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Delayed emergence from anesthesia, Emergence delirium, Dexmedetomidine, Cleft palate, Tonsillectomy, What&,rsquo s Known The etiology of emergence agitation (EA) in children is not exactly known. The risk factors associated with EA are age, pre-operative anxiety, inhaled anesthetics, anesthetic technique, type of surgery, and postoperative pain. What&,rsquo s New EA is a preventable side effect of inhalational anesthetics. Anesthesiologists should choose the most appropriate technique or drug to reduce the incidence of EA toward smooth recovery from anesthesia. Dexmedetomidine is a safe and effective choice due to its sedative and analgesic properties. IntroductionEmergence agitation (EA) in children is a dissociated state of consciousness characterized by irritability, uncompromising stance, and inconsolability. It is commonly exhibited as incoherence, prolonged crying, kicking, or thrashing. 1, The incidence of EA is not exactly known but has been reported to vary from 2% to 80%. 2, , 3, EA usually occurs within 30 minutes after termination of general anesthesia in the post-anesthesia care unit (PACU). Although it is usually short-lived, it may harm the child, since an agitated child may pull out indwelling catheters or cause bleeding at the surgical site. Not only will these be disturbing sights for the parents, but will also necessitate additional nursing care. 2, The etiology of EA is not completely understood, but reported risk factors are age, pre-operative anxiety, inhaled anesthetics, anesthetic technique, type of surgery (head and neck), and postoperative pain. 2, Sevoflurane is an inhalational anesthetic for both the induction and maintenance of anesthesia in children. It provides rapid induction and emergence from anesthesia, due to its low blood solubility, and has desirable properties such as agreeable odor, less airway irritation, and stable hemodynamic profile. However, sevoflurane is associated with increased EA in children, 3, particularly in adenotonsillectomy and cleft palate repair surgery. Adenotonsillectomy is the first-line treatment for obstructive sleep apnea. It is a common procedure with an estimated prevalence rate of 15% in those under the age of 15. 4, , 5, Cleft palate is the most common congenital anomaly of the gastrointestinal tract representing 15% of all congenital anomalies. 6, These surgeries are common in children and associated with increased EA after sevoflurane anesthesia due to severe pain, upper airway narrowing, tongue swelling, and a sense of suffocation. 7, Pediatric anesthesiologists should always consider adjuvant drugs to reduce EA. Several drugs such as benzodiazepines, opioids, ketamine, and propofol have been used to reduce EA. However, the main concern is their side effects such as pain, postoperative nausea and vomiting, and respiratory depression. 8, Dexmedetomidine is a potent &,alpha 2-adrenoreceptor agonist with sedative and analgesic properties. 9, It has been used as an adjuvant to local anesthetics to prolong the duration of neuraxial blocks 10, and is shown to reduce bleeding during neurosurgical operations. 11, Various studies have investigated the efficacy of dexmedetomidine toward EA prevention compared to other drugs or placebo. 12, - 14, However, to the best of our knowledge, no studies have investigated the effect of dexmedetomidine administration at different time points during surgery. Hence, we assessed the efficacy of dexmedetomidine infusion on EA at two-time points, namely during the first and last 10 minutes of adenotonsillectomy and cleft palate repair surgery. In addition, we assessed the pain score, sedation score, extubation time, PACU length of stay, and hemodynamic changes in pediatric patients undergoing these surgeries.Patients and MethodsA randomized, parallel, double-blind clinical trial was conducted at Mofid Children&,rsquo s Hospital affiliated to Shahid Beheshti University of Medical Sciences (Tehran, Iran) from November 2016 to March 2017. The study protocol was approved by both the Institutional Review Board and Medical Ethics Committee of the University (number, IR.SBMU.MSP.95.281). The trial was registered at the Iranian Registry of Clinical Trials (registration number, IRCT 2016122031497N1).The sample size was calculated using the below formula. 14, Considering a dropout rate of 20%, alpha level probability=0.05, and power=0.80, a sample size of 80 participants (40 per group) was required. N = ( Z 1 - &,alpha 2 + Z 1-&,beta ) 2 ( P 1 ( 1 - P 1 ) + P 2 ( 1 - P 2 ) ) ( P 1 - P 2 ) 2 where, &,alpha =0.05, &,beta =0.2, Z1=1.96, P1=0.30, P2=0.61Accordingly, a total of 81 children, who underwent adenotonsillectomy or cleft palate repair surgery were enrolled in the study. The inclusion criteria were children aged nine months to nine years and those with American Society of Anesthesiologists (ASA) physical status class 1. The exclusion criteria were children with a history of congenital cardiac disorder, mental retardation, liver disease, renal disease, allergy to any drugs used in this study, and a history of acute upper respiratory infection. Written informed consent was obtained from the parents of the eligible children. The basic method of simple randomization was used to assign the children to two groups, namely early (group A, n=41) and late (group B, n=40) administration of dexmedetomidine. Randomization was carried out by a nurse anesthetist (not involved in the study), using computer-generated random numbers in sealed envelopes. The same nurse also prepared and labeled sets of two 10 mL syringes of the same shape and size. The syringe labeled A contained dexmedetomidine (Precedex&,reg , Hospira Inc., Lake Forest, USA) at a concentration of 10 mcg/kg and the syringe labeled B contained physiologic saline solution (Darou Pakhsh Pharma Chem, Tehran, Iran). All children orally received midazolam 0.5 mg/kg (Caspian Tamin Pharmaceutical Co., Iran) 30 minutes before entering the operating room. Standard monitoring of all patients included non-invasive monitoring of arterial blood pressure, heart rate, oxygen saturation, electrocardiogram, and capnography. Anesthesia was induced by inhalation of sevoflurane 8% (Baxter, USA) through a face mask and decreased gradually to 1 MAC (minimum alveolar concentration) after the loss of consciousness. Then, an IV catheter (SUPA, Iran) was inserted followed by intravenous administration of fentanyl 1 &,micro g/kg and atracurium 0.5 mg/kg (both from Aburaihan pharmaceutical Co., Iran). After three minutes, patients were intubated and administered a mixture of 50% nitrous oxide (Shomal Co., Iran), oxygen, and 1 MAC sevoflurane for maintenance of anesthesia. All patients received Ringer&,rsquo s solution (Samen pharmaceutical CO., Iran) for maintenance fluid therapy. Vital signs were recorded every five minutes, and in the case of hemodynamic changes &,gt 20% above the baseline, the patient was treated and excluded from the analysis. After intubation, children in the early group were administered dexmedetomidine infusion (syringe labeled A) during the first 10 minutes and saline solution (syringe labeled B) during the last 10 minutes of surgery. The reverse applied to children in the late group, i.e., they were injected with the syringe labeled B during the first 10 minutes and with the syringe labeled A during the last 10 minutes of surgery. At the end of the surgery, all anesthetics were discontinued and the patients ventilated with 100% oxygen. Upon reaching optimal general conditions, patients were extubated and transferred to the PACU. As the primary outcome, the sedation level of children was measured using the Ramsay sedation scale (table 1,). The scale is scored from one to six, where higher scores indicate a higher level of sedation. 15, Secondary outcomes were the time from discontinuation of anesthetic drugs to extubation, arterial blood pressure and heart rate (recorded every 10 minutes by a trained nurse blinded to grouping), and the level of postoperative pain (measured using the FLACC scale). The FLACC (face, legs, activity, cry, consolability) scale is used to assess pain based on five criteria and scored in the range of 0-10 (table 2,). 16, , 17, Children with pain scores &,gt 4 were given fentanyl 0.5 &,micro g/kg for rescue analgesia. As soon as the discharge criteria were fulfilled, the children were transferred to the appropriate ward and the PACU length of stay was noted. LevelCharacteristics1Patient awake, anxious, agitated, or restless2Patient awake, cooperative, orientated, and tranquil3Patient drowsy, with response to commands4Patient asleep, brisk response to glabella tap or loud auditory stimulus5Patient asleep, sluggish response to stimulus6Patient has no response to firm nail-bed pressure or other noxious stimuliTable 1.Levels of sedation according to the Ramsay sedation scale.FaceNo particular expression or smileOccasional grimace or frown, withdrawn, disinterested, sad, appears worriedFrequency to the constant quivering chin, clenched jaw, distressed looking face, expression of fright/panicLegsNormal position or relaxed usual tone and motion to limbsUneasy, restless, tense, occasional tremorsKicking or legs drawn up, marked increase in spasticity, constant tremors, jerkingActivityLying quietly, normal position, moves easily, regular, rhythmic respirationSquirming, shifting back and forth, tense/guarded movements, mildly agitated, shallow/splinting respirations, intermittent sighsArched, rigid, or jerking severe agitation, head-banging, shivering, breath-holding, gasping, severe splintingCryNo cry (awake or asleep) Moans or whimpers, occasional complaint, occasional verbal outbursts, constant gruntingCrying steadily, screams or sobs, frequent complaints, repeated outbursts, constant gruntingConsolabilityContent, relaxedReassured by occasional touching, hugging, or being talked to distractibleDifficult to console or comfort, pushing caregiver away, resisting care or comfort measuresTable 2.The criteria for the FLACC behavioral pain scale. Each of the five categories (F) face, (L) legs, (A) activity, (C) cry, (C) consolability is scored from 0-2, resulting in a total score between zero and ten Statistical Analysis The data were analyzed using SPSS software (version 20.0). Quantitative and qualitative variables were presented as mean&,plusmn SD and frequency and percentages, respectively. Quantitative variables between groups were compared using an independent t test. Qualitative variables between groups were compared using Fisher&,rsquo s exact t test and Chi squared test. Using 95% confidence interval, P values less than 0.05 were considered statistically significant. ResultsFrom a total of 98 eligible children scheduled for an adenotonsillectomy or cleft palate repair surgery, 17 were excluded due to allergy or asthma (n=7), congenital heart disease (n=4), and parental objection to participation (n=6). Eventually, 81 children were enrolled in the study and randomly assigned to two groups (figure 1,).Figure 1. The CONSORT diagram shows the allocation process throughout the trial.There was no significant difference between the early and the late groups concerning the patients&,rsquo demographic data such as age, weight, female/male ratio, the total time of anesthesia, operative time, and PACU length of stay. However, extubation time in the early group was significantly shorter than late group (9.59&,plusmn 3.15 vs. 15.43&,plusmn 8.40 min, P&,lt 0.001) (table 3,). Group A (early) Group B (late)P valueAge (months)59.81&,plusmn 29.4369.42&,plusmn 36.600.195*,Weight (kg)18.76&,plusmn 6.6018.94&,plusmn 6.230.959*,Sex (n, %)Male25 (61)21 (52.2)0.505#,Female16 (39)19(47.5)Total time of anesthesia (minutes)89.27&,plusmn 31.2683.38&,plusmn 26.250.373*,Surgical time (minutes)60.24&,plusmn 27.6852.25&,plusmn 23.230.164*,Extubation time (minutes)9.59&,plusmn 3.1515.43&,plusmn 8.40&,lt 0.001*,PACU length of stay (minutes)24.72&,plusmn 10.2528.21&,plusmn 9.700.135*,*Independent sample t test #Chi square test |