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Preoperative Alprazolam Reduces Anxiety in Ambulatory

Surgery Patients: A Comparison with Oral Midazolam

Jan L. De Witte, MD*, Carmen Alegret, MD†, Daniel I. Sessler, MD‡, and Guy Cammu, MD*

*Department of Anesthesiology and Intensive Care, OLV-Hospital, Aalst, Belgium; †Department of Anesthesiology, AZGroeninge, Kortrijk, Belgium; and ‡Outcomes Research™ Institute, Department of Anesthesiology, University of Louisville, Louisville, Kentucky, and the Ludwig Boltzmann Institute, University of Vienna, Vienna, Austria

Because an oral formulation of midazolam is not ap-proved in certain countries, we evaluated oral alprazo-lam as an alternative. Forty-five outpatients scheduledfor gynecological laparoscopic surgeryparticipated in a

double-blinded study to compare the effectiveness andside effects of oral alprazolam 0.5 mg with midazolam7.5 mg, as a reference drug, and placebo. We evaluatedpsychomotor function by means of theTrieger Dot Test(TDT) and the Digit-Symbol Substitution Test. Simplememory tests were performed. Data were analyzedwith 2 or paired Student’s t-tests, or with one-wayanalysis of variance with the Student-Newman-Keulsor Kruskal-Wallistest, as appropriate;P0.05wascon-sidered statistically significant. Alprazolam and mida-zolamboth decreased anxiety scores morethan placebo(P 0.05). One hour after premedication, the Digit-

Symbol Substitution Test score was similar in allgroups, whereas the TDT score was greater (indicatingimpairment of performance) in the alprazolam groupthan in the placebo group (P 0.05). Sedation scores,

extubation time, and discharge times in the active druggroups did not differ from placebo. At discharge fromthe postanesthesia care unit, the TDT score was greaterin both activedrug groupscomparedwith placebo (P0.05). Five patients, exclusively in the midazolamgroup, had amnesia (P 0.05). We conclude that alpra-zolam may be an effective alternative to midazolam foranxiety reduction without causing amnesia. However,it may cause greater impairment of psychomotor func-tion in the early postoperative period.

(Anesth Analg 2002;95:1601–6)

Many outpatients have preoperative anxiety;therefore, it would be desirable to find a ben-zodiazepine for oral premedication with a

strong anxiety-reducing effect and minimal psy-chomotor impairment. Midazolam is an obvious pos-sibility because its short duration of action (1) makes ita recommended benzodiazepine for surgical proceduresin outpatients (2–5). However, the oral formulation of midazolam is not approved in certain countries.

Benzodiazepines differ in their ability to relieve pri-mary or secondary (e.g., situational) anxiety, act as ananticonvulsant, provide muscle relaxation, and inducesedation. Ansseau et al. (6) calculated an anxiolyticindex for oral benzodiazepines by using the ratio of

the total primary and secondary anxiolytic activityscores divided by the total muscle relaxant and seda-tive activity scores. Using this index, one can select ananxioselective benzodiazepine. For example, praz-epam (20 mg, Lysanxia®) has the highest anxiolyticindex (2.32). However, prazepam is inappropriate as apremedicant in ambulatory surgery because its peakeffect occurs 7.8 h after administration and its metab-olite nordazepam has a half-life (t1/2) of 40–50 h.Alprazolam (Xanax®; Pharmacia NV, Brussels, Bel-gium) at 0.5 mg has the second highest anxioselectiveactivity (index of 2.26). In contrast to prazepam, it has

an onset time of 1.4 h and an elimination t1/2 of 10.6 hin normal-weight subjects. Given these pharmacoki-netic properties and its major anxiety-reducing effectsin patients with primary anxiety and panic attacks (7),alprazolam is a possible alternative to midazolam forpremedication in surgical outpatients.

The primary objective of this study was to assessthe efficacy, psychomotor performance, and sideeffects of 0.5 mg of alprazolam as a premedicant infemale outpatients. In this placebo-controlled study,the effects of alprazolam were compared with thoseof midazolam 7.5 mg.

Supported by NIH Grant GM 58273 (Bethesda, MD), the JosephDrown Foundation (Los Angeles, CA), and the Commonwealth of Kentucky Research Challenge Trust Fund (Louisville, KY). Theauthors do not consult for, or accept honoraria from, any companiesrelated to this research.

Accepted for publication August 8, 2002.Address correspondence and reprint requests to Jan De Witte, MD,

Department of Anesthesiology and Intensive Care, OLV-Hospital,Aalst, Belgium. Address e-mail to [email protected].

DOI: 10.1213/01.ANE.0000034732.94835.EC

©2002 by the International Anesthesia Research Society0003-2999/02 Anesth Analg 2002;95:1601–6 1601

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MethodsAfter institutional approval and written informed con-sent, 45 adult ASA status I–II women scheduled forminor outpatient gynecological laparoscopic surgeryparticipated in a double-blinded study. Patients taking

analgesic, sedative, antidepressant, or antiepilepticdrugs were excluded. Other criteria for exclusion in-cluded refusal, allergy or contraindications to either of the study medications, age 50 yr, gastric ulcer, obe-sity (body mass index [weight/height2] 28; obesityincreases the volume of distribution and eliminationt1/2 of alprazolam and midazolam), pregnancy, endo-crine or neuropsychiatric disease, or a history of drugor alcohol abuse. Patients with a Clinical Global Im-pression (CGI) score for anxiety 2 assessed by aninvestigator (8) were asked to participate in the study(0 relaxation, 1 apprehension, 2 mild anxiety, 3

moderate anxiety, 4

manifest anxiety, 5

severeanxiety, 6 very severe anxiety).Participating patients were randomly assigned to

receive alprazolam (0.5 mg, Xanax), midazolam(7.5 mg, Dormicum®, Roche B.V., Mijdrecht, TheNetherlands), or placebo 60 –90 min before surgery.All study drugs were given orally. The hospital phar-macist prepared the study medications. To blind theindividual administering the drugs, the commerciallyavailable drug tablets were placed in opaque capsulesfilled with an inactive powder.

Anesthesia was induced IV with 2–3 mg/kg of propofol, 0.2 g/kg of sufentanil, and 0.5 mg/kg of

ketorolac (maximum, 30 mg). Endotracheal intubationwas facilitated by IV administration of 0.2 mg/kg of mivacurium. Mechanical ventilation was adjusted tomaintain an end-tidal Pco2 near 4.6 kPa. Anesthesiawas maintained with 66% N2O in oxygen and desflu-rane 1.2 minimum alveolar anesthetic concentrationunless blood pressure decreased by more than 20%.Supplemental doses of 0.1 g/kg of sufentanil wereadministered at the discretion of the anesthesiologistuntil 20 min before the anticipated end of surgery. If arterial hypertension developed, 5–10 mg/kg of labe-talol was administered IV. Drugs not mentioned in theprotocol were excluded. Patients were actively warmedto keep core temperature (esophageal) normothermic.

When the trocars were removed from the abdomi-nal cavity, 2 g of propacetamol was infused over10 min, and desflurane was adjusted to an inspiratoryconcentration of 3.5% in 100% oxygen. Neuromuscu-lar block was antagonized, if necessary, by IV admin-istration of 2.5 mg of neostigmine along with 1.0 mg of atropine. Mechanical ventilation was decreased tomaintain the end-tidal Pco2 near 4.6 kPa. At the lastskin stitch, desflurane was discontinued, and 100%oxygen was administered. Spontaneous breathing wasallowed when the patient was awake or fighting the

ventilator. Patients were considered awake when they

opened their eyes on demand or after gentle tactilestimulation; they were later tracheally extubated.

In the postanesthesia care unit (PACU), patientsreceived standard postoperative care, including oxy-gen administration via a nasal cannula (3 L/min).

Tramadol 3 mg/kg was infused over 10 min, alongwith 4 mg of ondansetron for patients requiring addi-tional analgesia. Nausea or vomiting was treated withIV ondansetron (2 mg) at 5-min intervals to a maxi-mum dose of 6 mg. Tramadol 100 mg was adminis-tered IV over 10 min for treatment of shivering.

PACU discharge criteria included being awake andorientated, able to breathe deeply and cough freely,

blood pressure within 20% of preoperative values,temperature 36.0°C, absence of shivering, minimalpain, and minimal nausea. Patients were dischargedfrom the ambulatory surgery clinic between 4:00 and6:00 pm on meeting discharge criteria, which included

being awake and well orientated, vital signs within20% of preoperative values, temperature 38.0°C, novomiting, ability to ingest oral fluids, pain well con-trolled with oral analgesics, and ability to walk with-out dizziness.

The effects of the study drugs on anxiety, sedationlevel, and psychomotor performance were assessedfour times: immediately after obtaining informed con-sent (baseline), on arrival in the operating room (OR),on discharge from the PACU, and before being dis-charged to home. Anxiety was scored by an investi-gator using a 7-point CGI scale (0 relaxation, 1 apprehension, 2 mild anxiety, 3 moderate anxi-

ety, 4 manifest anxiety, 5 severe anxiety, 6 verysevere anxiety) and by the patient using a 100-mmvisual analog scale (VAS) (0 relaxed, 100 veryanxious, near panic). We assessed the degree of seda-tion on a five-point scale (0 alert, 1 arouses tovoice, 2 arouses with gentle tactile stimulation, 3 arouses with vigorous tactile stimulation, 4 lack of responsiveness) and with a VAS scale (0 –100 mm).

Psychomotor state was assessed with the TriegerDot Test (TDT) and the Digit-Symbol Substitution Test(DSST) (9). The TDT is a variation of the Bender-Gestalt test in which the patient is asked to connect aseries of dots arranged in a specific pattern. Points aresubtracted for missing a dot. TDT deviation representsthe cumulative distance (in millimeters) between thedrawn line and missed dots. The DSST is a subtest of the Wechsler Adult Intelligence Scale. It is a timed pen-and-paper test in which patients are required to appro-priately match numbers and symbols. The score is thenumber of symbols correctly matched during 90 s.

Patients were observed in the recovery unit bystudy nurses. Arterial blood pressure, heart rate, andrespiratory rate were monitored during the observa-tion period. Arterial oxygen saturation was monitoredcontinuously. Pain and postoperative nausea and

vomiting were evaluated with 100-mm-long VASs. All

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adverse effects, including dizziness and headache,were recorded. Before discharge from the clinic, amemory test was performed; it consisted of four ques-tions to which the patients had to answer yes or no: 1)Do you remember being brought to the operating

room? 2) Do you remember the object (a euro calcu-lator) shown just before induction of anesthesia? 3) Doyou remember the operating room? and 4) do youremember the recovery room?

Patients were called at home the day after surgeryand asked whether they experienced any side effects.The memory tests were repeated. Patient satisfactionabout anxiety reduction by the premedicant drug wasassessed and scored as sufficient, insufficient, and in-different (“don’t know”). Patients were asked whetherthey would like the same premedication if they re-quired a future operation.

Before the study began, a sample size of 15 patients

in each group was determined by a power analysis ( 0.05; 0.10) on the basis of the assumption that adifference of 20 mm (sd, 15 mm) between groups on aVAS scale for anxiety would be clinically important.

Differences among the three groups were compared by using 2 or paired Student’s t-tests, or one-wayanalysis of variance with Student-Newman-Keuls orKruskal-Wallis tests, as appropriate (StatView forWindows, version 5.0; SAS Institute Inc., Cary, NC).For example, the DSST and TDT scores were not nor-mally distributed; they were thus analyzed with non-parametric statistical methods. All results are pre-sented as means sd. P 0.05 was considered

statistically significant.

ResultsOne-hundred-ten patients were assessed for eligibil-ity; 77 had a CGI score 2. Of these 77 eligible pa-tients, 32 were excluded for reasons including refusal(n 13), chronic use of sedative or antiepileptic drugs(n 8), obesity (n 6), neurologic disease (n 4), andgastric ulcer (n 1). Three of the patients who de-clined to participate did so specifically for fear of receiving a placebo. Among the 45 patients includedin the three study groups, demographic and anestheticvariables, duration of anesthesia, extubation time,

baseline anxiety scores, and the interval between pre-medication (baseline) and arrival in the OR were sim-ilar (Table 1).

In all groups, patient-assessed anxiety scores ex-pressed on a VAS scale were decreased significantly (P 0.05) at arrival in the OR compared with their

baseline scores (Fig. 1). However, the decrease wasgreater (P 0.05) in the alprazolam (to 19 16 mm)and midazolam (to 23 12 mm) groups than in theplacebo group (to 38 18 mm). The quality of anxiety

reduction in the placebo group (n 15) the day after

surgery was considered insufficient in 7 patients anddoubtful in 3 others.

The VAS assessment of sedation on arrival in theOR in the midazolam group (32 29 mm) was slightlygreater than in the alprazolam group (23 20 mm),

and both groups had greater scores than patientsgiven placebo (7 20 mm). The sedation VAS andCGI scores at arrival in the OR and at discharge fromthe PACU, however, did not differ significantlyamong the groups (Table 1).

In Figure 2, the DSST scores were normalized to baseline values to account for interpatient differencesin test-taking ability. The DSST scores were similar ineach group on arrival in the OR. However, scores in

both treated groups were less than in the placebogroup at subsequent measurements.

The number of missed dots in the TDT score atarrival in the OR was higher in the alprazolam group

compared with the placebo group (P 0.05). At dis-charge from the PACU, both active-drug groups per-formed significantly worse on the TDT test comparedwith placebo (P 0.05) (Fig. 3). However, at dischargefrom the day clinic, the TDT scores again decreased to

baseline in all groups. The differences in TDT devia-tion showed similar statistical significance amonggroups for the TDT score. During the interview on thefirst postoperative day, 5 of 15 patients in the mida-zolam group had amnesia for the object shown onarrival in the OR. These five patients did not remem-

ber the OR, either; however, all patients remembered

their stay in the PACU. None of the patients givenalprazolam or placebo demonstrated any amnesia.The incidence of nausea or vomiting and other sideeffects in the PACU did not differ significantly amongthe groups, nor did discharge times from the PACU.

DiscussionAnesthesiologists may consider the administration of anxiety-reducing drugs unnecessary when anxietylevels are low in outpatients presenting for minorsurgery, and most adults having ambulatory surgeryare not premedicated (10). In the studied outpatientpopulation, 70% had a CGI score for anxiety 2. Threepatients even declined to participate in the study toavoid the risk of being given a placebo. The majorityof this outpatient population (61%) was willing to takea premedicant for reduction of anxiety. These resultsare consistent with previous studies in which up to80% of outpatients expressed a preference for a com-

bination of anxiety-reducing and hypnotic premedica-tion before surgery (3).

Oral premedication with 0.5 mg of alprazolam de-creased anxiety to the same extent as the reference

drug, 7.5 mg of midazolam. Eighty percent of the

ANESTH ANALG AMBULATORY ANESTHESIA DE WITTE ET AL. 16032002;95:1601–6 ORAL ALPRAZOLAM VERSUS MIDAZOLAM IN AMBULATORY PATIENTS

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patients judged alprazolam as an effective anxiety-reducing drug, a percentage that does not differ sig-nificantly from the midazolam group. In contrast, only33% of the patients given placebo were satisfied with

their premedication.

Figure 1. Anxiety scores before and after transfer to the operatingroom (OR), expressed by patients on a visual analog scale (VAS),decreased statistically significantly after the administration of bothactive drugs (P 0.001) and placebo (P 0.01). However, theanxiety decreased less in the placebo group than in either active

drug group (P 0.05). Data are presented as means sd.

Figure 2. The Digit-Symbol Substitution Test (DSST) score at arrivalin the operating room (OR) was similar in all groups. At discharge

from the postanesthesia care unit (PACU), the DSST score in theplacebo group was higher than in both active drug groups (P 0.05). At discharge from the day clinic, the DSST score was lower inthe alprazolam group compared with placebo (P 0.05) but wasequal to baseline. Within the placebo group, DSST scores increasedat every assessment compared with baseline (P 0.05). In themidazolam group, the DSST score at discharge from the day clinicwas higher than the baseline value (P 0.05). Data are presented asmeans sd.

Table 1. Demographic Characteristics and Perioperative Variables

VariableAlprazolam

(n 15)Midazolam

(n 15)Placebo(n 15)

Age (yr) 34 9 33 9 35 9Weight (kg) 61 9 61 9 60 10

Height (cm) 164 5 166 6 164 5ASA physical status (I/II) 14/1 14/1 15/0Time interval— baseline to OR (min) 68 20 59 20 64 25Anxiety CGI score— baseline (0–6) 3.6 0.9 3.8 1.0 2.9 1.2Anxiety CGI score—OR (0–6) 1.3 1.1 1.3 1.2 2.4 1.5Sedation CGI score—OR (0–4) 0.7 0.7 1.1 0.9 0.3 0.7Sedation VAS score—OR (0–100 mm) 23 20 32 29 7 20Duration of anesthesia (min) 53 22 54 24 48 11Central temperature at extubation (°C) 35.9 0.5 36.1 0.4 36.0 0.6Amount of sufentanil administered (g) 14 3 14 4 12 2Extubation time (s) 387 119 376 162 360 229Nausea or vomiting (%) 13% 20% 20%Time to discharge from PACU (min) 66 27 74 33 73 26Amnesia (%) 0% 33%* 0%Sedation CGI score—PACU (0–4) 0.7 0.8 0.6 0.6 0.3 0.5Sedation VAS score—PACU (0–100 mm) 10 13 13 19 7 10Sedation CGI score—discharge (0–4) 0.1 0.3 0 0 0.1 0.3Drowsiness at discharge (%) 20% 0% 13%Anxiety reduction (insufficient/don’t know/sufficient) 2/1/12 0/0/15 7/3/5*

Data are presented as means sd, number of patients, or percentage of patients (%).CGI Clinical Global Impression scale; VAS visual analog scale; baseline before premedication; OR operating room; PACU postanesthesia care unit;

discharge at discharge from the ambulatory surgery clinic.* P 0.05 among groups.


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The VAS and CGI assessments of sedation showedhigher scores in the active drug groups at arrival in theOR and on discharge from the PACU but failed todemonstrate any statistical difference among groups.In this study, statistical power was insufficient to de-tect differences in sedation. The TDT score, whichindirectly quantifies sedation, showed a statisticallysignificant difference between the alprazolam groupand the placebo group (Fig. 3). Although anotherstudy confirmed that oral midazolam (7.5 mg) doesnot produce significant sedation before surgery incomparison to placebo (12), other studies demonstratea significant sedative effect (sleepy, but easily arous-

able) (1,2). In a recent study of Brosius and Bannister(13), only 40% of patients treated with the large doseof 20 mg of midazolam exhibited detectable sedation,with marked interindividual variability in plasma mi-dazolam levels. Detectable preoperative sedation waspredictive of prolonged emergence.

At discharge from the PACU, the placebo group hadsignificantly better DSST and TDT scores than the twoactive-drug groups (P 0.05). Within the placebogroup, the DSST score was significantly higher thanthe preceding score at arrival in the OR and at dis-charge from the PACU (P 0.05). These data presum-ably reflected learning in the placebo group. In con-trast, absence of learning in patients receivingalprazolam indicated a subtle impairment in psy-chomotor performance. In the midazolam group, psy-chomotor impairment was also obvious at dischargefrom the PACU, with a decreased DSST score com-pared with the assessment at arrival in the OR (P 0.05). At discharge from the day clinic, the DSST scorein the midazolam group was significantly greater than

baseline values, which indicated learning. The effectsof the premedicant drugs on psychomotor skills werediscrete and transient; discharge times were not af-fected. This is consistent with previous research on

midazolam. Midazolam at a dose of either 5 mg given

IM 30 – 60 minutes before surgery or 0.04 mg/kg givenIV as premedication does not prolong discharge time,despite worsening of psychomotor skills (5,14).

In the midazolam group, 5 patients (33%) could notrecall the object shown at arrival in the OR or their time

in the OR; however, they did remember the PACU. Acomparable incidence of transient anterograde amnesiaafter 7.5 mg of midazolam has been observed previously(1,2). A dose-response effect of midazolam on memory issuggested, because 15 mg of oral midazolam (1,2) and0.1 mg/kg of IM midazolam (15) result in increasedincidences of anterograde amnesia. In contrast, 0.5 mg of alprazolam did not induce amnesia in the studied pa-tients. Even at a larger dose of 1.0 mg, no amnesic effectof alprazolam was noted (8).

Other benzodiazepines available in oral preparationhave been used for premedication in adult outpa-tients. Preoperative discomfort and apprehension sig-

nificantly decrease with diazepam (0.25 mg/kg, Val-ium®) (16,17). We did not select oral diazepam as anactive comparator in this study because the anxiolyticindex for diazepam (10 mg) is only half the value of alprazolam (0.5 mg) (6). Diazepam emulsion (7 mg IV)and midazolam (3 mg IV) were found to comparablyreduce anxiety and improve patient comfort duringneedle localization procedures, without prolongingdischarge times (4). Sublingual premedication with0.25– 0.50 mg of brotizolam (Lendormin®) results insatisfying anxiety reduction in adult outpatients, withrestoration of the sedation score and the ability towalk freely 7 hours after premedication (18). In dental

outpatients, sublingual triazolam (0.25 mg, Halcion®)appears to be an effective drug for anxiety reductionand sedation, with a rapid onset and short t1/2 (19).However, brotizolam and triazolam have the lowestanxiolytic indices among benzodiazepines (6), whichsignifies that their sedative activity is more prominent.Sedation is not a desirable property for fast-tracking inambulatory surgery.

In conclusion, premedication to reduce anxiety wasconsidered desirable by most of the adult female out-patients. Oral premedication with alprazolam (0.5 mg)was comparable to midazolam (7.5 mg) in reducingpreoperative anxiety. Patients receiving midazolamexperienced transient amnesia. Sensitive tests demon-strated a minor impairment of psychomotor functionwith both benzodiazepines; however, neither drugprolonged extubation or discharge times.

The authors thank Greet De Smet, hospital pharmacist, for thepreparation of capsules with active drug or placebo.

References1. Biro P, Weidmann G, Pietzsch S, et al. Dose-dependent effects of

oral premedication with midazolam. Anasthesiol Intensivmed

Notfallmed Schmerzther 1997;32:672–7.

Figure 3. The Trieger Dot Test (TDT) was used to assess sedationlevels and psychomotor recovery. At arrival in the operating room(OR), the number of missed dots in the alprazolam group wassignificantly higher than in the placebo group (P 0.05). At dis-charge from the postanesthesia care unit (PACU), both active druggroups had a significantly higher TDT score compared with placebo(P 0.05). Data are presented as means sd.

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2. Lanz E, Schafer M, Brunisholz V. Oral premedication withmidazolam for local anesthesia. Anaesthesist 1987;36:197–202.

3. Raeder JC, Breivik H. Premedication with midazolam in out-patient general anaesthesia: a comparison with morphine-scopolamine and placebo. Acta Anaesthesiol Scand 1987;31:509 –14.

4. van Vlymen JM, Sa Rego MM, White PF. Benzodiazepine

premedication: can it improve outcome in patients undergoing breast biopsy procedures? Anesthesiology 1999;90:740–7.

5. Shafer A, White PF, Urquhart ML, Doze VA. Outpatientpremedication: use of midazolam and opioid analgesics. Anes-thesiology 1989;71:495–501.

6. Ansseau M, Doumont A, Diricq S. Methodology required toshow clinical differences between benzodiazepines. Curr MedRes Opin 1984;8:108 –14.

7. Dawson GW, Jue SG, Brogden RN. Alprazolam: a review of itspharmacodynamic properties and efficacy in the treatment of anxiety and depression. Drugs 1984;27:132– 47.

8. Franssen C, Hans P, Brichant JF, et al. Comparison betweenalprazolam and hydroxyzine for oral premedication. Can J An-aesth 1993;40:13–7.

9. Hindmarch I. Psychomotor function and psychoactive drugs.Br J Clin Pharmacol 1980;10:189 –209.

10. Cammu G, Smith I. Day surgery, including the preoperativeassessment of the patient: a UK experience by a Belgian anaes-thetist. Acta Anaesthesiol Belg 2000;51:173– 85.

11. Deleted in proof.12. Raybould D, Bradshaw EG. Premedication for day case surgery:

a study of oral midazolam. Anaesthesia 1987;42:591–5.13. Brosius KK, Bannister CF. Oral midazolam premedication in

preadolescents and adolescents. Anesth Analg 2002;94:31– 6.14. Richardson MG, Wu CL, Hussain A. Midazolam premedication

increases sedation but does not prolong discharge times after

brief outpatient general anesthesia for laparoscopic tubal steril-ization. Anesth Analg 1997;85:301–5.

15. Reinhart K, Dallinger-Stiller G, Dennhardt R, et al. Comparisonof midazolam, diazepam and placebo i.m. as premedication forregional anaesthesia: a randomized double-blind study Br JAnaesth 1985;57:294 –9.

16. Jakobsen H, Hertz JB, Johansen JR, et al. Premedication beforeday-surgery: a double-blind comparison of diazepam and pla-cebo. Br J Anaesth 1985;57:300 –5.

17. Jansen EC, Wachowiak-Andersen G, Munster-Swendsen J, Val-entin N. Postural stability after oral premedication with diaze-pam. Anesthesiology 1985;63:557–9.

18. Laub M, Espersen K, Ejlersen E, Krintel JJ. Sublingual premed-ication with brotizolam. Acta Anaesthesiol Scand 1992;36:764 – 6.

19. Berthold CW, Dionne RA, Corey SE. Comparison of sublin-

gually and orally administered triazolam for premedication before oral surgery. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 1997;84:119 –24.


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