Dexamethasone for the Prevention of Recurrent Laryngeal Nerve Palsy After Thyroid Surgery

8/12/2019 Dexamethasone for the Prevention of Recurrent Laryngeal Nerve Palsy After Thyroid Surgery

1/8

ORIGINAL ARTICLE

Dexamethasone for the Prevention of RecurrentLaryngeal Nerve Palsy and Other ComplicationsAfter Thyroid Surgery

A Randomized Double-Blind Placebo-Controlled Trial

Mario Schietroma, MD; Emanuela Marina Cecilia, MD; Francesco Carlei, MD; Federico Sista, MD;Giuseppe De Santis, MD; Laura Lancione, MD; Gianfranco Amicucci, MD

Importance : Recurrent laryngealnerve dysfunction andhypoparathyroidism are well-recognized, importantcom-plications of thyroid surgery. The duration of convales-cence after noncomplicated thyroid operation may de-pend on several factors, of which pain andfatigue are themost important. Nausea and vomiting occur mainly on

theday of operation. Glucocorticoids arewell known fortheir analgesic , ant i- inf lammatory, immune-modulating andantiemetic effects. However, there is littleinformation in the literature on theuse of steroids in thy-roid surgery, andthe information that is available is con-flicting.

Objective : To investigate whether preoperative dexa-methasone could improve surgical outcome in patientsundergoing thyroid surgery.

Design : A randomized double-blind placebo-controlled trial. A 30-day follow-up for morbidity wasperformed in all cases.

Setting : All patients were hospitalized in a public hos-pital.

Participants : From June 2008 through August 2011,328 patients were randomized to receive either intrave-nous dexamethasone, 8 mg,administered90 minutesbe-fore skin incision, or saline solution (placebo).

Interventions : Intravenous dexamethasone, 8 mg.

Main Outcomes and Measures : The primary endpoints were temporary or permanent recurrent laryn-geal nerve palsy. Transient and definitive hypoparathy-

roidism, pain and fatigue scores, nausea, and the num-ber of vomiting episodes were also registered.Preoperativelyand at several timesduringthe first 24post-operative hours, we measured C-reactive protein, inter-leukin 6, and interleukin 1 levels.

Results : In the dexamethasone group, the rate of tem-porary recurrent laryngeal nerve palsy (4.9%) was sig-nificantly lower compared with theplacebo group (8.4%)(P=.04). Also, postoperative transient biochemical hy-poparathyroidism occurred more frequently in the pla-cebo group (37.0%) than in the dexamethasone group(12.8%). Dexamethasone use significantly reduced post-operative levels of C-reactive protein ( P=.01) and inter-leukin6 andinterleukin1 (P=.02), fatigue ( P=.01),andoverall pain during the first 24 postoperative hours(P=.04), as well as the total analgesic (ketorolac tro-methamine) requirement ( P=.04). Dexamethasone usealso reduced nausea and vomiting on the day of opera-tion ( P=.045).

Conclusions and Relevance : Preoperative adminis-tration of dexamethasone, 8 mg, reduced postoperativetemporary recurrent laryngeal nerve palsy and hypo-parathyroidism rates and reduced pain, fatigue, nausea,and vomitingafter thyroid surgery. However, these datarequire further analysis in randomized prospectivestudies.

Trial Registration : clinicaltrials.gov Identifier:NCT01690806

JAMA Otolaryngol Head Neck Surg. 2013;139(5):471-478

T OTAL THYROIDECTOMY OR thyroidlobectomyhasbeenacceptedas thecurrent sur-gical therapyforbenignandmalignant thyroidal disor-ders, 1-5 but extensive resection might in-crease the risk of postoperative complica-tions. 6,7 Recurrent laryngeal nerve (RLN)dysfunction and hypoparathyroidism are

well-recognized, important complica-tions of thyroid surgery. 8 Complicationrates of thyroidectomy have a varyingrangefor bothRLNinjury(0% to14%)andpermanent hypoparathyroidism (1% to11%). 9 Paralysisof vocal cords maycauseserious phonatory, respiratory, and psy-chological problemsthat limit workingca-pacities and quality of life of the pa-

Author Affiliations:Department of Surgery,University of LAquila, Abruzzo,Italy.

JAMA OTOLARYNGOL HEAD NECK SURG/ VOL 139 (NO. 5), MAY 2013 WWW.JAMAOTO.COM471

2013 American Medical Association. All rights reserved.

wnloaded From: http://archotol.jamanetwork.com/ on 06/15/2013


2/8

tients. 5 Complications especially related to the RLN andparathyroid glands can be prevented with the appropri-ate surgical technique during total thyroidectomy.

The surgical technique is one of the important fac-torsaffecting the outcome of thyroidectomy. 7 In thepast,most surgeons avoided dissections in close proximity tothe RLN to prevent its injury. Recently, endocrine sur-geons consider this unacceptable. The identification andpreservation of the RLN are essential to avoid its in-

jury.10

Meticulous hemostasis and delicate technique arerequired to prevent nerve injury. Once found, the nerve,with all the identified branches, must be followed supe-riorly through the entire course until it enters the lar-ynx. 11 This surgical technique, which requires more dis-sections, mayharm the RLNand parathyroid glands. 7 Infact, recurrent laryngeal nerve palsy (RLNP) may resultfromdirect mechanicaldamagewithout disruption.Thisdisparity between anatomic neural integrity and actualRLN function probably results from trauma to the in-tact nerve. Nerve manipulation during thyroid surgerymaycause neural edema andconsequent dysfunction, re-sulting in anything from neurapraxia to axonotmesis.

The duration of convalescence after noncomplicated

thyroid operationmay dependonseveral factors, ofwhichpain, fatigue, and sociocultural factors are the most im-portant. Pain and fatigue are most intense on the day of operation and the following day. Nausea and vomitingoccur mainlyon the day ofoperation and only rarelycon-tribute to prolonged convalescence.

Glucocorticoids are well known for their analgesic,anti-inflammatory, immune-modulating, and anti-emetic effects, although the mechanism by which glu-cocorticoidsexert their actionis yet tobeclarified. 12 Thereare both experimental and clinical data supporting thenotion that the steroid administration may prevent or re-duce neural edema. 13-15 Patientswith idiopathicfacialpalsyhave shown improved facial nerve function after an em-

pirical course of corticosteroids.16,17

Several random-ized clinical trials in many different major andminor sur-gical procedures have been conducted to examine theeffects of a perioperative single-dose glucocorticoid ad-ministration on surgical outcome. 18 The overall resultson postoperative outcome have either been positive andin favor of glucocorticoid use, with postoperative nau-sea andvomiting and pain outcome parameters most sig-nificantly improved,orshownnodifferencebetween studygroups. 18-21

Regardingtheuseof steroids in thyroid surgery, thereis little information in the literature, and the informa-tion that is available is conflicting. In their book, Lore etal22 have mentioned the benefit of intraoperative ste-

roids in thyroid surgery. Wang et al23

reported a studythat found no statistically significant benefit. We undertook the present studyto investigatewhether

preoperative use of dexamethasone could improve surgi-caloutcome in patients undergoing either total thyroidec-tomy or total lobectomywith routine identificationofRLN.Our primary end points were to evaluate the role of dexa-methasone in preventing or treating postoperative RLNPand in preventing hypoparathyroidism. We also investi-gated the effects of dexamethasone on pain, fatigue, nau-sea, vomiting, and the duration of convalescence.

METHODS

From June 2008 through August 2011, 336 patients were ran-domized. Exclusion criteria were American Society of Anesthe-siologists (ASA) physical class III or IV, age older than 75 years,and pregnancy. Patients were not included if they had chronicpain due to a disease other than thyroid disease; if they had anysigns of renal, hepatic, and immunological disease; if they re-ceivedopioidsor tranquilizers( 1 week of treatmentbeforethy-

roidectomy); if they spoke only a foreign language or had men-tal disorders; or if they had a history of alcohol or drug abuse.Finally,because the developmentof surgicalcomplicationsmightinfluence thechosenoutcome parameters, we decided before thestart of the study to exclude these patients, and the results wereanalyzed according to the protocol. The study protocol was ap-proved by the ethical committee of the Faculty of Medicine of the University of L Aquila, and all patients gave their written in-formed consent to participate in the study.

Patients were followed from the day before the operationand daily during the first postoperative week. The day of op-eration was defined as day 0 and the first day after operationas day 1, the second day after as day 2, and so on.

A 30-dayfollow-up formorbidity wasperformed in allcases.The present study included several contacts between patientsand study observers during the first postoperative 24-hour pe-riod.

Total thyroidectomy or lobectomywas performedby a tech-nique of capsular dissection. The delicate technique was per-formed by seeking, identifying, and exposing the RLN with allbranches and following its coursewith careuntil it enteredlar-ynx. When dissection proceeded to the ligament of Berry area,RLN was identified where it coursed through the ligament orclose to it. Wherea large thyroidmassor substernal goiter wasencountered, RLN was identified and traced from the recur-rent nerve triangle, as advocated by Lore .24 However, specialcare wasnot given to identify superior laryngeal nerves. All theparathyroid glands were identified, if possible.

Allpatients were operated on by 2 surgeons (M.S. and G.A.).All patients received preoperative and postoperative flexible la-ryngoscopic examinationsof thevocalcords. If vocal cord palsywas identified, initial follow-up examinations were performedweekly and then every 3 to 4 weeks thereafter until recovery;the dysfunction was considered permanent if it persisted after6 months. Patients were excluded from the study if they hadpreoperative RLNP or nerves encased by cancer, in whichcasethe nerves were intentionally removed.Postoperatively total se-rum calcium concentrations were obtained at 24, 48, and 72hours (also at 96 and 120 hours in patients with hypocalce-mia). Hypocalcemia was defined as at least 1 serum calciummeasurement below 8.1 mg/dL (reference range, 8.1-10.4 mg/ dL) (to convert to millimoles per liter, multiply by 0.25). Oralcalcium supplementation with or without vitamin D analoguewas given if patients developed symptomatic hypocalcemia orwhen the serum calcium level was less than 8.1 mg/dL. An in-travenous calcium gluconate, 10%, infusion was administered

for significant hypocalcemic symptoms or when oral therapyproved inefficacious. Patients were discharged when the se-rum calcium level was higher than 8.1 mg/dL. Hypocalcemiawas considered permanent if it persisted after 6 months.

All patients received general anesthesia similarly. Preanes-thesia wasaccomplished withatropinesulfate,0.01mg/kg, pluspromethazine hydrochloride, 0.5 mg/kg; induction with so-dium thiopental, 5 mg/kg, and atracurium besylate, 0.5 mg/ kg; and tracheal intubation and assisted ventilation with ni-trogen dioxide and oxygen in a 2:1 ratio. After intubation,anesthesia wasmaintained with oxygenin air, sevoflurane,andremifentanil hydrochloride, 0.25 g/kg/min.





3/8

Amoxicillin-clavulanic acid, 2200 mg, was given at the be-ginning of surgery. In the postoperative anesthesia care unit(PACU), vital signs (blood pressure, pulse, respiration, pulseoximetry, and adequate answering) were monitored every 15minutes by a consultant. Patients were discharged from thePACU when vital signs were normalized. We used a prophy-lactic multimodal analgesic technique for treatment of post-operative pain. Thus, patients received incisional local anes-thetics using15 mL(75mg)of bupivacainehydrochloride, 0.5%.Intravenous ketorolac tromethamine, 30 mg, was adminis-

tered every 6 hours on the first day after operation, and after-wards,on demand. Intravenous ondansetron hydrochloride, 4mg,wasadministered forantiemetic treatment on demand. Painwas registered preoperatively, several times during the first 24postoperative hours, and daily during the first postoperativeweek. Pain was measured on a visual analog scale (VAS) withend points labeled no pain, and worst possible pain, andona verbal rating scale(VRS)(0=no pain; 1= lightpain; 2= mod-erate pain; and 3=severe pain). Moreover, the pain was re-corded at rest (supine position) and during mobilization (su-pine to sitting position) preoperatively and 1, 2, 3, 6, and 24hours after operation (ie, investigator-recorded instant painscores). In addition, the patients themselves registered the pain(VAS and VRS) (self-reported registration). Self-reported reg-istrations were completed the day before operation (at 8 PM),on the day of operation (at 6 hours preoperatively and then at6 hours postoperatively, both the investigator-recorded in-stantpain score andthe patients self-registered pain score wererecorded), and daily until postoperative day 7 at 8 PM. At thesame intervals, patients also rated fatigue on a 10-point ordi-nal scale (1=fit; 10=fatigued). 25 Patients were instructed thatself-reported registrations should coverpainand fatigue withinthe period since the last measurements.

Patients evaluated nausea and vomiting over 2 postopera-tive intervals: 0 through 6 hours and 6 through 24 hours afteroperation. 26 Nausea was rated on a VRS (0=no nausea; 1= mildnausea; 2=moderate nausea; and 3=severe nausea), and thenumber of vomiting episodes were registered (0=no episodes[none]; 1=1 episode [mild]; 2 =2 or 3 episodes [moderate];3= 3 episodes [severe]).

Serialvenous blood samples were taken at 0, 30,60, 90, 120,and 180 minutes, at 12 and 24 hours, and then dailyuntil post-operative day 6. The plasma concentration of C-reactive pro-tein (CRP) was measured using a competitive CRP enzyme-linked immunosorbent assay (ELISA) kit.

Serum concentration of interleukin 1 (IL-1 ) and interleu-kin 6 (IL-6) were measured using a quantitative sandwichELISA kit (R&D System) according to the manufacturers de-scription (ranges: IL-1 , 3.9-250 pg/mL 1; and IL-6, 3.13-300pg/mL 1).Serumsamples (100 L)were dispensedinto thewellsof 96-well microtiter plates, which had been coated with therelevant monoclonal cytokine antibody. After incubation for2 hours at room temperature, unbound proteins were washedaway fromthe wells, to which subsequently an enzyme-linkedantibody was added and directedagainst the relevant cytokinefor another 2 hours at room temperature. After further rinsing

to remove unbound antibody, a substrate solution was addedto each well, and the mixture was incubated for 20 minutes at37 C. The reaction was terminated with the addition of a stopsolution. Adsorption was determined by using an ELISA platereading at 450 nm. Serial dilution of the relevant recombinantcytokine provided the standard curve. Assays were performedon duplicate samples. Samples were diluted appropriately withthe diluent providedin the kit if the levels of neat sampleswerebeyond the linear measuring range.

Patients were randomized by means of a sealed envelopemethod (on the basis of a block-randomized computer-generated list), and the randomization code was kept un-

known to any of the investigators until the study was com-plete. Patients were randomized to receive intravenousdexamethasone, 8 mg (Decadron; Merck Sharp& Dohme), 90-minutes before skin incision,or saline placebo. Thedrug or pla-cebo solution was drawn into a syringe by a nurse not partici-pating in the study and was delivered to the investigator (M.S.)who was outside the medicine room and unaware of the con-tent. The saline and dexamethasone solutions appeared trans-parent and completely identical at the time the syringes weregiven to the investigator. Thus, the patients, the anesthesiolo-

gist, the surgeon, and the study observer were all blinded withrespect to the study group. The study drug was administeredto the patient within 5 minutes after being drawn into the sy-ringes.

For statistical analyses, we used the Mann-Whitney, Fried-man, Fisher exact, 2, Spearman rank correlation coefficientand log-rank tests whenappropriate. Postoperative 24-hour re-sults were specifically analyzed for intergroup differences. Inaddition, postoperative fatigue and pain scores from repeatedassessments at different time points were added together forintergroup comparison (added total painscores and added totalfatigue scores).

Nausea and vomiting scores were evaluated separately forthe 0- through 6-hour period and the 6- through 24-hour pe-riod. From each period, thehighest severity score andthe high-est incidence of nausea and vomiting were used as a measureof nauseaand/or vomiting forthe entire24-hour period. P .05was considered statistically significant. Data are given as me-dian (range) if not stated otherwise.

RESULTS

A total of 328 patients were available for analysis(Table 1 ); 8 patients (4 in each treatment group) wereexcluded from the study. There were 163 patients in thedexamethasone group and 165 in the placebo group(Table 1).

The overall risk of temporary RLNP was 6.7% (22 of 328) and permanent RLNP was 1.2% (4 of 328)

(Table 2 ). The risk of temporary and permanent RLNPinthedexamethasonegroupwas 4.9% (8of163)and 1.2%(2 of 163), respectively. The risk of temporary and per-manent RLNP in theplacebo group was 8.4% (14 of 165)and 1.2% (2 of 165), respectively (Table 2). In the dexa-methasone group, the rate of temporary RLNP was sig-nificantly lower compared with the placebo group(Table2) ( P = .04, Mann-Whitney test), whereas the dif-ference did not reach statistical significancebetween the2 groups for permanent RLNP ( P = .20). Among the 22patients who had temporary RLNP, the recovery timesranged from7 to 41 days (mean, 24.2 days) and from 18to 72 days (mean, 48.6 days) for patients with or with-out preoperative dexamethasone, respectively ( P = .048

Mann-Whitney test). Postoperative transient biochemi-cal hypoparathyroidism occurred more frequently in theplacebo group thanin thedexamethasonegroup (Table2).In the dexamethasone group and placebo group, 21(12.8%)and61 (37%) patients, respectively, requiredoralcalcium carbonate supplementation postoperatively, al-though these patients showed no clinical symptoms of hypocalcemia. This difference was statistically signifi-cant ( P = .045) (Table2).The lowest serum calcium levelwas 7.2 mg/dL in the placebo group vs 7.6 mg/dL in thedexamethasone group. Also, postoperative definitive hy-





4/8

poparathyroidism occurred more frequently in the pla-

cebo group (4 patients [2.4%]) than in the dexametha-sone group (3 patients [1.8%]), but this difference wasnot statistically significant ( P = .97).

Fatigueincreased significantly inboth groups( P .01,Friedman test) ( Figure 1 A). In the dexamethasonegroup, fatigue scores were significantly lower 24 hoursafter operation ( P .01, Mann-Whitney test) andthroughout the postoperative week compared with theplacebo group ( P = .01, Friedman test). The added me-dian total postoperative fatigue scores were 28 (range,10-62) in the dexamethasone group and 39 (range, 16-64) in the placebo group ( P = .01, Mann-Whitney test).

In the dexamethasone group, self-reported VASscoresfor pain were significantly lower on day 1 after operation

compared with the placebo group (Figure 1B) ( P = .04,Mann-Whitney test). The added median total VAS scoresof pain (covering the first postoperative week) were 52(range, 0-251) inthedexamethasonegroupand148 (range,13-406) intheplacebogroup( P .05,Mann-Whitneytest).In both treatment groups, self-reported scores of pain in-creased duringthefirstpostoperative week ( P .01,Fried-man test), but differences between groupsdidnot changesignificantly duringthetest period( P = .12,Friedmantest).

Nine patients in the dexamethasone group and 21 intheplacebo grouprequired 1 ormore supplementarydoses

of ketorolacduring their hospital stay ( P = .10, Fisher ex-act test),with a significantly lower totaldose in thedexa-methasone group ( P = .04,Mann-Whitneytest)(Table 1).Spearman correlation coefficients for the association be-tween the total dose of postoperative supplementary an-algesic during hospital stay and pain (first 24-hour pe-riod) were 0.53 ( P = .01) and 0.58 ( P = .01) for thedexamethasone and placebo groups, respectively. Afterhospitaldischarge, 2 patients in thedexamethasone group

and 9 in the placebo group required supplementary an-algesic (in total, analgesics were taken 18 times by11dif-ferent patients [ P = .08, Fisher exact test]).

During the first 6 postoperative hours, the incidenceand severity of nausea wassignificantly lower ( P = .045,

2 test and Mann-Whitney test) in the dexamethasonegroup, andvomiting wassignificantly reduced during theentire 0 through 24-hour period compared with pla-cebo( P = .045, 2 test andMann-Whitney test).Eight pa-tients in the dexamethasone group vs 21 in the placebogroup received intravenous ondansetron for antiemetictreatment once or multiple times during their hospitalstay (P = .11, Fisher exact test) (Table 1).

SerumCRPlevel increasedsignificantly in both treat-

ment groups during the study period ( P = .01, Fried-man test), but the increase was significantly higher in theplacebo group ( P = .01, Friedman test) (Figure 1C).

Before the operation, serum IL-1 or IL-6 levelswerenot significantlydifferent between the2 groups. Figure 2shows thechronological changes in serumIL-1 andIL-6levelsafter surgery. In theplacebo group, theserumIL-1and IL-6 levelsbegan to significantly increase as early as1 hour from thebeginning of operation, revealinga peakat the sixth hour (approximately 4 hours after opera-tion) and, thereafter, declining to preoperative levels by6 days. However, in the dexamethasone group, the in-crease in the serum IL-1 and IL-6 levels was delayedand the peak values were significantly lower in the pla-

cebo group ( P .05, Friedman test).Noapparent signs ofadverseeffectsof thestudy drugswere observed. Four patients in each group were ex-cluded from the study. In the dexamethasone group, 2patients had preoperative RLNP and 2 patients devel-oped a wound infection. In the placebo group, 2 pa-tients had the RLN encased by cancer and 2 patients de-veloped a wound infection. Thus, 4 patients (2 from eachstudy group) developed postoperative wound infec-tions.

DISCUSSION

The identification, careful exposure, and preservation of the RLN throughout its course are important to preventnerve injury. 11 Theapproach for the identificationof theRLN during surgery on the thyroid gland was describedin some previousstudies. 11,27,28 Although Bergamaschi etal29 reported that the RLN identification failed to reduceinjury rate, there are many studies demonstrating a sig-nificant decrease in the rate of RLN injury maintainedbytheidentification of thenerve. 5-7,27,30 WagnerandSeiler 7reported that in total thyroidectomy the permanent injury rate significantly increased from 3.8% to 7% when

Table 1. Characteristics of Patients in the Dexamethasoneand Placebo Groups

Characteristic

DexamethasoneGroup

(n = 163)

PlaceboGroup

(n = 165)

Sex, No.Male 64 66Female 99 99

Age, mean (range), y 49 (28-67) 46 (25-66)Thyroid disease, No. (%)MNG 99 (10.7) 102 (61.8)Toxic MNG 25 (15.3) 24 (14.5)Graves disease 16 (9.8) 16 (9.6)Papillary carcinoma 12 (7.3) 13 (7.8)Follicular carcinoma 5 (3) 5 (3)Recurrent MNG 6 (3.6) 5 (3)

Types of thyroid surgeryTotal thyroidectomy 125 (76.6) 128 (77.5)Lobectomy 38 (23.3) 37 (22.4)

ASAI 106 104II 57 61

Duration of surgery, mean(range), min

57 (33-102) 56 (35-98)

Total thyroidectomy 71 (50-102) 69 (51-98)Lobectomy 38 (33-61) 36 (35-58)

Stay in hospital, d 2 2Patients requiring ketorolac

tromethamine, No.9a,b 21a

Patients requiring ondansetron,No.

8c 21c

Abbreviations: ASA, American Society of Anesthesiologists; MNG,multinodular goiter.

aP = .10, Fisher exact test.bThere was a significantly lower total dose in the dexamethasone group

(P = .04, Mann-Whitney test).cP = .11, Fisher exact test.





5/8

the nerve wasnot identified. Ma ttiget al 27 demonstrated

that routine preparation of the RLN decreased the per-manent injury rate from 5.99% to 0.88%.Empirically, some surgeons use steroids during thy-

roid operations inanattempt to reducepostoperative neu-ral edema resulting from inevitable nerve manipulationduring identification of RLN, as well as to promote re-covery of nerve function when nerve paralysis occurs.However, there have only been few published data con-cerning the efficacyof preoperativeor intraoperative ste-roid use in the management or prevention of nerve dys-function resulting from operation. Wang et al 23 used a

single intravenous dose of intraoperative corticoste-

roids (100-mg hydrocortisone) and concluded that in-traoperative steroids didnot produce benefit in terms of reducing postoperative temporary and permanentRLNP rates, but it did shorten the recovery time for pa-tients with temporary RLNP. This study was prospec-tive but not randomized. On the contrary, Lore et al22said that the rate of temporary RLNP can be reducedfrom 9% to 2.6% with the use of preoperative or/and in-traoperative steroids. In addition, the use of steroids re-duces the longest duration of temporary vocal cord pa-ralysis from 9 to 2 months.

Table 2. Recurrent Laryngeal Nerve Palsy and Hypoparathyroidism

Variable

Patients, No. (%)

P ValueDexamethasone Group

(n = 163)Placebo Group

(n = 165)Total

(n = 328)

Recurrent laryngeal nerve palsyTransient 8 (4.9) 14 (8.4) 22 (6.7) .04Permanent 2 (1.2) 2 (1.2) 4 (1.2) .20

Hypoparathyroidism

Transient 21 (12.8) 61 (37.0) 82 (25.0) .045Permanent 3 (1.8) 4 (2.4) 7 (2.1) .97

0Preop

10

9

1 0

- P o

i n t

O r d

i n a l

S c a

l e

Days After Operation

3

Placebo

Placebo

Placebo

Dexamethasone

Dexamethasone

Dexamethasone

4

5

6

7

8

2

1

A

1

2 3 4 5 6 7

0Preop

9

P l a s m a

C R P L e v e l

, m g

/ d L

Time After Beginning the Operation

3

4

5

6

7

8

2

1

C

1 h 2 h 3 h 4 h 5 h 6 h 24 h 2 d 3 d 6 d 12 d

0Preop

35

V i s u a l

A n a l o g u e

S c a

l e

Days After Operation

15

20

25

30

10

5

B

1 2 3 4 5 6 7

Figure 1. Changes in fatigue and overall pain scores and serum C-reactive protein (CRP) levels. A, Changes in fatigue scores (10-point ordinal scale: 1 = fit,4 = slightly tired, 7 = tired, and 10 = fatigued) in patients receiving placebo or dexamethasone. Patients who received dexamethasone were significantly lessfatigued on postoperative day 1 (* P .01). B, Changes in overall pain scores (visual analog scale) in patients receiving placebo or dexamethasone. Patients whoreceived dexamethasone experienced significantly less overall pain on postoperative day 1(* P .05). C, Changes in serum CRP levels in patients receivingplacebo or dexamethasone. The increase in CRP level was significantly higher in the placebo group (* P = .01). Preop indicates preoperation. For CRP, to convertmilligrams per deciliter to nanomoles per liter, multiply by 95.24.





6/8


7/8

Kehlet 18 provide a comprehensive review of these trialsand endorse the use of a single-dose preoperative ste-roid. As an immune modulation strategy, such therapyappears to shift the balance of inflammation in favor of anti-inflammatorymediators in a variety of surgical pro-cedures. Some aspects of cardiac 41 and pulmonary func-tion 42 have been shown to improve, but usually in smallstudies with insufficient statistical power to detect reli-able clinical differences. Trials aimed at evaluating ad-

verse effects of preoperativesingle-dose steroids have alsobeen inconclusive becauseof size and design. When con-sidered together, however, it appears that this therapy(dexamethasone, 8 mg) is safe; it particularly does notincrease complications one might expect, such as infec-tions and impaired wound healing. A recent meta-analysis 43 concluded thatperioperative administrationof high-dosemethylprednisolone (30-35mg/kg), a dose ap-proximately 50 times thedose used in our study, was notassociated with significant adverse effects. In our study,we found no apparent adverse effects or complicationscaused by dexamethasone treatment because only 2 pa-tients in each surgical group developed a postoperativewound infection. It also appears that the timing of ste-

roid administration is important (1-2 hours preopera-tively) if excess inflammatoryactivationsand relatedpost-operative morbidity are to be attenuated.

The analgesic effect of glucocorticoid is provided byinhibiting phospholipase enzymes and, accordingly,blocking both the cyclooxygenase and the lipoxygenasepathway in the inflammatory chain reaction, 12 as well assuppressing tissuelevelsofbradykinin 44 andreleasing neu-ropeptides from nerve endings, 45 both of which may en-hance nociception in inflamed tissue and the surgicalwound. In the present study, dexamethasone reducedpain. Our results are in accordance with the analgesiceffect of dexamethasone, 8 mg, in patients undergoinggynecologic operation 46 and dental extractions. 47 Inare-

cent review18

regardingtheeffects of perioperative single-dose glucocorticoid administration, randomized trialsfrom several minor and major surgical procedures wereanalyzed. 18 The authors concluded that glucocorticoidadministration in major abdominal surgery probably hasno or limited analgesic effect, but may have an analgesiceffect in minor surgical procedures, and that glucocor-ticoid administration definitely has an analgesic effect indental surgery. 18

The incidence andseverityof postoperative nausea andvomiting have been significantly decreased by preopera-tive single-dose steroid administration in several stud-ies.19 This canbeexplainedbya central antiemetic mecha-nism involving endogenous prostaglandin and opioid

production.19

In a recent meta-analysis of 17 randomizedclinical trials, a single dose of dexamethasone in combi-nation with 5-HT 3 receptor antagonists significantly re-duced postoperative nauseaand vomitingcompared withplacebo, but the optimal dose of this combination needstobe identified. 19 Furthermore, therole ofconcomitant useof 5-HT3 receptor antagonist remains to be clarified. 20,48-50

In the present study, intravenous dexamethasone wasadministered 90 minutes before skin incision. Glucocor-ticoidsbindto the intracellular glucocorticoid receptor,andeffects arepredominantly mediated throughanalteredpro-

tein synthesis via gene transcription. 51 Therefore, the on-set of biological action is generally 1 to 2 hours, depend-ing on the route of administration. 12 Unfortunately, moststudieshaveadministeredglucocorticoids immediatelybe-fore induction of anesthesia, 18 includingtheother trials inpatientsundergoing laparoscopiccholecystectomy. 48-50 Be-cause activations of the early mediators of the metabolicresponse to surgery occur immediately after the surgicalincision,administration ofglucocorticoids1 to2 hourspre-

operatively may be important to achieve the full postop-erative benefit of the treatment. 52In conclusion, we demonstrated that a single dose of

preoperative dexamethasone (administered 90 minutesbefore skin incision) was effective in preventing tempo-rary RLNP during thyroid operation and in reducing theduration of temporary RLNP. This is especially impor-tant for the patients with locally advanced cancer, pa-tients with Graves disease, and patients undergoing re-operation in which the incidence of RLNP may be tripleor more. 7,53-57 Also postoperative transient biochemicalhypoparathyroidism occurred less frequently with pre-operative single-dose dexamethasone.

Moreover, dexamethasone improved surgicaloutcome

after thyroid surgery in terms of significantly less pain, fa-tigue,nausea, andvomiting, andpatientsresumed their rec-reationalactivity significantly fastercomparedwith thepla-cebogroup.Thissimpletherapy,in theabsence ofincreasedmorbidity from thesingledoseofsteroids,warrantsbroaderapplication in thyroid surgery.

Submitted for Publication: April 20, 2012; final revi-sion received July 17, 2012; acceptedFebruary14, 2013.Correspondence: Mario Schietroma,MD, Universit de-gli Studi di LAquila, Facolt di Medicina e Chirurgia,Dipartimento di Scienze Chirurgiche, Presso OspedaleS. Salvatore, Edificio Delta 6, 67100 Coppito (AQ), Italy([email protected]).Author Contributions: Dr Schietroma had full access toall the data in the study and takes responsibility for theintegrity of the data and the accuracy of the data analy-sis. Study concept and design: Carlei. Acquisition of data:Cecilia, Sista, De Santis, and Lancione. Analysis and in-terpretation of data: Schietroma and Amicucci. Draftingof the manuscript: Cecilia, Sista, De Santis, and Lanci-one. Critical revision of the manuscript for important in-tellectual content: Schietroma, Carlei, and Amicucci. Sta-tistical analysis: De Santis and Lancione. Administrative,technical, and material support: Schietroma, Cecilia,Car-lei, Sista, and Amicucci.Conflict of Interest Disclosures: None reported.

REFERENCES

1. Bron LP, O BrienCJ. Totalthyroidectomy for clinically benign disease of the thy-roid gland. Br J Surg . 2004;91(5):569-574.

2. Dener C. Complication rates after operations for benign thyroid disease. Acta Otolaryngol . 2002;122(6):679-683.

3. Erog luA, Unal M, Kocaog lu H. Totalthyroidectomyfor differentiated thyroid car-cinoma: primary and secondary operations. Eur J Surg Oncol . 1998;24(4):283-287.

4. RosatoL, AveniaN, Bernante P,et al.Complicationsof thyroid surgery: analysisof a multicentricstudy on 14,934 patientsoperated on in Italy over5 years.World J Surg . 2004;28(3):271-276.





8/8

5. Sturniolo G, D Alia C, Tonante A, Gagliano E, Taranto F, Lo Schiavo MG. The re-current laryngeal nerve related to thyroid surgery. Am J Surg . 1999;177(6):485-488.

6. Thomusch O, Sekulla C, Dralle H. Is primary total thyroidectomy justified in be-nign multinodular goiter? results of a prospective quality assurance study of 45hospitals offering different levels of care [in German]. Chirurg . 2003;74(5):437-443.

7. Wagner HE,Seiler C. Recurrentlaryngeal nerve palsy afterthyroidgland surgery.Br J Surg . 1994;81(2):226-228.

8. McHenry CR. Patient volumes and complications in thyroid surgery. Br J Surg .2002;89(7):821-823.

9. Harness JK, Fung L, Thompson NW, Burney RE, McLeod MK. Total thyroidec-tomy: complications and technique. World J Surg . 1986;10(5):781-786.

10. Hisham AN, Lukman MR. Recurrent laryngeal nerve in thyroid surgery: a criticalappraisal. ANZ J Surg . 2002;72(12):887-889.

11. Ardito G, Revelli L, D Alatri L, Lerro V, Guidi ML, Ardito F. Revisited anatomy ofthe recurrent laryngeal nerves. Am J Surg . 2004;187(2):249-253.

12. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stressresponses? integrating permissive, suppressive, stimulatory, and preparativeactions. Endocr Rev . 2000;21(1):55-89.

13. Jones KJ, Drengler SM, Oblinger MM. Gonadal steroid regulation of growth-associated protein GAP-43 mRNA expression in axotomized hamster facial mo-tor neurons. Neurochem Res . 1997;22(11):1367-1374.

14. Bansberg SF, McCaffrey TV. The effect of systemic triamcinolone acetonide onnerve repair. Otolaryngol Head Neck Surg . 1987;96(2):158-164.

15. Lipton R, McCaffrey TV, Ellis J. The beneficial effect of triamcinolone acetonideon nerve repair with autogenous grafts. Otolaryngol Head Neck Surg . 1986;94(3):310-315.

16. Stankiewicz JA. A review of the published data on steroids and idiopathic facialparalysis. Otolaryngol Head Neck Surg . 1987;97(5):481-486.

17. Austin JR, Peskind SP, Austin SG, Rice DH. Idiopathic facial nerve paralysis: arandomized double blind controlled study of placebo versus prednisone.Laryngoscope . 1993;103(12):1326-1333.

18. Holte K, Kehlet H. Perioperative single-doseglucocorticoidadministration:patho-physiologic effects and clinical implications. J Am Coll Surg . 2002;195(5):694-712.

19. Henzi I, Walder B, Tramr MR. Dexamethasone for the prevention of postopera-tive nausea and vomiting: a quantitative systematic review. Anesth Analg . 2000;90(1):186-194.

20. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Granisetron/dexamethasone combina-tion for the prevention of postoperative nausea and vomiting after laparoscopiccholecystectomy. Eur J Anaesthesiol . 2000;17(1):64-68.

21. Schietroma M, Giuliani M, Zoccali G, et al. How does dexamethasone influencesurgicaloutcome after laparoscopicNissenfundoplication? a randomized double-blind placebo-controlled trial. Updates Surg . 2010;62(1):47-54.

22. Lore JM Jr, Farrell M, Castillo MB, . Endocrine surgery. In: LorJM Jr, MedinaJE, eds. An Atlas of Head and Neck Surgery. 4th ed. Philadelphia, PA: Elsevier;2005:963-965.

23. Wang LF, Lee KW, Kuo WR, Wu CW, Lu SP, Chiang FY. The efficacy of intraop-erative corticosteroids in recurrent laryngeal nerve palsy after thyroid surgery.World J Surg . 2006;30(3):299-303.

24. Lore JM Jr. Practical anatomical considerations in thyroid tumor surgery. Arch Otolaryngol . 1983;109(9):568-574.

25. ChristensenT, Stage JG,Galbo H, Christensen NJ,Kehlet H. Fatigue andcardiacand endocrinemetabolic response to exercise afterabdominal surgery. Surgery .1989;105(1):46-50.

26. Greif R, Laciny S, Rapf B, Hickle RS, Sessler DI. Supplemental oxygen reducesthe incidence of postoperative nausea and vomiting. Anesthesiology . 1999;91(5):1246-1252.

27. Ma ttig H, Bildat D, Metzger B. Reducing the rate of recurrent nerve paralysis byroutine exposure of the nerves in thyroid gland operations [in German]. Zen- tralbl Chir . 1998;123(1):17-20.

28. Pimpl W, RiegerR, Waclawiczek HW,MeiserG, Zukriegel M, BoecklO. Techniqueof recurrent laryngeal nerve exposure within the scope of interventions of the thy-roid gland [in German]. Wien Klin Wochenschr . 1992;104(15):439-442.

29. BergamaschiR, BecouarnG, Ronceray J, Arnaud JP.Morbidityof thyroidsurgery.Am J Surg . 1998;176(1):71-75.

30. Hermann M, Alk G, Roka R, Glaser K, Freissmuth M. Laryngeal recurrent nerveinjury in surgery for benign thyroid diseases: effect of nerve dissection and im-pact of individual surgeon in more than 27,000 nerves at risk. Ann Surg . 2002;235(2):261-268.

31. Vittimberga FJ Jr, Foley DP, Meyers WC, Callery MP. Laparoscopic surgery andthe systemic immune response. Ann Surg . 1998;227(3):326-334.

32. Mayers I, Johnson D. The nonspecific inflammatory response to injury. Can J Anaesth . 1998;45(9):871-879.

33. GuptaA, WatsonDI. Effectof laparoscopy onimmune function.BrJ Surg . 2001;88(10):1296-1306.

34. Cruickshank AM, Fraser WD, Burns HJ, Van Damme J, Shenkin A. Response ofserum interleukin-6 in patients undergoing elective surgery of varying severity.Clin Sci (Lond) . 1990;79(2):161-165.

35. Perlmutter DH, Dinarello CA, Punsal PI, Colten HR. Cachectin/tumor necrosisfactor regulates hepatic acute-phase gene expression. J Clin Invest . 1986;78(5):1349-1354.

36. Sakamoto K, Arakawa H, Mita S, et al. Elevation of circulating interleukin 6 aftersurgery: factors influencing the serum level. Cytokine . 1994;6(2):181-186.

37. Ohzato H, Yoshizaki K, Nishimoto N, et al. Interleukin-6 as a new indicator ofinflammatory status: detection of serum levels of interleukin-6 and C-reactiveprotein after surgery. Surgery . 1992;111(2):201-209.

38. Spa th-Schwalbe E, Hansen K, Schmidt F, et al. Acute effects of recombinant hu-man interleukin-6 on endocrine and central nervous sleep functions in healthymen. J Clin Endocrinol Metab . 1998;83(5):1573-1579.

39. Nagelschmidt M, Fu ZX, Saad S, Dimmeler S, Neugebauer E. Preoperative highdose methylprednisolone improves patients outcome after abdominal surgery.Eur J Surg . 1999;165(10):971-978.

40. Schulze S, Andersen J, Overgaard H, et al. Effect of prednisolone on the sys-temic response and wound healing after colonic surgery. Arch Surg . 1997;132(2):129-135.

41. Yared JP, Starr NJ, Torres FK, et al. Effects of single dose, postinduction dexa-methasone on recovery after cardiac surgery. Ann Thorac Surg . 2000;69(5):1420-1424.

42. Bigler D, Jonsson T, Olsen J, Brene J, Sander-Jensen K. The effect of preop-

erativemethylprednisoloneon pulmonary functionand painafterlung operations.J Thorac Cardiovasc Surg . 1996;112(1):142-145.43. Sauerland S, Nagelschmidt M, Mallmann P, Neugebauer EA. Risks and benefits

of preoperative high dose methylprednisolone in surgical patients: a systematicreview. Drug Saf . 2000;23(5):449-461.

44. Hargreaves KM, Costello A. Glucocorticoids suppress levels of immunoreactivebradykinin in inflamed tissue as evaluated by microdialysis probes. Clin Phar- macol Ther . 1990;48(2):168-178.

45. HongD, ByersMR, Oswald RJ.Dexamethasonetreatmentreduces sensory neu-ropeptides and nerve sprouting reactions in injured teeth. Pain . 1993;55(2):171-181.

46. McKenzie R, TantisiraB, Karambelkar DJ, Riley TJ, AbdelhadyH. Comparisonofondansetron with ondansetron plus dexamethasone in the prevention of post-operative nausea and vomiting. Anesth Analg . 1994;79(5):961-964.

47. Baxendale BR, Vater M, Lavery KM. Dexamethasone reduces pain and swellingfollowing extraction of third molar teeth. Anaesthesia . 1993;48(11):961-964.

48. Coloma M, White PF, Markowitz SD, et al. Dexamethasone in combination with

dolasetron forprophylaxis inthe ambulatory setting:effecton outcomeafter lapa-roscopic cholecystectomy. Anesthesiology . 2002;96(6):1346-1350.

49. Wang JJ, Ho ST, Liu YH, et al. Dexamethasone reduces nausea and vomitingafter laparoscopic cholecystectomy. Br J Anaesth . 1999;83(5):772-775.

50. Wang JJ, Ho ST, Uen YH, et al. Small-dose dexamethasone reduces nausea andvomiting after laparoscopic cholecystectomy: a comparison of tropisetron withsaline. Anesth Analg . 2002;95(1):229-232.

51. Donnelly LE, Newton R, Kennedy GE, et al. Anti-inflammatory effects of resve-ratrol in lungepithelialcells: molecularmechanisms.AmJ Physiol Lung Cell Mol Physiol . 2004;287(4):L774-L783.

52. Wang JJ, Ho ST, Tzeng JI, Tang CS. The effect of timing of dexamethasone ad-ministration on its efficacy as a prophylactic antiemetic for postoperative nau-sea and vomiting. Anesth Analg . 2000;91(1):136-139.

53. Chiang FY, Wang LF, Huang YF, Lee KW, Kuo WR. Recurrent laryngeal nervepalsy after thyroidectomy with routine identification of the recurrent laryngealnerve. Surgery . 2005;137(3):342-347.

54. Razack MS, Lore JM Jr, Lippes HA, Schaefer DP, Rassael H. Total thyroidec-tomy for Graves disease. Head Neck . 1997;19(5):378-383.

55. Agarwal A, Mishra SK. Role of surgery in the management of Graves disease.J Indian Med Assoc . 2001;99(5):252, 254-256.

56. Steurer M, Passler C, Denk DM, Schneider B, Niederle B, Bigenzahn W. Advan-tages of recurrent laryngeal nerve identification in thyroidectomy and parathy-roidectomy and the importance of preoperative and postoperative laryngo-scopic examination in more than 1000 nerves at risk. Laryngoscope . 2002;112(1):124-133.

57. Flynn MB, Lyons KJ, Tarter JW, Ragsdale TL. Local complications after surgicalresection for thyroid carcinoma. Am J Surg . 1994;168(5):404-407.



Documents

Dexamethasone for the Prevention of Recurrent Laryngeal Nerve Palsy After Thyroid Surgery