.33-35 Conversely, in human studies,one of the trials available reported signs of decreasedealing,2,3,49,52,53,57-59,63,69 and with a reduced heal-

ng rate incidence of zero, no meta-analysis could beerformed. The result being that the administrationf CS does not induce a significantly reduced heal-

ng rate.Regarding infection rate, several clinical human stud-

es have concluded that no increased infection rate iseen because of CS administration.2,3,49,52,53,57-60,63,69

IGURE 4. Forest plot of number of events without infection (cortihich a corticosteroid (experimental) versus placebo (control) wostoperative infections) has been noted. A schematic graph (cent1 � increased risk of postoperative infection). On the right sid

onfidence interval; RR, relative risk.


uffman3 reported that 2 subjects in the control group g

nd 1 in the steroid group had an infection. Milles andesjardins58 reported 1 infection in the placeboroup. Neupert et al63 reported 2 infections in the CSnd placebo groups. Schmelzeisen and Frölich60 re-orted 3 infections in the placebo group and 5 inhe CS group. A forest plot of the selected 9 arti-les49,52,53,57-60,63,69 was created.Figure 4 shows the results from 9 randomized clin-

cal trials of 434 bilateral M3 surgery sites treated withS or placebo with the composite endpoint beingostoperative infection or no infection (results fromhe first postoperative week). Figure 4 shows the RRf infection for the CS compared with placebo group,nd individual estimates of RR are quite consistent atstraight, with 2 exceptions at 0.91 and 1.10, indi-

ating no increased risk of postoperative infection inither group. The confidence intervals of all 9 studiesverlap, and a formal assessment of heterogeneitysing the Cochran �2 test for homogeneity (statisticsest, Q8 � �, P � .0001, I2 � NaN% [NaN%, NaN%])hows a consistency across studies and that the com-ined estimate of RR can be trusted.The �2 test shows an estimated RR of 1.0041

0.9451, 1.0669) for CS compared with placebo, indi-ating a slightly higher but nonsignificant risk of in-ection (P � .8937, Z � 0.1336) and that CSs do notncrease the risk of infection significantly.

In all available trials in orthognathic surgery, anti-iotics were administered, and thus these trials can-ot be used to conclude any increased risks of

nfection.1,4,70-72

iscussion

The aim of this review was to confirm or reject thedema-decreasing effect of CS administration in sur-

id use in oral surgery) shows a comparison of 9 selected trials ininistered. With each trial, the number of events (number of no

ws the selected trials according to the combined estimated RR (RR95% CI), W (fixed), and W (random) values are displayed. CI,


costeroas admer) shoe, RR (

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In surgical extraction, most trials showed a sig-ificant decrease in edema after CS administrationsing different doses, routes, and durations of treat-ent,49,52,53,56-62,69 with �2 test showing an esti-ated RR of edema of 0.4 compared with placebo

P � .0001), indicating that CS administration de-reases the risk of postoperative edema signifi-antly.In oral surgery, the threshold dose value of meth-

lprednisolone is expected to be 0 to 25 mg, abovehich any single dose of methylprednisolone ad-inistered will result in a significant decrease in

dema. This indicates that if a minimum dose isreferable, a preoperative injection into the masse-er muscle of methylprednisolone �25 mg (or anquivalent anti-inflammatory dose of another CS) isffective in decreasing edema.In orthognathic surgery, fewer trials are available,

ut these show a significant decrease of edema whenSs are administered at different doses and durationsf treatment.70,72 It seems plausible that 1 intravenousose of methylprednisolone �85 mg (or an equiva-

ent anti-inflammatory dose of another CS) adminis-ered preoperatively results in a significant decreasen edema, but more research is needed to verify this.nsufficient data on the edema-decreasing effect of CSfter orthognathic surgery did not allow a meta-anal-sis.No trials reported an increased need of analge-

ic treatment postoperatively after CS administra-ion.49,52,53,56,58-63,69 This shows that CS administra-ion does not suppress the �-endorphin level andhereby increase the patient’s perception of pain.8

Several trials reported significantly decreaseddema and analgesia,49,52,56,59,60,62 indicating a strongorrelation between edema and pain decreases. How-ver, Pedersen,69 Skjelbred and Løkken,53 Buyukkurtt al,61 and Milles et al58 found a significant decreasen edema but no significant decrease in pain con-ected to the low dose58,61,69 and/or postoperativedministration timing.53,69 Neupert et al63 found noignificant decrease in edema but a significant de-rease in pain. A �2 test showed that the estimatedR of analgesia with CS is 2.9 compared with placeboP � .0001), indicating that CS administration de-reases the risk of postoperative pain significantly.Human trials on CS and neuroregeneration indi-

ated that CS promotes neuroregeneration.12,13,78

owever, there is no accepted conclusion on whathould be the administered dose or the onset anduration of treatment to support the conclusions pre-ented.

In their animal study, Galloway et al79 concludedhat a primary neuroregeneration effect was not sta-
istically significant. Further clinical trials are needed. w
Although rare, long-term adrenal suppression seemso take place unpredictably with doses of methylpred-isolone �4 mg (above physiologic levels)25,26 for

onger than 5 days27-29 and when the treatment dura-ion is longer than 1 to 2 weeks, regardless of theose.30 Female gender40 and a history of psychoticehavior41 were found to increase the risk of steroid-

nduced psychosis. This was, however, not well-doc-mented in the literature, and other researchers dis-gree.14 There seems to be a connection between anncreased risk and a dose of prednisolone �40 mg/ay,14,42,43 especially when using a CS with a longalf-life.44 Further clinical trials are needed.Avascular osteonecrosis seems to occur more fre-

uently with high dosages.17-20 Doses of dexametha-one �16 mg/day21 and methylprednisolone �1,830g within 30 hours22,23 are expected to increase the

isk. A retrospective study of 2,773 patients treatedith high-dose, short-duration CS administration con-

luded that none of the patients developed avascularsteonecrosis in the subsequent 1 to 5 years.78 There-ore, it seems that there is a minimally increased riskhen administering high-dose CS over a short period.ther predisposing factors such as smoking, alcoholonsumption, and hard physical labor are alsohought to increase the risk.24 Further clinical trialsre needed.

Regarding increased infection rates, in oral surgery, mostrials reported infection rates49,52,53,57-60,63,69 and only 160

ound an increased risk. A �2 test showed an esti-ated RR of 1.0041 for CS compared with placebo,

ndicating a slightly higher but nonsignificant risk ofnfection (P � .89) and that the administration of CSid not increase the risk of infection significantly.ence, there is no significantly increased risk of in-

ection and the use of prophylactic antibiotics shouldot be administered, unless other indications areresent.The fear of CSs causing decreased healing has shown to

e less plausible, because none of the available trials re-orted any signs of this.2,3,49,52,53,57-59,63,69

Some factors present in this study might be per-eived by others as problematic. With respect to theeview, the division of the available articles on edemand pain into only 2 categories, those with and thoseithout significant decreases in edema and/or pain,akes this study less sensitive to gradual changes

ecause even the slightest decrease in edema will beegistered in the same way as a substantial decrease.owever, the aim of this study was to evaluatehether any decrease in edema and pain was present,ot to determine the degree of edema and/or pain.The lack of differentiation between the methods

sed to evaluate edema and pain (in the respectivelinical trials) also makes this study less sensitive. This
as considered; however, all selected trials were sig-

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ificant with regard to their respective studies andere compared in this regard.With regard to the meta-analysis, edema is believed

o be greater in the mandible, and the comparison oftudies including only mandibular or maxillary andandibular M3 surgical extractions could be viewed

s a potential bias. However, because maxillary andandibular extractions were done bilaterally and in a

ouble-blind manner (including the upper and loweraws on the same side during the same operation),his was considered to be of lesser importance.

Regarding the evaluation of edema, 4 stud-es52,53,56,57 used a mechanical device/facebow, 1tudy59 used a facial plethysmograph, and 1 study58

sed an observer to grade the facial edema. Using anbserver was less precise than the other 2 methods,ut acceptable, because it was the same observerho graded all edemas.With respect to analgesia, postoperative pain was

valuated in 3 different ways; 3 studies52,53,59 used aisual analog scale, 1 study56 used number of tabletsmedication diary), and 1 study63 let the patienthoose the least painful side. We chose these 3 dif-erent ways to quantify postoperative pain as theame.

Whether these findings can be extrapolated tother surgical fields, such as apicoectomy, implantentistry, treatment of odontogenic pathologic condi-ions, and traumatic fractures, is difficult to concluderom this review. It seems plausible that if an inflam-atory reaction is present and thus edema and pain

re expected, the administration of a CS preopera-ively would be expected to decrease edema andain, thereby causing fewer postoperative complica-ions.

In conclusion, these findings suggest that CS admin-stered in combination with oral surgery producesignificant decreases in edema and pain (P � .0001or both comparisons).

A nonsignificant (P � .8937) increased infectionate (RR, 1.0041) after CS administration comparedith placebo shows that antibiotic prophylaxis in

ombination with a CS is not indicated unless otherndications are present.

A minimal risk of developing temporary adrenaluppression is present because of the administrationf a CS in the dose required for oral surgery (preop-rative injection in the masseter muscle of methyl-rednisolone �25 mg or equivalent drug). Thus far,here is no evidence of other side effects, but furtheresearch is needed to verify this.

In orthognathic surgery, it seems a preoperativentravenous dose of methylprednisolone �85 mg orn equivalent drug results in decreased edema, buthis needs further research. Most trials showed that
Ss contribute to neuroregeneration, but further stud-
es are needed. An elevated risk for the developmentf avascular necrosis, steroid-induced psychosis, anddrenal suppression is present with the higher dosageequired for orthognathic surgery advised in this anal-sis.The present findings suggest that the administra-

ion of CSs in oral surgery decreases edema and painignificantly, with no higher risk of infection and withinimum risk of other side effects.

cknowledgment

The authors thank Thomas Alexander Gerds, Associate ProfessorDepartment of Biostatistics, University of Copenhagen, Copenha-en, Denmark), for the statistical analysis performed.

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