European Journal of Anaesthesiotogy 2005; 22: 189-196© 2005 European Society of Anaesthesioiogy

ISSN 0265-0215

Original Article

Melatonin vs. midazolam premedication in children:a double-blind, placebo-controlled study

A. Samarkandi*, M. Naguib^, W. Riad*, A. Thalaj*, W. Alotibi*, E Aldammas*, A. Albassam^

King Saud Unwersity, Departments of Anesthesia and 'Surgery, Riyadh, Saudi Arabia; 'University of Iowa Collegeof Medicine, Department of Anesthesia, Iowa City, IA, USA

SummaryBackground and abjective: Unlike midazolam, melatonin premedication is not associated with cognitive

impairment in adults despite its anxiolytic properties. The use of melatonin as a premedicant in children hasnot been reported. This randomized, double-blind, placebo-controlled study compared the perioperative effectsof different doses of melatonin and midazolam in children.

Methods: Seven groups of children (« = 15 in each) were randomly assigned to receive one of the followingpremedicants. Midazolam 0.1, 0.25 or 0.5mgkg~^ orally, melatonin 0.1, 0.25 or 0.5mgkg~^ orally eachmixed in 15 mg kg acetaminophen, or placebo only (15 mg kg acetaminophen). Anxiety and temperamentwere evaluated before and after administration of the study drug, on separation from parents and on the intro-duction of the anaesthesia mask. At week 2 postoperatively, the behaviour of the children was measured by thePost Hospitalization Behaviour Questionnaire.

Results: Melatonin or midazolam each in doses of 0.25 or 0.5 mgkg~^ were equally effective as premedicantsin alleviating separation anxiety and anxiety associated with the introduction of the anaesthesia mask. A trendwas noted for midazolam to prolong recovery times as the dosage increased. The use of melatonin was associ-ated with a lower incidence {P = 0.049) of excitement at 10 min postoperatively, and a lower incidence(P = 0.046) of sleep disturbance at week 2 postoperatively than that observed with midazolam and controlgroups. No postoperative excitement was noted in the melatonin groups at 20, 30 and 45 min.

Discussion: Melatonin was not only as effective as midazolam in alleviating preoperative anxiety in children,but it was also associated with a tendency towards faster recovery, lower incidence of excitement postoperativeiyand a lower incidence of sleep disturbance at week 2 postoperatively.

Keywords: ADJUVANTS. ANAESTHESIA, midazoiam, melatonin; ANAESTHESIA, DRUG THERAPY, premedication;PAEDIATRICS; RANDOMIZED CONTROLLED TRIALS; ANXIETY, separation.

A large body of evidence indicates that the pinealhormone melatonin (N-acetyl-5-methoxytryptamine)has several important physiological functions, includ-ing regulation of circadian rhythms [11, regulation ofthe reproductive axis 12] and antioxidant activity [3].

Correspondence to: Prnf. Mohamed Naguib, University of Texas MD AndersonCancer Ontcr, Department ol Anesrhesiology and Pain Medicine, 1515 HolcombeBoulevard. Unit -^2, Houston, TX 77()3(), USA. Tel: +1 3! 9 3'i6 7471; Fax: +1

2940

Accepted for publication May 2004 EJA 1930

However, it is perhaps the best known by medical andlay personnel alike for its hypnotic actions. The hyp-notic effects of melatonin are considered an integralcomponent of its physiological role. For instance,intravenous (i.v.) administration of large doses ofmelatonin to rats resulted in hypnotic effects similarto that observed with equipotent doses of thiopentaland propofol [4]. Oral melatonin is used to enhanceboth the onset and quality of sleep (51, alleviate jetlag 16], for premedication of adult patients [7,81 andfor treatment of sleep disorders in adults [91 as well

190 A. Samarkandi et al

as in children [10,11]. The ase of melatonin in childrenwith sleep disorders is associated with significantimprovement in behavioural measures |12|.

Preoperative anxiety is associated with postopera-tive psychological and behavioural problems in chil-dren [13,141. Predictably, the use of anxiolytics suchas midazolam is expected to decrease the incidence ofthese negative sequalae [1 5,16]. On the other hand,oral premedication with midazolam in children canresult in adverse effects such as delayed recoveryfrom anaesthesia [17] and paradoxical reactions [18]such as anxiety, and behavioural changes.

We have demonstrated in adults that, unlikemidazolam, premedication with melatonin results inpreoperative anxiolysis and sedation without impair-ment of cognitive and psychomotor skills and with-out affecting the quality oi recovery I7,8l. Althoughmelatonin has been extensively used for treatment ofsleep disorders in children, we are not aware of anyreport of its use as a premedicant in children.

This prospective, randomized, double-blind,placebo-controlled study was designed to comparethe anxiolysis, sedation, and postoperative behaviourin children aged 2-5 yr after premedication withdifferent doses of melatonin or midazolam.

Methods

After obtaining institutional approval (King KhalidUniversity Hospital, Riyadh, Saudi Arabia) andinformed parental consent, we studied 105 childrenaged 2-5 yr and ASA I who were undergoing minorelective surgery for inguinal hernia, undescendedtestis, hydrocoele and hypospadias under generalanaesthesia. We excluded patients who were takingmedication within the last 2 weeks before surgery,had a history of prematurity, had had prior surgeryor hospital admission, or had any stressful life expe-rience (e.g. death in the family, divorce, etc.) [191.All patients were allowed food ad libitum up to 8hbefore surgery, and a maximum of 10 mLkg clearliquid up to 4 h before the anticipated time of induc-tion of anaesthesia.

The temperament of the child was assessed by aparent using the Emotionality, Activity, Sociability,Impulsivity (EASI) score of child temperament asdescribed by Buss and colleagues [20,211. Each ofthe aforementioned categories consisted of five itemsand a score of five is allocated to each item. The max-imum score in each category is 25. Higher scoresindicate high baseline values of EASI.

Approximately 1 h before surgery, patients weretransported to an isolated quiet room in the operat-ing suite. A pulse oximeter probe was placed on allpatients, and SpO_> was recorded continuously. Patientswere randomly assigned using computer-generated

random numbers to one of seven groups (H = 15 ineach). The premedicants in the seven groups were asfollows: 0.1, 0.25, or 0.5mgkg~' oral midazolam(Dormicum , F. Hoffmann-La Roche Ltd, Basel,Switzerland) mixed in 15mgkg""' acetaminophen(Tempra, Mead Johnson Nutritionals, IN, USA), 0.1,0.25, or 0,5 mg kg oral melatonin (GeneralNutrition Corporation, Pittsburgh, PA, USA) mixedin 15mgkg"' acetaminophen, or 15mgk;g~' oralacetaminophen alone (controls). Study drugs andplacebo were prepared by the pharmacist in a syringefrom which the needle had been removed andmarked only with a coded label to maintain the dou-ble-blinded nature of the study. The patients, par-ents, anaesthesiologists and the assessor were blindto group assignment.

The child's anxiety was assessed by the ModifiedYale Preoperative Anxiety Scale (mYPAS) [22] before(baseline), 10, 30, and 45 min after premedicationand was repeated at separation from the parents andat introduction of the anaesthesia mask. The five cat-egories of the mYPAS (activity, emotional expressivity,state of arousal, vocalization and use of parents) havea different number of items. Partial weights werecalculated and then added to a total score (for detailssee [22]). Higher scores indicate high levels of anxiety.To account for interpatient differences, mYPAS scoreswere normalized to baseline scores for each patient.Changes in scores relative to baseline values werecompared.

Parental presence was not allowed during inductionof anaesthesia in order to test for the effect of premed-ication on separation of anxiety from parents. Standardmonitoring was used. Anaesthesia was induced in allpatients using an oxygen—nitrous-oxide-sevofluranetechnique. Once the child was anaesthetized, an i.v.cannula was inserted, and at adequate depth of anaes-thesia a laryngeal mask was inserted. Anaesthesia wasmaintained with oxygen—nitrous-oxide—sevoflurane.Caudal block with bupivacaine 0.25% using a dose of1 ml kg ' was performed on all patients after laryngealmask insenion. Following discontinuation of sevoflu-rane and nitrous oxide, time to open eyes sponta-neously (emergence) and time to a score of 8 on themodified Aldrete score [23] were recorded.

A trained nurse who was blinded to the premed-ication protocol evaluated every patient during therecovery period. The rates of recovery and postopera-tive pain/discomfort were evaluated every 5 minusing a modified Aldrete score and a modified pain-discomfort scale, respectively (Table 1)[17,23,24I. Ifthe total score on the pain/discomfort scale at anyevaluation point exceeded three, the child was con-sidered as suffering from poscanaesthetic excitementand/or pain and was treated with 1-2 pg kg"' of fen-tanyl i.v.. Incidence of adverse effects was recorded.

© 2005 European Society of Anaesthesiology, Eatx^njeamai of Anaesthsiohgy 22: 189-196

Melatonin premedkation for children 191

Table I. The miKlifieJ Aldrete score [231 and the paiii/discomtbrt scaic [24].

Modified Aldrete score Score Pain/discomtort scale Score

ActivityNot movingNon-purposeful movemencMoving extremities purposefully

RespirationApnea/needs airway supportSliii[low or limitedDeep breathing/coughing

ConsciousnessUnresponsiveResj-Hintling to stimuliFully awake

Oj saturation<90%90-94%

0I2

012

012

01

CrymgNot cryingResponding to comfortingNot responding to comforting

Movi ngNoneRestlessThrashing

AgitationAsleep or calmMild agitationSevere agitation/hysterical

0I2

012

012

Postoperative nausea and vomiting was treated with0.1 mgkg~' (maximum of 2 mg) of ondansetron.

Two weeks after surgery, parents were contactedover the telephone by an investigator blinded to thegroup assignment, and the Post HospitalizationBehaviour Questionnaire (PHBQ) was completed.This questionnaire consists of 27 items divided intosix categories of anxiety (general anxiety, separationanxiety, sleep anxiety, eating disturbances, aggressionagainst authority, and apathy/withdrawal) [13,251.For each item the parent compared the child s behav-iour before surgery with behaviour at week 2 post-operatively. Five response options were provided andwere scored as follows: much less than before surgery( — 2), less than before surgery (— 1), not changed (0),more than before surgery (+1), and much more thanbefore surgery ( + 2) [131.

Statistical analyses were carried out using theBMDP statistical package (release 7.01, University ofCalifornia Press, Berkeley, CA, 1994) and StatXaxtfor Windows (release 4.0.1, CYTEL Software Corpo-ration, Cambridge, MA, 1999)- Unless otherwisespecified, results were expressed as means and 95%confidence intervals (95% CI) or medians andinterquartile ranges (25-75%), and were consideredsignificant when P < 0.05.

With a sample size in each of the seven groups of14, a 0.05 level X"-test has 90% power to detect adifference in proportions characterized by a varianceof proportions (V = ^( 'i — p,,f/G) of 0.045 and anaverage proportion of 0.607. Based on the findings ofour previous studies [7,8], we assumed that placebowould have a sedative and an anxiolytic effects in20% of patients whereas different doses of midazo-lam and melatonin would have sedative and an anx-iolytic effects in at least 50% of patients.

Normally distributed data were analysed with one-way or two-way analysis of variance (ANOVA) withrepeated measures, wherever appropriate. If theseANOVAs were significant, then Dunnett's post hwtest was used to compare the study groups to thecontrol group. Equality of variances was tested bythe Levene's test. If the latter test was significant,data were analysed using x"-test or Kruskal-Wallistest for multiple comparisons using the Bonferroniadjustments.

Results

There were no significant differences among the sevengroups regarding baseline patient characteristics,temperament, surgery time, or anaesthesia time(Table 2). There were no differences in child's anxietyamong the seven groups in the preoperative holdingarea. The mYPAS anxiety baseline scores (95% CI)were 45 (35-56), 48 (36-60), 49 (40-59), 47 (36-57),53 (41-66), 49 (37-60), and 57 (49-66), respec-tively, in control, 0,1, 0.25, 0.5 mgkg~' melatoninand midazolam groups. However, on separationfrom parents and on the introduction of the anaes-thesia mask, children in 0.25 and 0.5 mgkg"^ mela-tonin or 0.25 and 0.5mgkg"' midazolam groupsexhibited significantly less anxiety compared withthe control group (Fig. 1).

Emergence from anaesthesia and the times toachieve a score of 8 on the modified Aldrete scalewere similar in all groups (Table 2). However, atrend was noted for midazolam to prolong recoverytimes as noted by the delayed time to achieve anAldrete score of 8 as the dosage increased (Table 2).The highest incidence of postoperative excitementoccurred during the first 20 min after arrival in the

© 2005 European Society of Anaeschesiology. European Joumal of Anaesthesiology 22:

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Melatonin premedication for children 193

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10 min 30 min 45 min Separation Maskintroduction

Figure I.Changes In tht level of anxiety (as assessed by the modified YalePostoperaiive Anxiety Scale imYPASj) relative to the haiclirte indifferent groups in the perioperative period. Separation = .separa-tion from the parents. "P < 0.01. 'P < 0.0.5 ps. control group(Dumett's test). Mean ± SD.

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Figure 2.Percentage of patients with postanaesthetic excitement as assessed hythe painldiscomfort scale. Significantly greater numher of patientsin the midazolam and control groups exhibited postanaestheticexcitement compared with 0.25 and0.5 Mgkg"' melatonin groupsT P = 0.046) at 10 min.

recovery room (Fig. 2). Significantly greater numberof patients in the midazolam and control groupsexhibited postanaesthetic excitement compared with0.25 and 0.5 mgkg" ' melatonin groups at lOmin

(P = 0.046) (Fig. 2). No postoperative excitementwas noted in the melatonin groups at 20, 30 and45 min (Fig. 2). The incidence of postoperative excite-ment at 20 min was not different among groups(P = 0.08). Postoperatively, 1-2 ^g kg"' of fentanyli.v. was administered (for treatment of excitement/pain) to five, five and three patients in 0.1, 0.25,0.5 mgkg ' melatonin groups, respectively. Corres-ponding number of patients who received fentanyl inthe midazolam groups were four, six and five, respec-tively. Seven patients in the control group receivedfentanyl.

The specific PHBQ category most affected wassleep disturbances. At week 2 postoperatively, fewerchildren in melatonin groups (P = 0.047) presentedwith sleep disturbances compared with midazolamand control groups (Fig. 3)- There were no signifi-cant differences among the groups in the incidenceof reported negative behavioural changes in the restof PHBQ categories.

No anaesthetic complications, such as laryn-gospasm, were noted in this study. In the recoveryroom, the incidence of nausea or vomiting rangedfrom 13% to 26% among the groups (P = n.s.).

Discussion

This study demonstrated that, in children, 0.25 and0.5 mgkg midazolam or melatonin were equallyeffective as premedicants in alleviating separationanxiety and anxiety associated with the introductionof the anaesthesia mask (Fig. 1). Further, melatoninwas superior to midazolam in reducing the incidenceof excitement at 10 min postoperatively (Fig. 2). Nopatient in the melatonin group exhibited postopera-tive excitement at 20, 30 and 40 min (Fig. 2). Atweek 2 postoperatively, fewer children in melatoningroups (P = 0.047) presented with sleep distur-bances compared with midazolam and control groups(Fig. 3). However, there were no significant differ-ences in negative behavioural changes observed in therest of PHBQ categories among the groups (Fig. 3).

Midazolam appears to be the most commonly usedpremedicant for children [261. Consistent with ourresults, orally administered midazolam (0.5 mg kg"')has been shown in several studies to significantlyreduce preoperative anxiety in young children 115,16].A study comparing three doses of midazolam (0.25,0.5 and 1.0mgkg"' up to 20mg) found all threedoses to be effective in terms of sedation-anxiolysisbut that a more rapid onset was produced with0.5 mgkg"' and 1.0 mgkg"' [271. In the latter study,midazolam 0.25 mg kg"' dose was found to have equalefficacy to the higher doses in nearly 400 patients[27]. However, we noted a tendency for patients whohad received 0.25 and 0.5 mgkg" ' midazolam, to

© 2005 European Society of Anaesthesiology, European Journal of Anaesthesiotogy 22: 189- \-9(>

194 A. Samarkandi et al

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General Separation Sleep Eating Aggressionanxiety anxiety disturbances disturbances to authority

PHBQ category

Apathy andwithdrawal

Figure 3.Behavioural changes in the six Post Hospi-talization Behaviour Questionnaire (PHBQ)categories between the set'cn groi/p.i, at week2 pmtiiperat'ively. Feicer chilelreri in me/a-tamn groups ('P = 0.047) presentee/ withsleep disturbances compared with midazo-lam and control groups.

have prolonged recovery times as noted by the delayedtime to achieve an Aidrete score of 8 (Table 2). Thisis different from rhar observed with melatonin wherethe mean times to Aldrete score of 8 for all treatmentgroups were the same as the control group (Table 2).

Our results seem co indicate that melatonin maybe an attractive alternative to midazolam. In adults,we have previously demonstrated that premedica-tion with either melatonin or midazolam was associ-ated with adequate preoperative sedation, anxiolysisand patient satisfaction [7,81. However, unlike mida-zolam, melatonin was not associated with impair-ment of cognitive and psychomotor skills and didnot affect the quality of recovery [7,81. Melatonin indoses up to lOmg has been used as an alternativeto conventional sedatives and general anaesthesiafor uncooperative children undergoing electroen-cephalography and MRI examination 128]. Melatoninis also used for treatment of sleep disorders in chil-dren [11,291. Melatonin is a potent free radical scav-enger [31, and it has been reported to dramaticallyimprove survival rates in newborns with septic shock[301. All of the aforementioned evidence attests tothe safety of melatonin in children and newborns.

Sleep disturbance is common postoperativeiy[31—331- In the present study, melatonin premedica-tion was associated with less sleep disturbancescompared with midazolam and placebo at week 2postoperativeiy (Fig. 3). This finding was not unex-pected since several studies have shown chat mela-tonin is essential in facilitating the onset of sleep,and loss of sleep is commonly attributed to distur-bance of melatonin secretion from the pineal gland[32341. Nocturnal concentrations of melatonin aresignificantly decreased after surgery and this canbe prevented by melatonin replacement [32,35].Melatonin has successfully been used to treat severepostoperative delirium unresponsive to antipsychoticsor benzodiazepines 1351.

The incidence of maladaptlve behavioural patterns2 weeks after surgery reported in the current study iscomparable to that noted by other investigators [14].Meta analysis showed that the incidence of behav-iour changes vary markedly and ranges from 7% to65% [25,361.

We used the modified pain/discomfort scale [24]in this study. This scale has been widely used by dif-ferent groups of investigators to assess postoperative

2005 European Society ot Anat^^thcsiology, Europmn Journal of Ariaeslhesio/ogy 22: 189-t96

Melatonin premedication for children 195

behaviour [17,37,381. This scale, however, does notdifferentiate between pain and excitement. Althoughsome of the children in this study received l-2jigkg~^of fentanyl i.v. postoperatively, most of our patientshad adequate analgesia from caudal blocks and oralacetaminophen (15mgkg~^). Therefore, we believethat the scores obtained from this scale reflect thebehaviour of the child in the postoperative period.

In this study, parental presence was not alloweddtiring induction of anaesthesia in order to test theeffect ot premedication on separation anxiety (one ofthe component of the mYPAS). Parental presenceduring induction of anaesthesia does not decrease theincidence of separation anxiety in children 139,40]and guidelines among hospitals and even countriesvary widely on this issue.

In conclusion, this study demonstrated that 0.25and 0.5mgkg~^ midazolam or melatonin wereequally effective as premedicants in alleviating sepa-ration anxiety and anxiety associated with the intro-duction of the anaesthesia mask in children. Further,melatonin has a decided advantage in that Its use wasassociated with a tendency towards iaster recovery(that was not statistically significant), a lower inci-dence of excitement postoperatively, and a lowerincidence of sleep disturbance at week 2 postopera-tively than that observed with midazolam groups.

Ack no w ledge men t

Support was provided solely from departmentalsources.

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2005 European Society of Anaesthesioiogy, European Journal af Anaeslhesiology 22: 189-196