Investigating the Effect of Dexmedetomidine in Controlling Postoperative Emergence Agitation in Children under Sevoflurane Anesthesia

Introduction Emergence agitation (EA) is one of the common problems during recovery from general anesthesia, especially in children. In this study, we investigated the effect of dexmedetomidine on the control of agitation after anesthesia with sevoflurane in children. Method This randomized control-placebo, double-blind prospective clinical trial was conducted on seventy-six children between 2 and 7 years with ASA (American Society of Anesthesiologists) class I who were candidates for elective adenoidectomy surgery and tonsillectomy. Participants were selected by an available sampling method. Patients were randomly placed in one of the two groups D (dexmedetomidine 0.5 μg/kg infusion within ten minutes) or P (placebo: normal saline infusion within ten minutes). A four-point scale evaluated agitation. Pain evaluation was done by FLACC (faces, legs, activity, cry, and consolability). The statistical software was SPSS version 23. P < 0.05 was considered statistically significant. Results The level of agitation was significantly lower in the intervention group (P < 0.05), except after 40 minutes in the PACU (Post Anesthesia Care Unit) (P=1.00). Patients in the control group experienced high pain scores when admitted at PACU, 10, 20, and 30 minutes after admission at PACU (P < 0.05). Pethidine and metoclopramide prescriptions in the intervention group were lower than in the control group (P < 0.05). Shivering occurred in five patients in the intervention group and nine in the control groups (P=0.032). Hypotension that required intervention occurred in 3 patients in the intervention group and one in the control group (P=0.024). Conclusion Our trial demonstrated that the prescription of 0.5 μg/kg of dexmedetomidine within ten minutes after intubation significantly reduced the EA frequency, pain severity, analgesic consumption, and PONV (postoperative nausea and vomiting). However, it caused delays in the emergence from anesthesia. This trial is registered with IRCT20160430027677N14.


Introduction
Agitation after awakening was frst expressed in 1960 and was defned as a dissociated phase of awakening that is accompanied by a series of emotional reactions so that the child becomes restless and even inconsolable.Children have no cooperation and sometimes show aggressive behavior [1,2].Tis complication is very stressful for children, their parents, and the medical staf.Despite the relatively large number of articles on EA (emergence agitation), there is limited information about its prevalence, pathophysiology, causes, or even its control or treatment.EA prevalence in the papers, depending on the determining method and criteria used by researchers, is reported between 25% and 80% [3].It seems that a series of possible causes are efective in its occurrences, such as preschool age, anxiety before surgery, personality characteristics, the early awakening after anesthesia, presence of pain, kind of surgery (such as eye or ear, nose, and throat surgeries), technique and type of drugs prescribed for anesthesia (Newer Inhalation Anesthesia agents such as isofurane, sevofurane, and desfurane), and even environmental issues [2][3][4].EA can have clinically signifcant consequences, such as the patient's self-injury, which causes pain or may even cause bleeding from the surgical site, difculty in taking care of a restless child, prolonged recovery time, the need for additional medical care, and fnally, increased costs [4][5][6].
Sevofurane is a halogenated inhalational anesthetic agent used to induce and maintain general anesthesia and widely used in pediatric anesthesia due to its lack of unpleasant odor, low blood-to-gas solubility ratio, rapid anesthesia induction, the early awakening of patients, stable hemodynamic maintenance, mild cardiovascular system depression, and low liver toxicity.Although there are many advantages to anesthesia with sevofurane, agitation when coming out of anesthesia (emergence agitation "EA") is one of the common side efects of anesthesia with this drug in children [7].
Various drugs such as opiates, benzodiazepines, ketamine, propofol, sodium thiopental, and α2-agonists such as dexmedetomidine have been used to prevent and treat this condition.Still, the results regarding their efectiveness are diferent and are always discussed [8].Meanwhile, a metaanalysis research found evidence in favor of dexmedetomidine being used as a premedication to control agitation in children undergoing both painful and nonpainful procedures [9].Nonetheless, it suggests that more research be done to determine the ideal DEX dosage, route, patterns, and timing as well as how it afects other results.Terefore, it appears that it will also be helpful in reducing children's agitation following surgery.
Dexmedetomidine is a specifc α2 adrenoceptor agonist with a ratio (α2/α1 � 1620/1).In addition, the drug has sedative and pain-relieving properties [10].Te sedative efect is caused by its action on α2 presynaptic receptors in the locus coeruleus, which reduces the release of adrenaline and facilitates the inhibitory activity of neurons, especially the gamma-aminobutyric acid system.Its analgesic efect is created through the α2 receptor on the posterior horn of the spinal cord and the supraspinal cord, reducing the secretion of substance P [11].It should be noted that although the sedative dose of dexmedetomidine does not cause respiratory depression, it can cause cardiovascular efects, so it needs careful monitoring.
Some studies have indicated that dexmedetomidine can reduce the prevalence of EA caused by sevofurane in pediatric patients.However, it is controversial, and they announced that more studies are required to evaluate the efect of dexmedetomidine on the prevention of PONV [9,12].Terefore, according to the mentioned points and the lack of such a study in our society, this clinical trial investigated the efect of dexmedetomidine in preventing or reducing the prevalence of agitation after anesthesia when coming out of anesthesia in children under general anesthesia with sevofurane.

Methods
In this randomized control-placebo, double-blind prospective clinical trial, after acquiring ethical approval from the university's ethics committee (ID: IR.UMSU.REC.1397.411and Date: 2019-01-16), parents were sufciently explained by the anesthesiologist about the procedure and performing the trial, and then parents signed the consent form.Seventy-six children between 2 and 7 years with ASA class I who were candidates for elective adenoidectomy surgery, tonsillectomy, or both were selected by an easy and available sampling method.Te study started on 2019-05-11, and sampling ended on 2019-07-26.After selecting one of 76 cards (containing cover) by parents, patients were randomly placed in one of the two groups D (dexmedetomidine) or P (placebo), where each group consisted of 38 people.Tis double-blind, randomized clinical trial is registered in Iranian Randomized Clinical Trials (ID: IRCT20160430027677N14 and Date: 2019-05-07).

Sample Size.
Based on the mean FLACC and Ramsy sedation scores in the Sadeghi et al. study, which compared the efcacy of early versus late administration of dexmedetomidine on EA in children undergoing oral surgery [13], and according to the formula for determining the sample size of analytical studies to compare the estimation of proportions in two groups (Pocock's method) and considering the test power of 90% and 95% confdence interval, the required sample size (considering the possibility of a 10% sample drop) for each group was determined to be 38 people.Six hours before the surgery, patients did not receive any solid food or milk; if necessary, they only consumed fltered liquids up to 2 hours before the surgery.None of the patients received premedication, and once patients arrived in the operating room, they were evaluated and scored in terms of agitation using the four-point scale method.Ten they were subjected to routine monitoring such as electrocardiography, pulse oximetry, and noninvasive sphygmomanometer.Without the presence of the parents, the children were subjected to induction of anesthesia by preoxygenation with O2 100%, sevofurane with its gradual increase up to a maximum of 8% and 100% oxygen.After losing consciousness, an intravenous line was inserted, 0.5 mg/kg of atracurium was injected, and then intubation was performed with an appropriate tracheal tube.Ten, for each of the patients in the intervention group, 0.5 μg/kg of dexmedetomidine, and in the placebo group, an equal volume of normal saline was infused within ten minutes.It should be noted that dexmedetomidine was taken from 100 micrograms per milliliter and diluted in a 50 ml syringe with normal saline to achieve a fnal 4 mcg/ml concentration.Te desired dose was placed in a ffty-milliliter syringe and injected through a syringe pump.Of course, the same volume and method were also prepared and performed for the placebo group so that a 50 ml syringe containing normal saline was loaded through a syringe pump.
Te method of preparing and injecting the drugs was done by an anesthetist who was unaware of which patient belonged to which group.Te drug containers were similar.After data collection, the anesthesiologist and ENT specialist were informed about the patients' groups.
In both groups, simultaneously with the injection of the study drugs, acetaminophen suppositories of 12 mg/kilogram and ondansetron 0.15 mg/kilogram were prescribed for each patient.Anesthesia was maintained with MAC (Minimum Alveolar Concentration) of 2-4% sevofurane and 50% oxygen, and 50% nitrous oxide.During anesthesia, heart rate, mean arterial pressure, arterial oxygen saturation (SPO2), and end-tidal CO2 (EtCO2) were continuously monitored.A decrease in heart rate or blood pressure up to 10% of the baseline value was acceptable, and less than that was corrected by reducing anesthetic drugs and administering fuids.If it was ≤60 HR, atropine 0.02 microgram/kilogram was injected.At the end of the surgery, the anesthetic gases were turned of.Te neuromuscular block was reversed by injecting 40 μg/kg of neostigmine and 20 μg/kg of atropine.After ensuring patients could maintain the gag refex, the presence of mimicry on the face, and observing the limbs' movements in a targeted way, the tracheal tube was removed after oropharyngeal suction.Te time between insertion and removal of the oral and pharyngeal pack was considered the surgery time, and the time from induction with sevofurane to removing the endotracheal tube was considered the anesthesia time.Te extubation time was calculated from the time of completion of the surgery to the removal of the endotracheal tube.Te emergence period from anesthesia was defned as when the patient spontaneously opened their eyes for more than 5 seconds.When entering PACU, the heart rate, mean arterial pressure, arterial oxygen saturation (SPO2), and breathing rate were recorded continuously for 30 minutes by the anesthesia nurse in PACU, who was unaware of the grouping of patients.For all patients, we placed a hot air blower in the PACU unit.Parents were not allowed in PACU according to hospital internal policies.Te study fow diagram is showed in Figure 1.

Randomization and Blinding.
Te participants and their parents were unaware of the groups' assignments.Te randomization process was done using a random number generator to ensure the allocation was truly random.In this clinical trial, participants were randomly assigned to either the interventional or placebo according to the random number table (38 people in the intervention group and 38 in the control group), and then the study began.
2.6.Measurements.Evaluation of agitation after anesthesia was done at six-time intervals.Te frst time was after extubation, then the time of leaving the operating room, and then 10, 20, 30, and 40 minutes after the patient was in PACU, which was evaluated by an Aonos four-point scale [14] and included 1 � calm, 2 � not calm, but could be easily calmed, 3 � moderately agitated or restless, and 4 � combative, excited, disoriented.Scores of one and two were defned as the absence of EA after anesthesia, and scores of three and four were interpreted as the presence of emergence agitation after anesthesia.Pain evaluation was done by FLACC (faces, legs, activity, cry, and consolability) [15].Te FLACC scale assesses pain for children between 2 months and seven years or individuals unable to express their pain.Te score 0 � relaxed and comfortable, 1-3 � mild discomfort, 4-6 � moderate pain, and 7-10 � severe discomfort/pain [15].If EA ≥3 or FLACC ≥5, pethidine was injected at 0.5 mg/kg, and if the symptoms of agitation after anesthesia did not decrease or disappear, the same dose was repeated 20 minutes later.In case of vomiting, 0.15 mg/kg of metoclopramide was injected.In addition to the frequency of agitation after anesthesia, the duration of surgery and anesthesia, the time interval of shutting of the anesthetic gases and removing the tracheal tube, the length of PACU, and complications such as bradycardia, decrease in saturation <95% SPO2, vomiting, shivering, and laryngospasm were recorded.Finally, the patients were discharged from the PACU ward according to Aldrette's score [7].

Statistical Analysis.
Data were reported using descriptive statistics (frequency and percentage) and mean-± standard deviation (mean ± SD).T-test was used to analyze quantitative data, and the chi-square test was used for qualitative variables.Te statistical software used was SPSS version 23.P < 0.05 was considered statistically signifcant.
Anesthesiology Research and Practice

Results
Te pediatrics' demographic data in the intervention and control groups are illustrated in Table 1.Te chi-square and t-tests showed no statistically signifcant diference between the two groups' data regarding gender, age, BMI, duration of anesthesia, and surgery (P > 0.05).It demonstrated that both groups were homogeneous in terms of demographic characteristics.Te mean time of emergence from anesthesia was signifcantly lower in the control group than in the intervention group (P � 0.001).

Mean Heart Rate.
Te mean heart rate in the intervention group after the injection of dexmedetomidine was signifcantly lower than the control group.However, there was no signifcant diference between the heart rate at the other designated times (Table 2).

Mean Arterial
Pressure.Te mean arterial pressure at 5 and 10 minutes after starting the surgery was lower in the intervention group than in the control group, and it was statistically signifcant (P < 0.05).Moreover, there were signifcant diferences between the two groups at times before transferring to PACU, when arriving at the PACU, and in the frst 10 minutes of PACU (P < 0.05) (Table 3).

Incidence of Agitation.
Te incidence of emergence agitation after anesthesia in the control group was signifcantly higher than in the intervention group (P < 0.05).So, 53.95% of patients in the control group and 34.21% in the intervention group had emergence agitation after anesthesia (Table 4).
Te mean stay in PACU was 40 ± 6.27 minutes in the control group and 42.32 ± 5.73 minutes in the intervention group.Tere was no signifcant diference between the length of stay in PACU between the two study groups (P � 0.183).

Te Mean Pain
Score.Patients in the control group experienced high pain scores when admitted to PACU, 10, 20, 30, and 40 minutes after admission to PACU compared with the intervention group, and this diference was statistically signifcant (P � 0.01), (P � 0.001), (P � 0.001), and (P � 0.001) respectively (Figure 2).Forty minutes after PACU admission, the mean pain score in the control group was lower than the intervention, but according to the t-test, it was insignifcant (P � 0.064).However, when patients were discharged from the PACU, the mean pain score in the intervention group was lower than the control group (P � 0.082).Regarding the agitation score, both groups were calm (P � 1.00) (Table 4).

Randomized (1:1)
Exclusion criteria were: Mental retardation or presence of neurological diseases; upper airway abnormality; history of asthma or other lung diseases; and presence of lung infections in the last four weeks.
Seventy-six patients aged 2 to 7 years, by ASA class I, were candidates for elective adenoidectomy surgery, tonsillectomy, or both.

Control group (N=38):
The patients in the control group received an equal volume of normal saline infusion within ten minutes.

Intervention group (N=38):
The patients in the intervention group received an infusion of 0.5 mg/kg/h of dexmedetomidine within ten minutes.4 Anesthesiology Research and Practice

Antiemetic and Analgesic Consumption.
Te rate of nausea and vomiting was signifcantly higher in the control group than in the intervention group.Hence, the control group required more ondansetron than the intervention group, which was statistically signifcant (P � 0.027).Moreover, the frequency of pethidine prescription in the intervention group was signifcantly lower than in the control group (P � 0.001) (Figure 3).Values are presented as mean ± SD or number.Te mean arterial pressure was signifcantly lower in the intervention group at 5 and 10 minutes after starting the surgery, before transferring to recovery, when arriving at the recovery, and in the frst 10 minutes of recovery (P < 0.05) * .
3.6.Complications.Shivering occurred in fve patients in the intervention group and nine in the control groups, and it was statistically signifcant (P � 0.032).Hypotension that required treatment occurred in 3 patients in the intervention group and one in the control group, which was statistically signifcant (P � 0.024).Bradycardia and hypoxemia in both groups were not observed.Tere was no laryngospasm in both studied groups.

Discussion
Agitation following general anesthesia is usually self-limiting and often disappears immediately [8].However, in many cases, it causes harm to oneself or others, in which case it needs treatment or even prevention [9].Dexmedetomidine is a strong α2 adrenoceptor agonist that causes analgesic and sedative efects without respiratory depression [10,11].Terefore, dexmedetomidine can be an efective adjuvant drug in anesthesia due to the reduction of the dose of anesthetic drugs and its analgesic properties [10,12].In our study, dexmedetomidine efectively reduced agitation after anesthesia without prolonging the emergence from anesthesia or delaying the patients' discharge from PACU.One reason for this could be the combination of analgesic and sedative efects of this drug, which protect against agitation after anesthesia.Previous studies showed P � 1.00 2 (not calm, but could be easily calmed) 0 (0.0%) 0 (0.0%) 3 (moderately agitated or restless) 0 (0.0%) 0 (0.0%) 4 (combative, excited, and disoriented) 0 (0.0%) 0 (0.0%) Regarding levels of emergence agitation after anesthesia, the level of agitation was signifcantly lower in the intervention group (P < 0.05), except forty minutes after staying in the recovery (P � 1.00).that dexmedetomidine with a dose of 0.1-0.5 μg/kg efectively reduced emergence agitation after anesthesia caused by sevofurane [16].In this trial, we used a dose of 0.5 μg/kg dexmedetomidine in bolus form after anesthesia induction which caused the frequency of emergence agitation after anesthesia in the dexmedetomidine group to be signifcantly lower than in the placebo group.In some similar studies, more bolus doses or even the diferent infusion types followed by bolus doses have been used, but the results similarly showed a signifcant reduction of agitation after anesthesia.In a trial conducted by Kim et al., they evaluated forty children undergoing ambulatory hernioplasty or orchiopexy; patients in the dexmedetomidine group received dexmedetomidine 1 μg/kg, followed by 0.1 μg/kg/h until the end of the surgery.In contrast, the saline group received volume-matched normal saline.Sevofurane was used for induction and maintenance of anesthesia, and a caudal block was performed in all patients.Teir trial demonstrated that end-tidal sevofurane concentration in the dexmedetomidine group was signifcantly reduced by 23.8-67% compared to the saline group during the operation.Moreover, postoperative pain and the incidence of emergence agitation after anesthesia were lower in the dexmedetomidine group than in the saline group (5% vs. 55%, P � 0.001) [17].Te reason for the lower prevalence of EA in the Na Young Kim study compared to our trial can be justifed by considering the higher dose prescribed in the Na Young Kim study and the less painful kind of surgery or even the presence of caudal block in their study.Te dose used in Kim's study and the method of injection of dexmedetomidine were diferent from the dose and injection method in our trial.Ahmed Mostafa Abd El-Hamid and Hany Mahmoud Yassin [18] investigated the safety and efectiveness of intranasal dexmedetomidine (1 μg/kg) in reducing the incidence and severity of emergence agitation after anesthesia in 86 patients who were scheduled for tonsillectomy or adenoidectomy under general anesthesia with sevofurane.Results showed a signifcant diference in the incidence of emergence agitation after anesthesia between the intervention group and control group (6.98% and 58%, respectively, with P � 0.001).Extubation, emergence, and discharge times were comparable in both groups.El-Sherbiny et al. [19] reported that adding dexmedetomidine to bupivacaine in sub-Tenon's block can alleviate postoperative emergence agitation and nausea and vomiting with better pain management and hemodynamic stability in pediatric strabismus surgery under sevofurane anesthesia [19].In KIran Sharma's trial, premedication of dexmedetomidine 10 min before induction of anesthesia at the dose of 1 μg/kg in children undergoing adenotonsillectomy resulted in a favorable efect on intraoperative hemodynamics, the signifcant decrease in postoperative emergence agitation without causing any excessive sedation, desaturation, or any other drug-related adverse events [20].Although the results of these investigations were somewhat similar to ours, the dose and method of administration of dexmedetomidine were utterly diferent.Our trial only prescribed an infusion of 0.5 μg/kg of dexmedetomidine within ten minutes of induction of anesthesia.Begum et al. [21] evaluated patients aged 2-12 years undergoing lower abdominal surgeries with sevofurane; results illustrated that both bolus and low-dose infusion of dexmedetomidine were efective for the prevention of emergence agitation after anesthesia with sevofurane, but bolus dose of dexmedetomidine was more efective.Dexmedetomidine has numerous benefcial features as a sedative and anesthetic.Te desirable physiological efects and few side efects of dexmedetomidine make it a compelling addition to anesthesia (both general and regional) for a wide range of procedures across all age groups.Kim et al. compared the preoperative administration of dexmedetomidine on the incidence and severity of emergence agitation after anesthesia in adults undergoing closed reduction of nasal bone fractures.Teir study illustrated that preoperative administration of dexmedetomidine had a lower incidence of emergence agitation after anesthesia, reduced agitation severity, and a shorter duration of agitation [22].Despite the diference in the method of dexmedetomidine administration, the type of surgery, and the age group in our study with the mentioned trial [22], the results of both studies were similar.However, the duration of agitation in our trial was not measured.Te cause of emergence agitation reduction after dexmedetomidine administration is unknown, but its analgesic and sedative efects may prevent this complication.However, recent meta-analyses have shown that the analgesic efects of dexmedetomidine do not seem to play a role in this regard [23], and even in other studies, it has been stated that the low prevalence of emergence agitation after anesthesia following the administration of dexmedetomidine can be due to the lower concentrations of sevofurane.Te combination of the efects of reducing the concentration of sevofurane due to the simultaneous administration of dexmedetomidine in the maintenance of anesthesia causes a decrease in the prevalence of emergence agitation after anesthesia [24].

Recovery
Using dexmedetomidine in our trial signifcantly reduced antiemetic and analgesic consumption, shivering incidence, and pain intensity in the intervention group until the 40minute postoperative time when pain scores were the same.Some studies demonstrated that pediatrics who received dexmedetomidine simultaneous with sevofurane Anesthesiology Research and Practice experienced a lower incidence of emergence agitation after anesthesia, pain, shivering, and PONV [5,18,[25][26][27][28].Also, they received lower amounts of antiemetic and analgesic [5,18,[25][26][27].Considering that agitation and pain evaluation in children is complicated, it should be remembered that pain may afect the level of the agitation and may be interpreted as agitation; on the contrary, pain may be considered as agitation.Tis issue also causes diferences in presenting different frequencies of emergence agitation after anesthesia in the diferent studies.So we evaluated agitation at 6-time intervals by a four-point scale, and pain evaluation was performed by FLACC (faces, legs, activity, cry, and consolability).In the El-Hamid and Yassin [18] investigation, the mean FLACC pain score in the intervention group (received dexmedetomidine) was signifcantly lower than the control group at all six-time intervals.Also, El-Sherbiny et al. [19] revealed that the pediatric candidates for strabismus surgery who received dexmedetomidine and bupivacaine in sub-Tenon's block had lower pain scores compared to the control group (only bupivacaine).
Dexmedetomidine can cause hemodynamic variation in patients (bradycardia and hypotension are more common), and it is related to the nature of the drug (alpha2 agonist).Tis drug can even cause a transient increase in blood pressure, probably caused by peripheral α-receptor stimulation.In this study, hypotension that required intervention occurred in 3 patients in the intervention group and one in the control group, which was statistically signifcant (P � 0.024).Te cases of hypotension were compensated by prescribing a small amount of IV fuids.Te bradycardia and hypoxemia in both groups were not observed.Hemodynamic disturbances with dexmedetomidine are common after minor surgeries, even with low doses, and reported in some clinical trials [17,25].

Conclusion
Our trial demonstrated that the prescription of 0.5 μg/kg of dexmedetomidine within ten minutes after intubation signifcantly reduced the emergence agitation after anesthesia, pain severity, postoperative analgesic consumption, and PONV without delaying anesthesia emerging and comparable adverse efects.

Study Limitations.
A limitation in our trial was parental psychological consideration which was not assessed in this study, and we recommend that in the other trials, the researchers consider it.

Suggestions.
Conducting more clinical investigations with diferent methods and large sample sizes in this feld and combining clinical knowledge and experience to generalize the results of evidence-based studies are suggested.

Figure 2 :
Figure 2: Mean pain score in both groups according to the FLACC scale.Compared with the intervention group, patients in the control group experienced high pain scores when admitted to PACU, 10, 20, 30, and 40 minutes after admission to PACU (P < 0.05).

Figure 3 :
Figure 3: Frequency of antivomiting and analgesic consumption.Te frequency of pethidine and ondansetron prescriptions in the intervention group was lower than in the control group (P < 0.05).

Table 1 :
Children's demographic data in both groups.Values are presented as mean ± SD or number.Tere were no signifcant diferences between demographic data in the two groups (P > 0.05).However, emergence from anesthesia was signifcantly lower in the control group (P � 0.001) * .

Table 2 :
Mean heart rate in both intervention and control groups.
Values are presented as mean ± SD or number.Te mean heart rate was signifcantly lower in the intervention group only after the injection of dexmedetomidine, 5 and 10 minutes after starting the surgery (P < 0.05) * .

Table 3 :
Mean arterial pressure in both intervention and control groups.

Table 4 :
Te incidence of emergence agitation in the control and intervention group.