Effects of preanesthetic administration of midazolam, clonidine, or dexmedetomidine on postoperative

Pediatric Anesthesia200717:667–674doi:10.1111/j.1460-9592.2006.02185.x Effects of preanesthetic administration of midazolam,clonidine,or dexmedetomidine on postoperative pain and anxiety in childrenANDRE´P.SCHMIDT M D†,EMILIA A.VALINETTI M D P h D†,DENISE BANDEIRA M S C P H D‡,MARIA F.BERTACCHI M D†,CLA´UDIA M.SIMO˜ES M D†AND JOSE´OTA´VIO C.AULERJR M D P h D††Division of Anesthesiology and Children’s Institute,Hospital das Clı´nicas,University of Sa˜oPaulo Medical School,Sa˜o Paulo,Brazil and‡Psychology Institute,Federal University of RioGrande do Sul,Porto Alegre,BrazilSummaryBackground:A growing interest in the possible influences of pre-andpostoperative anxiety and pain scores as outcomes of surgicaltreatment and benefits of anxiety or pain-reducing interventions hasemerged.The aim of this study was to evaluate the influence of threedifferent premedication regimens on postoperative pain and anxietyin children.Methods:A prospective,randomized,open-label clinical trial enrolled60schoolchildren.They were randomized for premedication with oralmidazolam0.5mgÆkg)1,oral clonidine4l gÆkg)1,or transmucosaldexmedetomidine(DEX)1l gÆkg)1,submitted to a pre-and post-operative evaluation of anxiety with the State-Trait Anxiety Inventoryfor Children and asked to report any pain in verbal and visual analogscales.We also evaluated secondary outcomes such as parents’anxiety,sedation,separation from parents,adverse effects andhemodynamic status.Results:Dexmedetomidine and clonidine were related to lowerscores of pain than midazolam.a2-agonists produced lower scoresof peroperative mean arterial pressure and heart rate thanmidazolam.Both groups had similar levels of postoperativestate-anxiety in children.There was no difference in preanesthesialevels of sedation and response to separation from parents betweengroups.Conclusions:Thesefindings indicate that children receiving cloni-dine or DEX preoperatively have similar levels of anxiety andsedation postoperatively as those receiving midazolam.However,children given a2-agonists had less perioperative sympatheticstimulation and less postoperative pain than those givenmidazolam.Correspondence to:Andre´P.Schmidt,Avenida Ramiro Barcelos,2600-Anexo,90035-003Porto Alegre,RS,Brazil(email:apschmidtus@ ).Ó2006The AuthorsJournal compilationÓ2007Blackwell Publishing Ltd667Keywords:anxiety;pain;premedication;midazolam;clonidine; dexmedetomidineIntroductionSeparation from the family,anticipation of post-operative pain,fear of surgery,incapacity,loss of independence and fear of death are factors that trigger perioperative anxiety(1).Studies have shown that surgical procedures generate high levels of anxiety(2,3).Consequently,there has been a growing interest in the possible influences of pre-and postoperative anxiety on the course and outcomes of surgical treatments and benefits of anxiety-reducing interventions(3).Relieving pre-and postoperative anxiety is a major concern for the pediatric anesthesiologist(4). Anxiety is defined as a set of behavioral manifesta-tions that can be divided into state-and trait-anxiety. State-anxiety is a transitory emotional condition that consists of feelings of tension,apprehension,ner-vousness,and worry.This state varies in intensity andfluctuates overtime.Trait-anxiety refers to indi-vidual differences in anxiety proneness,being a personality trait that remains relatively stable over time(5).High state-anxiety scores indicate high levels of anxiety at the time of evaluation,while high levels of trait-anxiety indicate an anxious personality disposition(6).Anxiety can produce aggressive reactions,increase distress and may make the control of postoperative pain difficult(1,7).Patients with high levels of preoperative state-anxiety are particularly vulnerable to severe pain after surgery (6,8).The benzodiazepine midazolam,an anxiolytic drug,has become the most frequently used prea-nesthesia medication given to children scheduled for surgery(1,2,4).Midazolam has a number of benefi-cial effects when used as premedication in children: sedation,reduction of vomiting,fast onset and limited duration of action(9,10).Despite having a number of beneficial effects,it is far from an ideal premedicant,having untoward side effects such as cognitive impairment,amnesia,long-term behavi-oral disturbances,and respiratory depression (11,12).However,new drugs such as the a2-agonists have emerged as alternatives for premedication in pedi-atric anesthesia.Clonidine,a selective centrally acting partial a2-agonist,has been reported to be a useful preanesthesia medication in children because of its sedative and analgesic properties(11–15). Dexmedetomidine(DEX)has a differential specific-ity for the a1:a2receptors of1:1620,compared with1:220for clonidine,being considered a full and highly selective agonist of a2-adrenergic recep-tors(16–20).Clinical investigations have demon-strated its sedative,analgesic and anxiolytic effects after intravenous administration to volunteers and postsurgical patients(16–20).Given the pivotal role of pain and anxiety as a stress factor in the postoperative period,the main aim of this study was to evaluate and compare the influence of three different premedication regimens on postoperative pain and anxiety in children.We also compared pre-and postanesthesia sedation, hemodynamic status,adverse effects on emergence, separation from parents,consumption of anesthetics and anxiety profile of parents.MethodsA prospective,randomized,open-label clinical trial of pediatric patients was performed in a tertiary care hospital in Southern Brazil.The protocol was eval-uated and approved by the Institution’s Research and Ethics Committee.Written informed consent was obtained from the person legally responsible for the child and verbal consent from the child.After power analysis(confidence interval of95% and power of80%),60schoolchildren were enrolled in the study,with ASA status I–II,and ages ranging from7to12years old.They were submitted to general or combined anesthesia for a variety of elective ambulatory surgical procedures.Exclusion criteria included children with chronic pain,cerebral palsy,autism,difficulty in understanding verbal commands,using analgesics and anticonvulsants during the preoperative period,or preanesthesia668 A.P.SCHMIDT ET AL.Ó2006The AuthorsJournal compilationÓ2007Blackwell Publishing Ltd,Pediatric Anesthesia,17,667–674medications before evaluation.None of the children enrolled in the study received oral premedication or analgesics before evaluation in the preoperative period.Randomization was performed according to a computer-generated random list.All children enrolled were asked to report any pain using two self-assessment instruments–a verbal scale and a visual analog scale(VAS).In the first,reported pain was graded from1to4,accord-ing to intensity:(i)none;(ii)slight;(iii)moderate;or (iv)severe(14,15).The VAS used in this study is a modification of the50cm scale proposed by Maun-uksela et al.(21)a red ramp20cm long and5cm high.The children were instructed to point out the degree of pain they were feeling on the scale, considering that the top of the ramp corresponded to maximum pain and the lower part to absence of pain.The score was achieved according to corres-ponding numbers on the back of the ramp in the place pointed out by the child.To stratify the data of VAS,cut off points were established from percen-tiles25,50,and75of the measures,corresponding to 0.1,3.8,and8.8cm.Based on these cut off points,the clinical significance of the values and the methodo-logical strategy used by Collins et al.(22),absence of pain corresponded to the range from0to percentile 25(0.1cm);mild pain corresponded to the range from thefirst percentile to the median(0.2–3.8cm); moderate pain corresponded to the range from the median to percentile75(3.8–8.8cm);and intense pain corresponded to the scores above the second percentile(8.8–20cm).The measurement of anxiety levels was performed through the State-Trait Anxiety Inventory for Chil-dren(STAIC),adapted to Brazilian Portuguese(23), during the pre-and postoperative periods.State-Trait Anxiety Inventory for Adults(STAI),adapted to Brazilian Portuguese(24),was used in the pre-and postoperative period to measure the anxiety of the parents.The questionnaire contains two separate 20-item,self-report rating scales for measuring trait-and state-anxiety.Children and parents responded on a three-or four-point scale.Total scores for situational and baseline questions separately range from20to60or80,with higher scores denoting higher levels of anxiety(23,24).The anxiety scales were individually applied,with the evaluator remaining beside the child,helping them to read it if necessary.The same was done during the appli-cation of STAI to the person responsible for the child.In the postoperative period,the application of the STAIC and STAI was restricted to items referring to the state of anxiety.According to previous studies (6,25,26),the mean of anxiety scale scores was used to determine the cut off point,so that individuals with scores above the average were classified as the high anxiety group and those with scores equal to or below the average as the low anxiety group.In the preoperative period,each child was assessed with the pain and anxiety scales before the surgical procedure to allow the child to get used to them.During this period the person responsible for the child answered the anxiety scale questions and the structured questionnaire to obtain data about demographic characteristics and chronic dis-eases.To minimize a possible influence of the word ‘pain’upon anxiety scores,the pain and anxiety scales were used in different pseudo-random se-quences(26,27).Immediately before surgery,children were rand-omized for premedication into three groups:(i) midazolam0.5mgÆkg)1PO30min before surgery (26,28);(ii)clonidine4l gÆkg)1PO90min before surgery(29);and(iii)transmucosal DEX1l gÆkg)1 45min before surgery(30).Patients were admitted to the operating room and evaluated for sedation[a four-point scale:(i)none,angry,or crying;(ii)slight, awake but calm;(iii)moderate,responding to verbal commands;and(iv)intense,sleepy]and separation from parents[(i)very difficult;(ii)restlessness;(iii) realizing the separation without restlessness;and (iv)does not realize,remaining calm].Children were monitored with pulse oximetry,EKG,and noninva-sive blood pressure ually an i.v.catheter was inserted and induction of anesthesia performed with propofol(4mgÆkg)1),fentanyl(up to 5l gÆkg)1),and rarely a muscle relaxant(atracurium 0.5mgÆkg)1or rocuronium0.6mgÆkg)1)to facilitate tracheal intubation in some patients.Anesthesia was maintained with sevoflurane or isoflurane and50% nitrous oxide in oxygen.Regional blocks with bupivacaine0.25%or ropivacaine0.2%before the surgical incision(epidural,sacral,iliohypogastric, ilioinguinal,penile,or local infiltration)were used according to routine.The extent of the surgical procedure,length of anesthesia and surgery,nerve block,doses of opioids,and recovery times were recorded.ALPHA2-AGONISTS AS PREMEDICATION669Ó2006The AuthorsJournal compilationÓ2007Blackwell Publishing Ltd,Pediatric Anesthesia,17,667–674To apply the pain and anxiety scales in the postoperative period,the child was fully conscious and orientated in time and space[two points in the consciousness item of the Aldrete and Kroulik’s (AK)scale],which was taken as the recovery time (31).All children enrolled were asked to report any pain in the postoperative period.Intravenous anal-gesia was administered according to the self-assess-ment scales of pain used in this study.Nonopioid analgesics were prescribed for slight to moderate pain and opioids for intense pain.The analgesic schedule followed the routine of the pediatric postanesthesia care unit(PACU).Children were discharged from PACU after achieving an AK score of9or10and time to discharge was noted for further analysis.We also evaluated hemodynamic parameters dur-ing and after anesthesia(heart rate,arterial pressure, endtidal CO2,SpO2),levels of postoperative sedation, consumption of anesthetics and analgesics,adverse effects on emergence or in the PACU(hypoxemia, bradycardia,nausea,vomiting,hypothermia,urinary retention,shivering,or hallucinations).Data were stored in EPI-INFO software version 6.0and analyzed by Statistical Package for the Social Sciences(SPSS)for Windows version12.0(Chicago, IL,USA)parametric data were expressed as mean and standard deviation(SD)and statistical analysis performed through analysis of variance plus Tukey test as a posthoc when appropriate.Nonparametric data are expressed as median and interquartile ranges(25%and75%)and statistical analysis performed with Kruskal–Wallis test plus Mann–Whitney U-test as a posthoc when appropriate. Differences in proportions between studied groups and postoperative state-anxiety and pain scores were tested by means of Pearson’s chi-squared test with Yates continuity correction in univariate ana-lysis(or by Fisher’s exact test when the number of expected observations wasfive or less in at least one cell).ResultsThe patient details are summarized in Table1.The average age of the children assessed was9.21years (SD±1.6).There was an equal distribution of males and females.The mean duration of surgery was 82.9min(SD±69.6)and anesthesia116.2min (SD±79.2).There was no difference in demographic characteristics between groups.Types of surgery performed during the study are shown in Table2. Taken together,the preanesthesia measurements of anxiety in children and adults and pain scores before surgery,show no statistically significant difference between groups.There was also no difference in preanesthesia levels of sedation (Figure1)and response to separation from parents between groups.However,DEX tended to reduce postoperative sedation,mainly at30min after admission to PACU(P¼0.25)as shown in Figure1. Recovery time(P¼0.13)and time for discharge from PACU(P¼0.15)compared with midazolam as shown in Table3,were not statistically significant.Table1Patient characteristicsCharacteristicsTreatmentP a Midazolam Clonidine DexmedetomidineGender,n(%)Male13(59%)13(72.2%)11(55%)0.23Female9(41%)5(27.8%)9(45%)Age(years)9(8–11)10(8–10)8(8–10)0.29Weight(kg)33(28.2–37.3)34.9(31.5–40)26(23.5–33.9)0.32ASA status,n(%)I15(68.2%)14(77.8%)15(75%)0.85II7(31.8%)4(22.2%)5(25%)Duration of anesthesia(min)135(61.2–162.5)85(65–115)90(61.2–117.5)0.19Duration of surgery(min)82.5(48.7–125)60(40–87.5)67.5(35–92.5)0.35Anesthetic blockade,n(%)13(59.9%)14(77.7%)15(75%)0.66a P<0.05was considered significant.Statistical analysis performed through ANOVA plus Tukey testfor parametric data.Kruskal–Wallis plus Mann–Whitney U-test was used for nonparametric data(n¼60patients).Data for age,weight,duration of anesthesia and surgery are median±inter-quartile range.670 A.P.SCHMIDT ET AL.Ó2006The AuthorsJournal compilationÓ2007Blackwell Publishing Ltd,Pediatric Anesthesia,17,667–674There were similar levels of postoperative state-anxiety after midazolam,clonidine,and DEX in the children.However,parents of children from the clonidine group had lower levels of anxiety than the midazolam group (Table 4).Although we did not find a difference in anxiety levels between groups,a 2-agonists were related to lower pain scores than midazolam in both verbal (P ¼0.05)and visual scales (P ¼0.0021)as shown in Table 5.After midazolam there were higher levels of mean arterial pressure and heart rate than after a 2-agon-ists,before and after induction of anesthesia and during the surgical procedure,as shown in Table 3.However,there were no differences between groups in adverse effects on emergence,consumption of anesthetics and analgesics,SpO 2and endtidal CO 2(data not shown).DiscussionIn this study,the influence of preanesthesia admin-istration of midazolam,clonidine,or DEX on the levels of postoperative anxiety and pain in children submitted to elective surgery was evaluated.We found a 2-agonists were related to lower levels of postoperative pain and after DEX there was a tendency to less sedation after surgery.However,no differences was found between groups in anxiety scores after surgery.The population sample studied was homogenous as the preanesthesia characteristics (gender,age,weight,preoperative anxiety,and pain status)of the patients were quite similar.The midazolam group tended towards an increased length of surgery and anesthesia,possibly related to two patients with long duration surgery (270min for correction of anal fistula and a cervical lesion excision),but without statistical significance.As high levels of preoperative state-(26)or trait-anxiety (25)may be a risk factor for postoperative state-anxiety and higher pain levels (5,32),it is essential to have a homogenousPre-anesthetic PACU admission 30 min afterDischarge fromClonidineDexmedetomidineTable 2Types of surgery performed Excision of cervical lesion Excision of lymph nodeInguinal/umbilical herniorrhaphy Orchidopexy CircumcisionCorrection of anal fistula Excision of pilonidal cystTable 3Comparison among pre-and postanesthesia secondary outcomes between groupsVariablesGroupsP a Midazolam Clonidine Dexmedetomidine Recovery time (min)47.2(59.0)40.2(25.7)28.8(20.4)0.3Time to discharge from PACU (min)62.7(47.0)53.7(23.6)41.4(20.6)0.15Mean arterial pressure (mmHg)(mean ±SD)Before induction 74.8(8.4)a 63.5(9.2)65.6(8.6)0.001a After induction 70.5(9.7)a 62.2(11.0)61.4(10.8)0.019a During surgery68.0(10.2)a 58.1(11.8)60.5(11.8)0.031a Mean heart rate (b Æmin )1)(mean ±SD)Before induction 107.2(19.8)a 80.8(10.2)85.4(12.7)0.001a After induction 105.1(20.8)a 79.5(10.6)87.1(13.7)0.001a During surgery109.2(23.2)a86.7(10.4)83.2(13.0)0.001aaP <0.05was considered significant (midazolam >dexmedetomidine ¼clonidine).Statistical analysis performed through ANOVA plus Tukey test (n ¼60patients).PACU,postanesthesia care unit;SD,standard deviation.ALPHA 2-AGONISTS AS PREMEDICATION 671Ó2006The AuthorsJournal compilation Ó2007Blackwell Publishing Ltd,Pediatric Anesthesia ,17,667–674population regarding preanesthesia anxiety scores to prevent potential confounding bias.Previous studies reported that a child’s anxiety is strongly affected by the state-and trait-anxiety of the parent,accompanying them during the pre-and postoperative evaluation(33).In this study,parents of children that received clonidine premedication had lower levels of postoperative state-anxiety than children from the midazolam group.This effect may reflect differences in postoperative pain control between clonidine and midazolam.However, clonidine did not significantly affect postoperative state-anxiety in children.A methodological issue regarding the tools used to measure anxiety in this study should be pointed out.Despite the fact that STAI and STAIC are widely used(25)and validated (23,24)for evaluating the level of anxiety in different situations(4,5,24)and the response to anxiolytic drugs(34),to date there is no gold standard to measure anxiety in children and adults(33).There-fore,the actual effects of premedication with a2-agonists may be further clarified with new tools. Moderate to intense pain and absence of nerve block are important risk factors for postoperative anxiety and have been described in numerous studies(6,32,33).The risk for high postoperative anxiety in children with moderate to intense pain is 14-fold higher and in those without nerve block it is fivefold higher(26).Oral clonidine medication redu-ces postoperative pain in children(29)and enhances postoperative analgesia provided by intrathecal morphine plus tetracaine without increasing the intensity of side effects from morphine(35),an effect that may be shared by DEX.In this study,a2-agonists were related to lower scores of postoperative pain than midazolam.This effect remains significant even controlling for poten-tial confounding factors such as postoperative anxi-ety and anesthetic blockade.However,it remains unclear if this effect is related to intrinsic pharma-cological properties of a2-agonists(activation of postsynaptic a2receptors in the substancia gelati-nosa of the spinal cord)or related to an anxiolytic effect not measured by this study(35).The potential bias caused by residual effect of anesthesia on measurement of pain and anxiety were controlled by the degree of consciousness,length of anesthesia and time elapsed until recovery.Table4Comparison among mainpostanesthesia outcomesbetween groups–anxiety scoresVariablesGroups(%)P a Midazolam Clonidine DexmedetomidinePostoperative STAIC,n(%)Low levels15(68.2%)12(66.7%)13(65%)0.82 High levels7(31.8%)6(33.3%)7(35%)Mean scores(mean±SD)31.7(10.3)27.6(5.9)30.2(7.9)0.35 Postoperative STAI,n(%)Low levels7(31.8%)a12(66.7%)13(65%)0.03a High levels15(68.2%)a6(33.3%)7(35%)Mean scores(mean±SD)39.6(5.2)a34.3(4.6)35.1(4.9)0.006a a P<0.05was considered significant.Statistical analysis performed through ANOVA plus Tukey test for anxiety scores.Pearson’s chi-squared test with Yates continuity correction or Fisher’s exact test in univariate analysis was used for categorical data(n¼60patients).Midazolam>clonidine as evidenced by Tukey test;midazolam¼dexmedetomidine(P¼0.46);and clonidine¼dexmede-tomidine(P¼0.13).SD,standard deviation;STAI,State-Trait Anxiety Inventory for Adults; STAIC,State-Trait Anxiety Inventory for Children.Table5Comparison among main postanesthesia outcomes betweengroups–pain scoresVariablesGroups(%)P a Midazolam Clonidine DexmedetomidineVerbal pain scale,n(%)None6(27.3%)9(50%)11(55%)0.05Mild5(22.7%)3(16.7%)5(25%)Moderate6(27.3%)6(33.3%)2(10%)Severe5(22.7%)0(0%)2(10%)Visual analog pain scale,n(%)None–mild4(18.1%)a11(61.1%)13(65%)0.0021aModerate–severe18(81.8%)a7(38.9%)7(35%)Mean levels,cm(SD)8.3(7.1)b 3.5(4.4) 4.4(6.1)0.046ba P<0.05was considered significant.Midazolam>clonidi-ne¼dexmedetomidine as evidenced by Mann–Whitney U-test.b P<0.05was considered significant.Midazolam>clonidi-ne¼dexmedetomidine as evidenced by ANOVA plus Tukey test.672 A.P.SCHMIDT ET AL.Ó2006The AuthorsJournal compilationÓ2007Blackwell Publishing Ltd,Pediatric Anesthesia,17,667–674Pretreatment with clonidine and DEX have been shown to decrease perioperative requirements for inhaled anesthetics and opioids(13,18,19,36)and decrease the minimum alveolar concentration for volatile anesthetics(13,18).However,this study investigating ambulatory pediatric surgery failed to prove this.Regarding preoperative sedation status and separation from parents,clonidine and DEX showed similar results compared with midazolam, as previously described elsewhere(11,12,30).Oral clonidine or DEX premedication blunts reflex tachycardia associated with direct laryngoscopy for tracheal intubation,decreases intraoperative lability of blood pressure and heart rate and decreases plasma concentration of catecholamines(37).In this study,we show that both clonidine and DEX are able to reduce mean arterial pressure and heart rate before and during the procedure,as with previous findings.The ability of a2-agonists to decrease sympathetic nervous system activity without para-lysis of compensatory homeostatic reflexes is highly desirable even in pediatric anesthesia(38).There were no differences between groups in adverse effects of studied drugs during emergence from anesthesia or follow-up in PACU.It demon-strates the safe profile of a2-agonists such as cloni-dine and DEX as preanesthesia medication in children as previously observed in adults(11,13,39). 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