CLINICAL GASTROENTEROLOGY

Flu1llazenil, a benzodiazepine receptor antagonist, in the

reversal of conscious sedation following gastroscopy. A placebo

controlled, dose finding study

Ll.()\PSLJ"lllr:RI :\NI \ Ml), NOH H ER~llllf'LL\ t,.ll), El IX)N Si iAILI R, MD,

LORN!· PR!t 'I:, M l ), Dr ANNI· DEAN, r, ID, M •\RtiA IU· r Lit ol IT, r, fl)

L SUTHERLAND, N HERSHFIELD, E SHAFFER, L PRICE, D DEAN, M LIGHT. Flumazenil, a benzodiazepinc receptor antagonist, in the reversal of conscious sedation following gastroscopy. A placebo controlled, dose finding study. Can J Gastrocnterol 1991;5(6):209-213. Tim Jouble-blind, placebo controlled, ,tuJy assessed the efficacy and safety of flumazenil, a benzoJiazcpine anrngonist, m reversmg diazepam-induced sedation in 60 patients undergoing endoscopy. Patients were randomly assigned tu nne of six treatment groups (placebo, S, l 0, 15, 20 or 25 µg/kg flumazenil) . Patient psychomotor function was determined using four standard assessments - Trieger, digit substitution, track tracing and canccllaunn tests. Fluma:cni l was well tolerated by all patients. A ll doses of tluma:cnil were superior co placebo in revcr ing sedation . No significant differen­ces were detected het ween the various treatment groups. Forty-five minutes after the flummenil infusion, there were no differences hctween flumazenil- and placebo-treated patients in p:,ychomotor function. Flumazcntl is a safe, effective meJ1car1nn which reverses d iazcpam-induccd comcious sedation . For most patients 0. 5 mg given intrnvenou~ly will reverse sedation. (Pour resume tioir /)age 210)

Key Words: Clinical trial, Diaze/)am, Flumazenil, Placebo controlled, Randomized ,rudy

Divmon oJ Cct1troe11t.:rology , Foor/11/Ls 110.1/nwl, l 'nM 'l'r.1,ry of C:al!{ary, ( ' 11l!{11ry , Alhl'rlll; ~nil Hoffmmm-1..lt lfoclw Lunitd, M1ss1ssw1~11. Onrarro

Com!1Jxmdenc.: mul r..:fmn11 Dr LR Swlt,·rland. H,um1 175 1, {3 ~O Hos/mal Dm·, NW/, Calliary, Al/,._,rra T2N 4NI. Tdl'p/wnl' (403) 220-4'i0Q, Fa:>. (403) 283-47·W

This /1<1f>e1· wa, />re,!'nred 111 /)(lrt ,H rite lnwrnauonal Svm/mmm1 on Flwna~.:nil in (;ene1•a, Sw1rzerlond

Recend Jin /mhlrrnuon }tme I ~, 1991 A,wf>t.:d Nowmh..:r 21 , 199 /

T ill L~I- ,)! t;A~TROINTESIINAL

L'ndosc\lpy ha, rcvoluu1m1zed the inve.,tigmion ,md treatment tl pa11ents with g,Mmmte,unal d"l'a,c. S1gn 1ftc­ant 1mprnvcmcnts 111 1 hl· design and flexihilit y ofthl' inst ruments have im­pmvl'd patient .1cccpt,111cc; however, most p,Htcnts, \\'hen 11!kred the oppor­run n y, choo~l' consc11>us sl.'dat ion when undcrgrnng endo,cnptc procedures ( 1,2).

Dia:.:cpam ha~ long hcen comitk·rcd en he t hi: drug of choice tor pal ients undergumg i:ndoscopy (3 ). It has a proven record of ,afcry and efficacy hut its usl' i, co111pl1catcd hy thromho­phlchitis (4). RL'ccntly, a water soluhle bcn:od1a:epine, miJazolam , was mtro­duccd (5-7). Because of its wa te r so lubility, midarnlam has been as­

sociated with less thromhophlchni,. Its amnesic potenual appems 10 he heller than diazcpam (8,9). Another altcrna­uvc ts Dia:cmuls (Pharmacia) which conuuns diazcpam in a lipid snluuon.

A I though both drugs arc ,ate, w dace thcri: ha, been no readily avatlahle

209

SllTIIERLAND et al

Le flumazenil, antagoniste des recepteurs des benzodiazepines, clans }'interruption d'une sedation consciente apres gastros, copie. Etude controlee contre placebo visant a determiner la posologie

RESUME: La presence etude a double insu controlee contre placebo visait a determiner l'efficacitc et l'innoc uite Ju flumazenil, ancagoniste Jes benzodiazepines, utilise pour imerrompre la sedatio n induitc par le dinzepam chez 60 patients subissant une endoscopic. Le:; patients onr ete repartis au hasard pmmi six groupcs Jc rraitement (5, 10, 15, 20, 25 µ g/kg de flumazenil ou placebo). La fonction psychomotrice a ete evaluee a !'aide de quatre examens standard (epreuve <le Trieger, tests Je substi tution de chiffres, de trace et de barrage). Le medicament a ete bien tolere par tousles patients. Toutes les doses de flumazcnil ont donne des resultats superieurs au placebo. Aucune difference significative n'a ete Jecelee parmi les divers groupes traires. Quarante-cinq minutes apres la perfusion de flumazenil, on n'a mJte aucune difference Jans la function psychomotrice entre les groupes de patients ayant re~u du flumazeni l er les sujets temoins. Le flumazenil est un medicament sGr et efficace, qui annule la sedation consciente induite par le diazepam. Oaru; la plupan Jes cas, ii suffit d'adminisrrer 0,5 mg par voie intraveineuse pour obtenir ce resultat.

revt:r~al agent for hen:()diazepines. Such a medication would have a variety of uses: it could he used 10 reverse seda­tion in patients who have received an excessive amount ol bcnzndiazepinc during a procedure; it could be given to

panents who dn not wish t\l remain in the recovery room until the sedat ion gradua lly wears off; and at could be used in the treatment of intentional henzo­J iazepinc overdose.

Diazepam and midmolam, as with the other benzodiazepines, act through enhancement of transm ission at the C,AHA inergic synapses 111 the central nervous system. This in teract ion at the GABA receptor affects the chloride channel resulting in sedation and am­nesia ( 10) . Flumazenil b a water soluble imidazohenzodiazcpine which c;rn nn­tagon i ze the sedm i ve effects nf bcnzn­d I aze pines through co mpetiti ve binding to the henzodia:epine receptor ( L L,I 2). lt has a scrum mean half- life nf 54 m1m. Recent reports h,1vc suggested that it is effect ive in reversing sedation induced for minor surgical procedures ( l 3- 16) and in the treatment of acute overdoses ( 17). Early studies suggested that a broad range of doses up to IO mg were required to effectively compete with the henzodiazepine receprnr.

The presenc study as;,essed the effec­tiveness of Oumazenil vi,1 a do uble­hlind, placebo controlled , do~e find ing

study in patients undergoing routine upper intestinal endoscopy.

PATIENTS AND METHODS Sixty patients wh\) were scheduled

to undergo gastroscopy for investiga­tion of various gastrointestinal symp­toms were randomly ass igned to one of six groups (placebo, 5, 10, 15, 20 or 25 µ g/kg flumazenil). A log was not kept of patients who refused to participate in the study. To ensure uniformity, a ll pat ients were between 18 and 60 yearl! nlJ, within 15% of ideal body weight ( 1983 Metropolitan Tables of l lcight and Weight), and were not ingesting any chronic medication (particularly H2 antagonists or hcnzodiazepines). Women of childbeari ng potential had to be using an effective means of con­trnceprion (mal contraceptives or an intraute rine device). A ll patients were in Ame ri can Soc iety of Anesthe­siologists class l or ll [181. Patients with a history of chronic illness or chemical dependency were excluded. The protocol was reviewed by the Conjoint Ethics Committee of the University of Calgary, Alberta.

Prior to endoscopy and as part of the routine ph,1rmacological safety evalua­tion, patients underwent routine labor­a1my assessment as well as ECG and che,t x-ray. Immediately hefore endos­copy the patients performed four swnd-

ard psychomotorfLmctton rests (Trieger [ 191, digit symbol suhst itutinn 1201, track tracing J 21 I and cancel larion rests [21 ]) to assess their ah ility to perform simple tasks with pencil and paper under the wpervision nf the study nurse. No premedicants were given. Patients were taken tu the endoscopy suite where the throm was anestheuzed with xylocaine J 1Xi spray. Diazepam (0.15 mg/kg) was giwn intrnvcnously to produce the desired sedative effect (relaxed, rcspomive to comm;rnJs, somewhat somnolent wnh nysragmus). If required, additional diazepam (up to 0.15 mg/kg) was given.

At the conclusion nf the endnscopy and l 5 mins after d iazepam, the 1esL medication (Oumazeni l or placebo) was infused over 2 mins. Five minutes after the test medication was given, rhl' psy­chomotor cvaluariom, were repeated, and were continued every LO mms unttl 90 mins after the injection.

Prior to d ischarge pat ients com­pleted a hrief questillnna ire regarding the ir recall and assessment uf the endo­scopy. Two to three days after rhe pro­cedure the patients returned for repeat laboratory assessment including ECG. Adverse events were reC()rded hy the study n urse at the time of endoscop\ and at the patient interview during the repeat visit. Statistical methods: Descriptive vari­ables were ana lyzed usingcmnparison of means and standard deviation. Psych,>­metric measures recorded during the tria l were analyzed using repeated measu res analysis of varia nce and analysis of covariance with t reatment group as the cofactors. Categorical out· come measures were ana lyzed using Pearson x2 tests to dctermme differen­ces between the treatment groups, as well as McNemar's x2 Lo determine dif­ferences between treatment visits.

RESULTS Sixty patients (3 1 males and 29

females) parucipated in the study with l O patients randomly assigned to each treatment group. Patients were enrolled over a 15 m,mrh pcriud from December 1986 L<> March 1988 (Ta hie I ) . There were nu significant differences hetwel!n rreatmenr groups in te rms of age, ,ex,

210 CAN J GASTROFNTERUI VOi 5 Nt) 6 NtWEMHER/l)ECEMHER 1991

weight or total dose of Jiazepam re­quired (Tahle I).

The re~ults of the T ricger and trnck tracer tests arc shown in Figure J. For the sake nf simplicity only one dnse nf flumazenil ( 15 µ g/kg) c1ml rlc1cehn are presented. Essenti,1l ly all doses of flumazenil were found to be superior rn placebo. Trieger testing cnu Id not Jemonstrate significant differences among the flumazenil gwups, hu t alt flumazenil-treated patients recorded significantly fewer dots missed com­pared to placebo treated pmienrs (Fig­ure l ). Patients who received vehicle ,inly demonstrated significant impair­ment with the track tracer test compar­ed with pat iencs receiving flummenil (Figure I). This improvement was no longer evidenr 45 mins after the proce­Jure. Analysis nf patient rerformance measured hy digit substitutinn .:ind can­cellation tests confirmed the effective­ness of a lt doses of flum,tzenil against placebo for the initin l 45 mins following flumazenil injection.

Side effect~ were infrequent and rarely serious. Adverse events probahly related to fl umazenil included: anxiety and diar11oresis in one pmient after 20 µg/kg flumazenil; headache in tme in­dividual; and a brief rcriod (60 s) of apnea, the latter two afrcr 2 5 µg/kg flumazenil. The period of apnea lKCur­red in a patient whn received 15 mg diazepam.

DISCUSSION Flumazcn il has heen used tu ,m ra­

gonize the effects of d1azepam and m1daznlam in a variety of clinical situa­tions. Its effect iveness has hecn noted m patients undergoing cystoscopy ( 13 ), opbthal mological surgery ( l 4 ), arthro­scopy ( 15) and thernreut ic ahortion (l6). It also shows promise in reversing gencrnl anesthesia (22) particularly when a benzodiazepine is given as pan of the induction (22). Patients admit­ted LO an intensive care unit with suspected drug uverdose who recci ved I mg of fl umazenil less frequently re­quired gastric lavage, intubation and bladder cat hcterization than rhose nm-1lomized to placchn (23).

Flumazend appears to be equally ef­fective in reversing midazolam- as

Flumazenil in endoscopy

TABLE 1 Characteristics of treatment groups

Parameter Vehic le 5 Flumazenil dosage (~19/ kg)

10 15 20 25 Male:female 6:4 4:6 5:5 7:3 4:6 5:5 ASA class (1/11) 5/5 6/4 6/4 7/3 9/1 6/4 Age (years) + SD 36±12 43+12 39±11 42±13 37±12 40±11 Weight (kg) ± SD 71±16 73±17 68±13 72±16 69-1:15 71±8 Mean flumazenil 0.00 0.37 0.68 1.07 1.39 1.78 dose (mg)

Diazepam dosage 0.26 0.24 0.25 0.27 0.27 0.26 (mg/kg) ±0.04 ±0.04 -+0.06 i0.02 ±0.04 i0.04

There were no significant differences between groups. ASA Amercion Society of Anesthesiologists

9.0 Trieger Test Results

"O Q) 7.2 Cl'I Cl'I

E Cl'I 5.4 -0

"O -0 3.6 ... Q)

..a E

1.8 :::, z

0.0 0 30 60 90 120 150

6.0 Track Tracer Test

Cl'I 4.8 C: 0 -~ > 3.6 Q)

"O -0

... 2.4 q)

..a E

"-....~~/ :::,

1.2 z

0.0 0 30 60 90 120 150

Time in minutes following procedure

Figure I ) R<!.rn/rs of Trieger ( top) and Track Tracer ( botto m) r.escing m f111mazenil- and /Jlt1cebo-rreated /1miems. Swtisucal/y ~iKJ11ficant differences are noted he tween both gro11f>~ umi/ 4 5 mms after the />rocedtffe ( /\N( XW A, P<O O I). • Vehicle; A Flumazenil 15 µg/l<g

CAN) GASTROENTFRClL VOL 5 No 6 NOVl:MBER/DH 'EMBl·R 1991 211

SUTI IERLA NDer al

diaze pam-induced sedation (24 -26 ). Generall y pa tients a rc awake and oriented within 5 mins of receiving tlu­mazenil (27).

The pre:,ent s tudy sugges ts tha t flumazenil-treated patients may requi re a shorter observation perioc.l a nd thus less nursing time following endoscopy. The refo re, p a ti ents wh o rece ive Clumazenil could proba bl y he d is­charged from the endoscopy suite to a Cl)mfortahle chair in the recovery ;;irea rather than h,1ek to t he ir stretcher and cubicle. Potentia l co~l ~.wings in terms of staffing and inc reased productivity have been suggested ( 13).

The ha lf- life of flumazenil is rela­tively short (54 mins) comparec.l with the ha lf-lives of diazepam (43 h) and midazolam (2.4 h). In ,me study 10% of pati ent~ dbcharged hrnnl' fo llnwing f1umazenil reversal suddenly fell asleep during the evening (28). T he phenom­enon has not been reported hy o ther in vest igators. The presen t stuc.ly and others (29) suggest that the effec t of f1umazenil is most evident in the first h our following induc tion of sedation . After l h the recovering f1umazenil ­trcated p1,tiem docs n ot diffe r from o ther he nm diazepi ne- treated pat ienrs.

A n xie ty h as been reported with rapid administration of h igh doses of flumazeni l (30). ln snme cases th is may he related en the patient's rapid awaken ­ing in an unfamiliar env ironment. None of the patie nts in the presen t study was an xio us fnl lowing reversal. A slower rate o f administratio n or limita­tio n of total dose should reduce inc i­dents of anxiety.

The present trial was designed with reference tn previously published re­ports sta ting t he required dosage of f1u­mazenil LO he hetween 20 and 49 µg/kg. Surprisingly, the present authors found that a ll doses of flumazen ii were effec­tive up to 45 mins afte r the procedure compared to placelx). l n fact modest amounts ( 5 p g/kg) were sufficient to

rouse the present patiem s. Eve n smaller dosages mny be effective. The present sample size was inadequate to evaluate all doses - approx imate ly 100 patients are required co exclude any significanr Jiff e rencc be tween any two dosage levels.

212

Flumazenil was we ll tole ratec.l and side effects we re few and insignificant in the present study. O n e patient had a brief period of apnca. This may have been re lated to the dose of diazepam given. The authors arc unaware of any study which reported npnea associa ted with the use of f1umazcnil. O the r inves­tigators have noted that f1umazenil reverses the e levation of a rteria l PC02, whi c h occu rs in diazep am-treated pa tients (3 l ) . S tudi es of carc.liovascular functio n indicate that there are n o sig­nificant cardiovascular effects whe n flumazenil is given to reverse diazepam sedat ion in pa tients undergoing cardiac cathe teriza t ion (3 l ,32 ).

There is a variety of possible ex­planations for the lack of significant ~liffo rences be tween various dosages of flumazenil. Fir~t , a lthm,gh there was a t rend towarc.ls d iffe re nces he tw een groups, this sample was not of suffic ient size co provide the sta tistical power re­quired. Second, the amount of diaze­pmn required to inc.luce a relaxed state varied markedly (l 1.5 to 31 mg). The dose of flumazenil give n was based on hody we ight, not diazepam dose, which might explain why a consistent im­provement in recovery as the dose of f1umazcnil inc reased could not he demo nstrated . Ho wever, the average dose of diazepam given did not vary s ignificantly hetween groups. Third, the patie n ts h ad no r rece ived pre­medicanrs such as meperidine. In the a uth o rs' experie nce a premedicant deepens the conscious sedation and al­lows a lowe r dose of diazepam to be given ; the refore, an opportunity to ex­amine a narrower range of diazepam doses in which co assess the efficacy of the various dosages of f1umazenil may have been missed . Finally, it is possible tha t only a small quantity of flumazenil is required to competitiv ely inhibit the benzod iazepine receptor.

No significant differences betwee n flumazenil- and placebo-treated pat ients could be dcmonstratcc.l 45 mins after f1umazeni l infusio n . This could be a problem wi th the various eva luation me thods (Trieger, digit substitution, track trac ing and cancella tion tests). These tests have been used by oth er invest iga tors in the assessment of mid-

azolam and d iazepam; however, their intensive use (every 10 mins) may in­duce a learning phenomenon which could make diffe re nt iat inn het ween groups ml>rc d ifficult (2 l ).

The results of this st udy a re in agree­ment wi th other rcplirts of the use of numazenil in the endoscopy su ite (26, 28,33). Flumazenil is cffect iv<.:, well

tolerated anc.l free from ~ide effects. W hi le there has been varic1 t ion 111 the dose of flumazenil used, a l I studies gave

patients between 0. 5 mg nnd 1.0 mg. The present data suggest that all of

the flumazeni l doses, from 0.37 mg (5.0 µg/ kg) tn 1.78 mg (25 µg/kg), were equa lly effective in reversing sedation in unpremed icated pa tien t~. This is in agreement with previous investigators who have recommended a dose of up to 0 .5 mg to reverse d iazepam-induced sedatio n (25 ) . Fl um aze ni l sh ows promise as a bcnzod iazepine amagonist. Although adverse effects from medica­tion in the endoscopy uni t c1re rare (34). the addi tion of flu mazen i l w the mec.licarion cart in the suite b appro­priate ; however, the mu tine use of fl u­mazenil to reverse sedation in patients requires furthe r investigation.

ACKNOWLEDGEMENTS: FunJ ing for thio project was proviJed hy I loffmann-L1 R oche Limi ted, Canada. T he authors ac­knowledge the efforts of N,mcy Racicot, R N, study nur,e, ,1:, well a, Joan Craig, RN and Jessie l)arl ing, RN, endoscopy nur~es.

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MEDIATORSINFLAMMATION

of

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Behavioural Neurology

EndocrinologyInternational Journal of

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Disease Markers

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BioMed Research International

OncologyJournal of

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Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

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Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Research and TreatmentAIDS

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Gastroenterology Research and Practice

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Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com