|Year : 2017 | Volume
| Issue : 2 | Page : 73-78
Comparative study between midazolam versus nalbuphine on prevention of emergence agitation after sevoflurane anesthesia in pediatric patients undergoing tonsillectomy with or without adenoidectomy
Khaled Sayed Ahmed Mohammed, Kamal El Den Haikal Ali, Hoda Ezz Alsaid Ahmed, Hesham Altatawy Ibrahem
Department of Anesthesia and Surgical Intensive Care, Faculty of Medicine, Tanta University, Tanta, Egypt
|Date of Submission||21-Feb-2017|
|Date of Acceptance||23-May-2017|
|Date of Web Publication||13-Oct-2017|
Khaled Sayed Ahmed Mohammed
Department of Anesthesia and Surgical Intensive Care, Faculty of Medicine, Tanta University, Tanta, 31631
Emergence agitation (EA) in children is increased after sevoflurane anesthesia. Nalbuphine and midazolam have been used for prophylactic treatment with controversial results.
The aim of the present study was to compare the effect of nalbuphine or midazolam before termination of sevoflurane-based anesthesia on the incidence and severity of EA in children.
Patients and methods
Totally, 90 children between 4 and 8 years of age and of American Society of Anesthesiologists I-II undergoing adenotonsillectomy under sevoflurane-based anesthesia were enrolled in the study. Children were randomly allocated to one of the two groups: group I received nalbuphine 0.1 mg/kg and group II received midazolam 0.03 mg/kg. The study drugs were administered 5 min before the end of surgery. In the postanesthesia care unit, the incidence of EA was assessed with Aonos four-point scale. Severity of EA was assessed with the pediatric anesthesia emergence delirium scale upon admission (T0), after 5 min (T5), 10 min (T10), 15 min (T15), and 30 min (T30).
The incidence and severity of EA were lower in group I as compared with group II at T0, T5, and T10.
Nalbuphine 0.1 mg/kg was more effective compared with midazolam 0.03 mg/kg in decreasing the incidence and severity of EA, when administered 5 min before the end of surgery in children undergoing adenotonsillectomy under sevoflurane anesthesia.
Keywords: emergence agitation, midazolam, nalbuphine, sevoflurane
|How to cite this article:|
Mohammed KS, Ali KE, Ahmed HE, Ibrahem HA. Comparative study between midazolam versus nalbuphine on prevention of emergence agitation after sevoflurane anesthesia in pediatric patients undergoing tonsillectomy with or without adenoidectomy. Tanta Med J 2017;45:73-8
|How to cite this URL:|
Mohammed KS, Ali KE, Ahmed HE, Ibrahem HA. Comparative study between midazolam versus nalbuphine on prevention of emergence agitation after sevoflurane anesthesia in pediatric patients undergoing tonsillectomy with or without adenoidectomy. Tanta Med J [serial online] 2017 [cited 2020 Aug 6];45:73-8. Available from: http://www.tdj.eg.net/text.asp?2017/45/2/73/216688
| Introduction|| |
Postoperative agitation, also referred to as emergence delirium in international literature, is a well-documented clinical phenomenon, particularly in children. It is characterized by mental confusion, irritability, disorientation, inconsolable crying, and increased recovery time in the postanesthesia recovery room, increasing parents’ concern and anxiety with respect to the clinical condition of their children . It can also lead to possible injury, damage to surgical dressings, lost intravenous catheters, disconnected cables and monitoring instruments, and source of dissatisfaction for parents, nurses, and others taking care of these children, and hence the children require extra nursing care and supplemental sedative and/or analgesic medications, which may delay patient discharge from hospital  and are seven times more likely to have new-onset separation anxiety, apathy, and eating and sleep problems ,.
It is during the first 30 min after emergence that the greatest incidence of agitation is observed, and the duration is generally limited. However, prolonged episodes of agitation lasting for up to 2 days have been described .
Sevoflurane is an inhalational anesthetic used widely as a pediatric or outpatient anesthetic due to its excellent hemodynamic stability and low blood solubility, which allows rapid induction and emergence from general anesthesia, as well as control of the depth of anesthesia. However, when sevoflurane is used alone it is associated with a higher incidence of EA in children. With sevoflurane anesthesia, the incidence of EA varies widely between 2 and 80% depending on the scoring system and the anesthetic technique used and is more frequently observed in preschool children. The incidence of EA has led many authors to propose prophylactic treatment to reduce its incidence. These have included propofol, α2-adrenoceptor agonists, and midazolam ,.
Nalbuphine hydrochloride is a synthetic opioid agonist‑antagonist. It is a potent analgesic and is essentially equivalent to morphine. It can also be used as a supplement to balanced anesthesia, for preoperative and postoperative analgesia , and may be a useful adjuvant to treat EA in children .
Midazolam is an agonist at γ aminobutyric acid–A receptors, and its desirable clinical effects range from anxiolytic to hypnotic depending on the percentage of receptor occupancy rather than plasma concentrations of the drug . It is also used to prevent EA after sevoflurane anesthesia .
In the literature, there is no study comparing nalbuphine and midazolam for prevention of sevoflurane EA. Thus, the aim of the study was to compare the effect of administration of a single dose of nalbuphine or midazolam before the termination of sevoflurane-based anesthesia on the incidence and severity of EA in children undergoing tonsillectomy with or without adenoidectomy.
| Patients and methods|| |
This randomized double-blind study was carried out at the ENT Department, Tanta University Hospitals, from May 2015 to November 2015 on 90 patients after approval of the local ethical committee (approval code: 2936/12/14). Written informed consent was taken from parents of 90 healthy children aged 4–8 years, with American Society of Anesthesiologists physical status I or II, scheduled to undergo tonsillectomy with or without adenoidectomy. Any child with parent refusal or preoperative agitation or physical developmental delay was excluded from the study. The patients were then randomized using a computer-generated randomization table to one of two equal groups: the nalbuphine group (group I) and the midazolam group (group II).
Preoperatively, patients were made to fast for 6 h for solids and 2 h for clear fluids. No premedications were taken for the purpose of the study. Upon arriving in the operating room each patient was monitored for heart rate (HR), ECG, SPO2, noninvasive blood pressure, and ETCO2. Parents were present and collaborated during facemask induction and then left the theater when their children closed their eyes. General anesthesia was induced for all children with oxygen 100% with fresh gas flow of 6 l/min and sevoflurane with increments of 1% at each breath up to 8%. Once an appropriate depth of anesthesia was obtained, an intravenous cannula was inserted and 10 ml/kg of lactated Ringer’s solution was infused over 20 min, followed by standard fluid maintenance therapy according to the patient’s weight. After adequate depth of anesthesia was reached, suitable endotracheal tube was inserted and sevoflurane concentration was reduced to 3 in 100% oxygen and fresh gas flow was reduced to 2 l/min. Spontaneous breathing was allowed provided ETCO2 remained below 50 mmHg; if ETCO2 exceeded 50 mmHg, the patient was excluded from the study and assisted ventilation was performed. Diclofenac sodium 2 mg/kg was given intravenously for intraoperative analgesia. At the end of the surgery and just before discontinuation of sevoflurane and extubation the study drugs were injected randomly as 0.1 mg/kg nalbuphine in group I and 0.03 mg/kg midazolam in group II.
Sevoflurane administration was discontinued immediately after the study drug injection, the fresh gas flow was increased to 8 l/min oxygen, and the patient was extubated precisely 60 s later. After extubation, patients were taken directly to the postanesthesia care unit (PACU) in a quiet and warm environment without any stimulus.
Demographic data (age, weight, and sex), type of surgery, duration of surgery, and duration of anesthesia were evaluated. HR, mean arterial blood pressure (MAP), SPO2, and respiratory rate (RR) were recorded at baseline before induction of anesthesia, at 10, 20, and 30 min intraoperatively, and at 5, 10, 20, and 30 min postoperatively. The incidence of EA was evaluated using Aono’s four-point scale , Replace:=wdReplaceAll, Format:=True, Forward:=True, MatchWildcards:=False, Wrap:=wdFindStop: 1=calm; 2=not calm but could be easily consoled; 3=moderately agitated or restless and not easily calmed; and 4=combative, excited, or disoriented, thrashing around. Scores of one and two were considered as absence of EA, and scores of 3 and 4 were analyzed as presence of EA. The severity of EA was evaluated using the pediatric anesthesia emergence delirium (PAED) scale devised by Sikich et al.  ([Table 1]) in the PACU at T0, T5, T10, T15, and T30. Children were considered severely agitated if they had a PAED scale of 15/20 or higher and were treated with intravenous propofol 1 mg/kg as rescue medication.
Postoperative pain was assessed using the modified Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) ([Table 2])  in the PACU at T5, T10, and T30. Children with CHEOPS score more than or equal to 6 received intravenous paracetamol 10 mg/kg as rescue analgesic.
Patients were discharged from the PACU when they satisfied stable vital signs: patent airway without manipulation, oxygen saturation more than or equal to 95% on room air, restoration of a state of alertness close to that observed before the procedure had begun, and state of quietness sufficient to ensure that the child is not distressed and will not harm him/herself or the attendants ([Table 2]).
| Results|| |
As regards the demographic data such as age, sex, and weight, type of surgery, duration of surgery, anesthesia, and emergence there was no significant difference between the two groups (P>0.05) ([Table 3]).
|Table 3 Demographic data, type of surgery and duration of surgery, anesthesia, and emergence in both groups|
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As regards incidence of EA according to Aono’s four-point scale in the two studied groups at awakening, it ranged from 1 to 4 in both groups with median values of 1 and 2 in groups I and II, respectively. In group I (the nalbuphine group) five (11.1%) patients had EA, whereas in group II (the midazolam group) 15 (33.3%) patients had EA. There was a statistically significant decrease in the incidence of EA in group I in comparison with group II (P<0.05) ([Figure 1]).
|Figure 1 Comparison of Incidence of EA according to Aono’s four point scale between the two studied groups.|
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As regards the severity of EA according to PAED in the two studied groups, there was a statistically significant increase in the severity of EA in group II compared with group I. Fifteen (33.3%) patients in group II had severe EA that lasted up to 10 min (PAED scale ≥15), whereas only five (11.1%) patients in group I had severe EA that lasted up to 5 min (PAED scale ≥15) ([Figure 2]).
|Figure 2 Comparison of severity of EA according (PAED) between the two studied groups.|
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As regards postoperative pain according to modified Children’s Hospital of Eastern Ontario Pain Scale (MCHEOPS) in the two studied groups, 13 (28%) patients in group II had postoperative pain (MCHEOPS ≥6) compared with only three (6%) in group I at 5 min. There was a significant decrease in MCHEOPS in the studied groups over time (P<0.05) ([Figure 3]).
|Figure 3 Comparison of postoperative pain according to MCHEOPS between the two studied groups.|
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As regards propofol and paracetamol consumption as rescue medications in the two studied groups, there was a statistically significant increase in total dose of propofol and paracetamol as rescue medications in group II compared with group I. Fifteen (33.3%) patients received propofol for the treatment of EA and 13 (28.9%) patients received paracetamol for the treatment of postoperative pain in group II, whereas five (11.1%) patients received propofol for the treatment of EA and three (6.7%) patients received paracetamol for the treatment of postoperative pain in group I (P<0.05) ([Table 4]).
As regards patients’ basic monitoring throughout the course of anesthesia (HR, MAP, peripheral oxygen saturation, end-tidal carbon dioxide, and RR), there was a nonsignificant difference between the two studied groups, except for HR and MAP in group II, which showed a significant increase postoperatively at all time intervals compared with group I (P<0.05) ([Figure 4] and [Figure 5]).
|Figure 4 Comparison of heart rate (HR) changes between the two studied groups.|
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|Figure 5 Comparison of the mean arterial blood between the two studied groups.|
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| Discussion|| |
The incidence of EA (using Aono’s four-point scale) and severity of EA (using PAED scale) were considered the primary outcomes in the present study, and we found a significant decrease in the incidence and severity of EA in the nalbuphine group (11%) in comparison with the midazolam group (33%) (which is within the usual range of EA after sevoflurane anesthesia) as indicated by the lower values of Aono’s four-point scale and PAED scale and the significantly lower need for postoperative rescue medication (propofol) in the nalbuphine group. Postoperative pain has been the most confounding variable when assessing a child’s behavior upon emergence because of the overlapping clinical picture with EA/emergence delirium. Inadequate pain relief may be the cause of agitation, particularly after short surgical procedures for which peak effects of analgesics may be delayed until the child is completely awake.
In agreement with our results, Dalens et al.  concluded that intravenous nalbuphine at the end of the procedure at a dose of 0.1 mg/kg seemed to offer the highest benefit/risk ratio when sevoflurane has been used as the sole anesthetic.
The results of the present study as regards the effect of midazolam on prevention of sevoflurane EA are in line with those of Ozcan et al. , who concluded that neither ketamine nor midazolam added to caudal block under sevoflurane anesthesia and further have effect on EA. Moreover, Breschan et al.  found that rectal midazolam given 10–15 min before surgery did not show any benefits for treating EA. Moreover, Abu-Shahwan and Chowdary  observed that the incidence of EA in children premedicated with midazolam for dental repair under sevoflurane anesthesia was as high as 34.2%.
In disagreement with our results, Cho et al.  concluded that giving 0.03 mg/kg of midazolam before the end of surgery reduces the incidence of EA in children scheduled for squint surgery. The difference with the results of the present study could be attributed to the less tissue trauma with strabismus surgery, and consequently less pain compared with adenotonsillectomy. Moreover, the mean age group in their study was 8 years, which was higher than that in our study (5 years). Moreover, Chen et al.  found that 0.05 mg/kg midazolam in combination with 0.5 µg/kg of fentanyl at the end of surgery was effective in reducing the incidence and severity of EA for cataract surgery, which could be attributed to the higher dose of midazolam in their study, and addition of 0.5 µg/kg of fentanyl to midazolam enhanced its effectiveness in reducing the incidence and severity of EA. Further, it can be attributed to the different nature of cataract surgery as compared with adenotonsillectomy as regards tissue trauma, which is more in adenotonsillectomy.
As regards the effect of studied drugs on RR and ETCO2, our results showed that there were no statistically significant changes in RR and ETCO2 and no apnea observed at all time intervals in the two studied groups.
In agreement with this study, Dalens et al.  found that no apnea was observed and no significant changes in ETCO2 at all time intervals with the nalbuphine group. Moreover, Cho et al.  concluded that there was no respiratory depression in patients who received either 0.03 or 0.05 mg/kg midazolam.
As regards hemodynamic parameters, our results showed that there was a significant increase in HR and MAP in the midazolam group compared with the nalbuphine group at postoperative measurements, especially at 5 and 10 min, which was associated with the increase in the incidence of EA in the midazolam group.
In agreement with our results, Dalens et al.  concluded that there were nonsignificant changes in vital parameters as regards HR, MAP, and SPO2 in the nalbuphine group. Moreover, Ozcan et al.  studied the effects of ketamine and midazolam on EA after sevoflurane anesthesia in children receiving caudal block and concluded that there were no significant changes in vital parameters except increase in HR and MAP postoperatively in the midazolam group more than the ketamine group.
As regards postoperative pain using the MCHEOPS scale, our results showed that there was a significant increase in pain score in the midazolam group (28%) compared with the nalbuphine group (7%) at 5 min.
In agreement with our results, Ozcan et al.  found that MCHEOPS scores were higher in the midazolam group than in the ketamine group.
| Conclusion|| |
From the results of the present study we concluded that the use of a small dose of nalbuphine (0.1 mg/kg) in sevoflurane-anesthetized children undergoing tonsillectomy with or without adenoidectomy was better than a small dose of midazolam (0.03 mg/kg) for the prevention of sevoflurane EA without any significant adverse effects.
One of the possible shortcomings of our study is the duration of surgery, which was different in patients who underwent tonsillectomy only and those who underwent adenotonsillectomy and this may affect the incidence of EA. Moreover, pain that results from adenotonsillectomy is more than that resulted from tonsillectomy alone due to more tissue trauma in adenotonsillectomy; thus, pain must be excluded to compare results in an optimal manner.
Further studies should be performed on a larger sample size of patients and different type of surgeries for generalization of these results.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Vlajkovic GP, Sindjelic RP. Emergence delirium in children: many questions, few answers. Anesth Analg 2007; 104:84–91.
Kuratani N, Oi Y. Greater incidence of emergence agitation in children after sevoflurane anesthesia as compared with halothane: a meta-analysis of randomized controlled trials. Anesthesiol 2008; 109:225–232.
Cravero J, Surgenor S, Whalen K. Emergence agitation in paediatric patients after sevoflurane anaesthesia and no surgery: a comparison with halothane. Paediatr Anaesth 2000; 10:419–424.
Redhu S, Jalwal GK, Saxena M, Shrivastava OP. A Comparative study of induction, maintenance and recovery characteristics of sevoflurane and halothane anaesthesia in pediatric patients (6 months to 6 years). J Anaesthesiol Clin Pharmacol 2010; 26:484–487.
] [Full text]
Johr M, Berger TM. Paediatric anaesthesia and inhalation agents. Best Pract Res Clin Anaesthesiol 2005; 19:501–522.
Silva LM, Braz LG, Modolo NS. Emergence agitation in pediatric anesthesia: current features. J Pediatr (Rio J) 2008; 84:107–113.
Guignard B. Monitoring analgesia. Best Pract Res Clin Anaesthesiol 2006; 20:161–180.
Dalens BJ, Pinard AM, Letourneau DR. Prevention of emergence agitation after sevoflurane anesthesia for pediatric cerebral magnetic resonance imaging by small doses of ketamine or nalbuphine administered just before discontinuing anesthesia. Anesth Analg 2006; 102:1056–1061.
Amrein R, Hetzel W. Pharmacology of drugs frequently used in ICUs: midazolam and flumazenil. Intensive Care Med 1991; 17:1–10.
Galinkin JL, Fazi LM, Cuy RM, Chiavacci RM, Shah UK, Jacobs IN et al.
Use of intranasal fentanyl in children undergoing myringotomy and tube placement during halothane and sevoflurane anesthesia. Anesthesiol 2000; 93:1378–1383.
Aono J, Ueda W, Mamiya K, Takimoto E, Manabe M. Greater incidence of delirium during recovery from sevoflurane anesthesia in preschool boys. Anesthesiol 1997; 87:1298–1300.
Sikich N, Lerman J. Development and psychometric evaluation of the pediatric anesthesia emergence delirium scale. Anesthesiol 2004; 100:1138–1145.
Mitchell P. Understanding a young child’s pain. Lancet 1999; 354:1708–1709.
Ozcan A, Kaya A, Ozcan N, Karaaslan H, Er E, Baltaci B et al.
Effects of ketamine and midazolam on emergence agitation aftersevoflurane anaesthesia in children receiving caudal block: a randomized trial. Rev Bras Anestesiol 2014; 64:377–381.
Breschan C, Platzer M, Jost R, Settener H, Likard R. Midazolam does not reduce emergence delirium after sevoflurane anesthesia in children. Paediatr Anaesth 2007; 17:347–352.
Abu-Shahwan I, Chowdary K. Ketamine is effective in decreasing the incidence of emergence agitation in children undergoing dental repair under sevoflurane general anesthesia. Paediatr Anaesth 2007; 17:846–850.
Cho E, Yoon S, Cho J, Lee HW. Comparison of the effects of 0.03 and 0.05 mg/kg midazolam with placebo on prevention of emergence agitation in children having strabismus surgery. Anesthesiol 2014; 120:1354–1361.
Chen J, Li W, Hu X, Wang D. Emergence agitation after cataract surgery in children: a comparison of midazolam, propofol and ketamine. Paediatr Anaesth 2010; 20:873–879.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]