Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 7  |  Issue : 3  |  Page : 282-288

Magnesium sulfate reduces sevoflurane-induced emergence agitation in pediatric patients


Department of Anesthesia and Intensive Care, Ain-Shams University, Cairo, Egypt

Date of Submission09-Feb-2013
Date of Acceptance24-Feb-2013
Date of Web Publication27-Aug-2014

Correspondence Address:
Rasha S Bondok
Department of Anesthesia and Intensive Care, Ain-Shams University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.139544

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  Abstract 

Background
Despite the fact that sevoflurane is widely used in pediatric anesthesia due to its fast and well-tolerated inhaled induction and rapid emergence, sevoflurane-induced emergence agitation (EA) in children is not uncommon. This study aims to test the effect of intraoperative magnesium sulfate on reducing the incidence of EA in children anesthetized with sevoflurane.
Materials and methods
The study included 50 male children, aged 3-6 years, with ASA status I or II, scheduled for elective inguinal herniorrhaphy under GA through laryngeal mask airway (LMA). The patients were allocated into two groups: group M (25 patients) received intravenous magnesium sulfate 10% (0.2 ml/kg), followed by a continuous infusion of 0.1 ml/kg till the end of surgery; group C (25 patients) received a similar volume of intravenous normal saline (0.2 ml/kg), followed by a continuous infusion of 0.1 ml/kg till the end of surgery. Anesthesia was induced using 6 l/min of O 2 100% with sevoflurane 8 vol%. Anesthesia was maintained with sevoflurane 1.5-2 vol% in an oxygen-air mixture. After LMA removal, the agitation scoring scale was used for assessing the quality of emergence. Agitation parameters were measured using a four-point scale. Agitated children were managed by giving intravenous midazolam (0.1 mg/kg).
Results
The study was completed by 42 children. Magnesium concentrations in group M were significantly higher [2.95 (0.50) mg/dl] compared with group C [2.01 (0.42) mg/dl; P < 0.001]. The emergence time was significantly longer in group M [19.11 (7.45) min] compared with group C [15.421 (6.54) min; P < 0.001]. Other recovery characteristics in terms of the time to LMA removal and the time to reach full Aldrete score were comparable between both groups. Heart rate and systolic blood pressure variables were significantly higher in group C compared with group M at the time of LMA removal (P < 0.01). At the postanesthesia care unit, there was no incidence of agitation reported in group M as compared with 11 patients in group C (P < 0.001). In group C, the mean duration of agitation was 16.4 (8.2) min and the mean dose of midazolam administered was 0.09 (0-0.2) mg/kg per child. No patients in group M complained of pain compared with group C at 5, 10, and 30 min after emergence from anesthesia (P < 0.001).
Conclusion
Intravenous magnesium sulfate infusion significantly reduced the incidence of sevoflurane-induced EA.

Keywords: emergence agitation, magnesium, sevoflurane


How to cite this article:
Bondok RS, Ali RM. Magnesium sulfate reduces sevoflurane-induced emergence agitation in pediatric patients. Ain-Shams J Anaesthesiol 2014;7:282-8

How to cite this URL:
Bondok RS, Ali RM. Magnesium sulfate reduces sevoflurane-induced emergence agitation in pediatric patients. Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2021 Apr 20];7:282-8. Available from: http://www.asja.eg.net/text.asp?2014/7/3/282/139544


  Introduction Top


Sevoflurane is widely used in pediatric anesthesia because of a fast and well-tolerated inhaled induction and rapid emergence from anesthesia. However, the occurrence of emergence agitation (EA) is a common phenomenon in children, with a reported incidence of up to 80% [1]. A variety of medications such as analgesics [2], opioids [3], benzodiazepines [4,5], and α-2 agonists [1, 6, 7] have been used with variable success. The reasons for a higher incidence of EA after sevoflurane are not fully understood. Sevoflurane in particular situations may exert an irritating side effect on the central nervous system. Epileptiform seizure activity in previously nonepileptic patients has been observed with electroencephalography during sevoflurane anesthesia [8-11]. Sevoflurane has a molecular structure similar to enflurane as both contain seven fluoride atoms, which is related to their excitatory properties. Enflurane has been demonstrated to exert its epileptogenic action through N-methyl-d-aspartate (NMDA) receptors. Therefore, it is assumed that the epileptogenic property of sevoflurane may be exerted through NMDA receptors [12]. However, no data on the direct effect of sevoflurane on NMDA receptors are available. Magnesium sulfate is a physiological calcium channel blocker and a noncompetitive NMDA receptor antagonist with antinociceptive [13,14] and anticonvulsant effects [15,16]. The aim of this study was to assess the effect of intravenous magnesium sulfate in reducing the incidence of EA after sevoflurane-based anesthesia in children.


  Materials and methods Top


This study was approved by the Research Ethical Committee at Ain-Shams University, and informed consent was obtained from the children's guardians. The participating children were male ASA physical status I or II aged 3-6 years scheduled for elective inguinal hernia repair.

Exclusion criteria included a family history of malignant hyperthermia, mental retardation, any neurological disease potentially associated with symptoms of agitation, known allergy to any of the medicines used, hepatic, renal, or cardiovascular dysfunction, bronchial asthma, hematological disorders, or parental regional block refusal.

All children fasted for 6 h preoperatively and were premedicated with oral midazolam (0.25 mg/kg) 30 min before the procedure [17]. The child's behavior upon separation from parents was evaluated with a three-point rating scale [1 = poor (anxious/combative); 2 = good (anxious/easily reassured); 3 = excellent (calm/drowsy] [18]. The quality of induction was evaluated with a four-point rating scale [1 = poor (afraid of mask, combative, crying); 2 = fair (moderate fear of mask, not easily calmed); 3 = good (slight fear of mask, easily calmed); 4 = excellent (unafraid, cooperative, accepts mask readily] [18].

Children expressing preoperative agitation despite midazolam premedication, as evidenced by difficult separation from the parents (a score of 1) or expression of fear or anxiety upon the application of the face mask during the induction of anesthesia (a score of <3), were excluded from the study.

The child was transferred to the operating theater and placed on a warming blanket. Noninvasive ECG, peripheral oxygen saturation (SpO 2), systolic, diastolic, and mean arterial pressure monitoring were recorded by a Drager Primus Infinity Delta Monitor (Drager Lόbeck, Germany) and baseline values were noted for each patient . An intravenous cannula was inserted and secured on the dorsum of the hand; normal saline solution was then infused at a rate of 4 ml/kg/h.

Anesthesia was induced using 6 l/min of O 2 100% with sevoflurane 8 vol% (Primus; Draeger Medical, Lόbeck, Germany). After achieving adequate depth of anesthesia, a laryngeal mask airway (LMA) of appropriate size for the age and the weight of the child was placed. Anesthesia was maintained with sevoflurane 1.5-2 vol% in an oxygen-air 60% mixture. End-tidal carbon dioxide and end-tidal sevoflurane concentrations were continuously monitored intraoperatively. The sevoflurane concentration during surgery was adjusted to maintain the patient's arterial blood pressure within 20% of the preinduction values. Spontaneous breathing was allowed provided EtCO 2 remained below 45 mmHg; if EtCO 2 exceeded 45 mmHg, the patient was assisted to maintain an end-expired carbon dioxide partial pressure of 35-45 mmHg throughout the intraoperative period. No sedative, muscle relaxant, or narcotic was administered during the operation.

After the induction of anesthesia, children received ultrasound-guided ilioinguinal nerve block for postoperative analgesia, using a total volume of 0.6 ml/kg bupivacaine (0.25%) on the ipsilateral side of the incision. Betadine solution was applied to the lower abdomen, and the block site was draped with sterile towels. A high-frequency linear ultrasound probe of 10 MHz, with the frequency set at general mode (Mindray M5; Mindray DS USA), was used, with a sterile cover placed on the right abdomen in the axial (transverse) plane just above the anterior superior iliac spine, from which the transducer was moved medially along the anterior superior iliac spine-umbilicus line. A 22-G short beveled needle was advanced to the fascial plane between the internal oblique and transversus abdominal muscles and placed adjacent to the ilioinguinal and iliohypogastric nerves, which is enclosed in the fascial split. The needle tip position was confirmed under real-time ultrasonography by the observation of a hypoechogenic pocket between the muscles upon injection of the local anesthetic. A successful block was defined clinically by the response to skin incision that was performed at least 15 min after placement of the block. An increase in the heart rate or the arterial blood pressure of greater than 10% compared with the postinduction/preblock levels, tachypnea, or spontaneous movements defined a failed or inadequate block. If the block was inadequate, rescue fentanyl (1 μg/kg) was administered and the child was excluded from further analysis.

After anesthesia induction, blood sample was withdrawn to determine baseline plasma magnesium levels. The children were randomly assigned to two groups using a computer-generated random number assignment. The magnesium group (group M) received 10% magnesium sulfate 20 mg/kg (0.2 ml/kg) as a slow intravenous bolus over 15 min followed by 10 mg/kg/h (0.1 ml/kg/h) as a continuous intravenous infusion during the operation, whereas the control group (group C) received the same volume of 0.9% sodium chloride in a double-blind manner. The solutions were prepared by the coordinator of the study, and the anesthetist in charge of the patients during the operation was unaware of the study medicine. A second blood sample was taken just before the removal of LMA.

At the completion of the surgery, sevoflurane was discontinued. The LMA was removed when the patients displayed a regular respiratory pattern but were still nonresponsive to stimulation. After achieving adequate spontaneous breathing, purposeful movement of all extremities and eye opening, the children were kept in the recovery position.

The following time intervals were recorded: the time of surgery, the time of anesthesia (from the start of induction to the end of surgery, which coincides with the discontinuation of sevoflurane), the time to removal of LMA (from the end of anesthesia to the removal of LMA), and the time of emergence (the time to the first response to a simple verbal command after discontinuation of sevoflurane).

In the OR, the following variables were also evaluated for all patients: tolerance of laryngeal mask removal and occurrence of adverse effects: cough, laryngospasm, desaturation (SpO 2 < 95%), the need for respiratory assistance, especially if SpO 2 was below 95%, and adverse reactions such as nausea and vomiting.

Upon arrival at the postanesthesia care unit (PACU), all children were met by one of their parents/guardians, who stayed with them until discharge. The agitation score was graded 1 if the child was calm, 2 if the child was not calm, but could be easily consoled, 3 if the child was moderately agitated or restless and not easily calmed, and 4 if the child was combative, excited, or disoriented, trashing around [19]. Scores 1 and 2 were regarded as representing nonproblematic behavior, and scores 3 and 4 indicated agitation. The agitation score was recorded immediately after removal of LMA, and continuously thereafter until all children were calm. In addition to the agitation score, the onset and the duration of agitation were recorded. Agitated children were managed by giving intravenous increments of midazolam (0.1 mg/kg), during which the child was monitored for any signs of respiratory depression. The total midazolam consumption was recorded. We identified the primary outcome of the study as the presence of agitation, whereas secondary outcomes included perioperative hemodynamics, the time to removal of LMA, the time of emergence, postoperative complications, and the time of discharge from the PACU.

Children's pain was evaluated by the Wong-Baker FACES pain rating scale at 5, 10, and 30 min after emergence. This scale consists of six cartoon faces with expressions on each face rating the degree of pain, where 0 corresponded to 'no pain', 1 to 'little pain', 2 to 'mild pain', 3 to 'moderate pain', 4 to 'severe pain', and 5 to 'the worst imaginable pain' [Figure 1] [20].
Figure 1: The Wong-Baker FACES pain rating scale [20].

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As pain is an important triggering factor for agitation, all patients who reported a pain score of more than 2 during the recovery period were excluded from the study and received a slow infusion of intravenous paracetamol (15 mg/kg) (Perfalgan 10 mg/ml; Bristol-Myers Squibb Pharmaceuticals, Australia). In the PACU, patient evaluation was performed by a second anesthetist who was blinded to the patient's treatment schedule. Warming devices were applied to every child to avoid the occurrence of hypothermia, and oxygen was administered to all children through a face mask. Oxygen saturation was continuously monitored by pulse oximetry to rule out hypoxemia. The heart rate, noninvasive systolic blood pressure, and SpO 2 values were recorded in the PACU at 5, 10, and 30 min after emergence. The incidence of adverse events such as vomiting, laryngospasm, and desaturation was also noted.

All patients in the PACU were followed until complete anesthetic recovery was assured. The time of discharge from the PACU upon reaching a Modified Aldrete's score [21] of at least 9 (full Aldrete score) was recorded. Parental satisfaction in the PACU regarding postoperative analgesia and calmness was recorded, where a score of 1 = excellent, 2 = good, 3 = poor, and 4 = bad.

Statistical analysis

SPSS for Windows 16.0 (Statistical Package for Social Sciences; SAS Institute Inc., Cary, North Carolina, USA) was used for analysis of data. The sample size for each study group was 25 (power 0.80 and α = 0.05 when Δ = 2.2; SD = 2.7 for the agitation score parameter). All variables were tested for normal distribution by the Kolmogorov-Smirnov test. In addition to descriptive statistical methods (mean ± SD), the t-test was used for comparisons among groups. Repeated measures data were analyzed by analysis of variance, and differences from the baseline values were analyzed by Bonferroni's method paired-sample t-test. The χ2 -test was used for qualitative parameters. A P value of less than 0.05 was considered statistically significant.


  Results Top


Fifty male children were enrolled in the study, of whom 42 completed the study. After the start of surgery, four patients from the group M and three from the group C had to be excluded because of inadequate ilioinguinal nerve block. After arrival at the recovery room, another patient from group M was excluded, because of pain in the area that had been operated on. This patient showed no signs of agitation.

Both groups were comparable regarding their demographic data and surgical and anesthetic duration [Table 1].
Table 1 Demographic data and surgical and anesthetic durations

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Baseline serum magnesium concentrations were comparable in both groups (P = 0.167). Serum magnesium concentrations in group M were significantly higher [2.95 (0.50) mg/dl] as compared with group C [2.01 (0.42) mg/dl; P < 0.001; [Table 2].
Table 2 Recovery characteristics, serum magnesium levels in the preoperative and the early postoperative periods

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The emergence time was significantly longer in group M [19.11 (7.45) min] compared with group C [15.42 (6.54) min; P < 0.01]. Other recovery characteristics in terms of the time to LMA removal and the time to reach full Aldrete score were comparable between both groups [Table 2].

Regarding the hemodynamic parameters, heart rate variables were significantly higher in group C compared with group M at the time of LMA removal (P < 0.01; [Figure 2]a). The systolic blood pressure in group C was also significantly higher than that in group M at both the time of LMA removal and after LMA removal (P < 0.001; [Figure 2]b). SpO 2 data were comparable between the two groups at all time intervals.
Figure 2: Hemodynamic parameters. Values are expressed as mean (SD) (**P < 0.01, *P < 0.001). (a) Heart rate. (b) Systolic blood pressure. LMA, laryngeal mask airway.

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Immediately after the removal of the laryngeal mask, no apnea was observed: four patients in group M developed SpO 2 below 95% compared with one patient in group C (P = 0.021). They were easily managed using assisted face mask ventilation in 100% oxygen for less than 1 min, no additional measures were necessary and all patients breathed spontaneously throughout the recovery phase [Table 3].
Table 3 Patients' condition immediately after removal of the laryngeal mask and adverse effects

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At the PACU, there was no incidence of agitation reported in group M as compared with 11 patients in group C (P < 0.001; [Table 4]). One child in group M was calmed within 3 min by his parent and was not considered agitated. In contrast, 11 children in group C were agitated and received midazolam as they were not calmed after parental presence; all the agitation episodes occurred immediately after emergence. The mean duration of agitation in group C was 16.4 (8.2) min and the mean dose of midazolam administered was 0.09 (0-0.2) mg/kg per child [Table 4].

No patients in group M complained of pain compared with group C at 5, 10, and 30 min after emergence from anesthesia (P < 0.01; [Table 5]).
Table 4 Incidence of agitation

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Table 5 Pain scores ≤2 in the postanesthesia care unit at 5, 10, and 30 min after emergence from anesthesia

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About 80% of the parents were satisfied with their child's postoperative analgesia and calmness, rating a score of 1 (excellent) in group M, compared with 31.8% in group C (P < 0.001; [Figure 3]).
Figure 3: Parents' satisfaction scores (1 = excellent, 2 = good, 3 = poor, and 4 = bad). Values are expressed as the number of patients (*P < 0.001).

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  Discussion Top


EA after anesthesia is highly disturbing to parents, patients, and recovery room personnel. Children are also at risk of physical harm during these episodes, and the need for additional supervision and medication often prolongs the recovery process [22,23]. Although there are no consistent scales to evaluate patients with EA, its incidence varies in the literature from 10 to 80% depending on the definition and the scale used to measure it [24]. Our study included male children 3-6 years of age who were exposed to sevoflurane anesthesia. The incidence of agitation in our study control group was 50%. The Watcha scale [19], which was utilized in this study, is a simpler tool to use in clinical practice and has a higher overall sensitivity and specificity than the other scales [25].

Because the underlying cause of EA is unknown, multiple contributory factors have been shown to be associated with its occurrence, including preoperative anxiety and pain [10,24]. Intense preoperative anxiety, both in children and their parents, has been associated with an increased likelihood of restless recovery from anesthesia [26]. To control confounding factors, all children in the study received midazolam preoperatively for anxiolysis; any child with either neurological disease potentially associated with symptoms of agitation or preoperative agitation despite midazolam premedication, as evidenced by difficult separation from the parents, or expression of fear or anxiety upon the application of the face mask during the induction of anesthesia was excluded.

In several studies, the pre-emptive analgesic approach reduced EA successfully, suggesting that pain may be its major source [6,27-29]. Children included in the study received an effective ultrasound-guided ilioinguinal nerve block for postoperative analgesia. Upon arrival at the PACU, all children were met by one of their parents, who stayed with them until discharge. Voepel-Lewis et al. [30] found that the most effective intervention for the treatment of EA was reuniting with a parent.

During sevoflurane anesthesia, epileptiform seizure activity in previously nonepileptic patients has been observed with electroencephalography [8-11]. Sevoflurane has a molecular structure similar to enflurane; both contain seven fluoride atoms, which is related to their excitatory properties. Enflurane was found to exert its epileptiform activity through the activation of NMDA receptors. It is therefore assumed that the sevoflurane-induced excitatory property may be exerted through NMDA receptors by a method similar to enflurane [12]. However, no data on the direct effect of sevoflurane on NMDA receptors are available. Magnesium sulfate is a physiological calcium channel blocker and a noncompetitive NMDA receptor antagonist with antinociceptive [13,14] and anticonvulsant effects [15,16]. Accordingly, as magnesium sulfate possesses an inhibitory effect on NMDA receptors, we therefore assumed it to be effective in treating sevoflurane-induced EA.

In our study protocol, MgSO 4 (20 mg/kg) was given after the induction of anesthesia, followed by a continuous infusion of 10 mg/kg/h till the end of surgery. Postinfusion serum magnesium levels were higher compared with preinfusion levels.

Magnesium sulfate caused a significant reduction in sevoflurane-induced EA with no delay in patient discharge. Similarly, Abu-Sinna and Talat [31] showed a significant reduction in the EA after sevoflurane anesthesia in adenotonsillectomy operations after a bolus dose of magnesium sulfate before the induction of anesthesia. In contrast, Apan et al. [32] showed no influence of magnesium sulfate infusion on sevoflurane-induced EA. This discrepancy may be attributed to several factors in their study. Firstly, the improper timing for initiating magnesium sulfate infusion, which was commenced 10 min before the end of surgery; secondly, failure to reach an effective serum magnesium level as the magnesium infusion was not preceded by a loading dose, and the very short duration of magnesium infusion [32].

Ketamine, similar to magnesium sulfate, displays both antinociceptive and NMDA receptor blocking affects [33]. Previous studies have shown the efficacy of using intravenous ketamine in reducing the incidence of EA after sevoflurane [34-36], which again may confirm the possibility of NMDA receptor antagonism contribution in preventing sevoflurane-induced EA.

Many studies showed that magnesium plays a role in postoperative analgesia most probably through its action as an NMDA receptor antagonist [37,38]. Magnesium sulfate significantly decreased the pain scores in our study. Because of its analgesic properties, magnesium sulfate could have influenced the agitation scores by an improved pain therapy. However, the design of our study negated the presence of pain in the postoperative period by the use of regional blockade.

Our results also show a significant stabilization in the heart rate and the systolic blood pressure during the removal of LMA and emergence in group M compared with group C. Plasma catecholamine concentrations are significantly lowered by magnesium, and hence, magnesium sulfate effectively blunts the sympathoadrenal hemodynamic stress responses during emergence from anesthesia [39-41]. Serum magnesium concentrations of at least 2-4 mmol/l (0.8-1.6 mg/dl) are required to exert these effects [38]. The reduction in blood pressure could be attributed to the vasodilatory effect of magnesium sulfate [39].


  Conclusion Top


Intravenous magnesium sulfate infusion significantly reduced the incidence of sevoflurane-induced EA.


  Acknowledgements Top


 
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41.James MFM. Magnesium: an emerging drug in anaesthesia. Br J Anaesth 2009; 103:465-467.  Back to cited text no. 41
    


    Figures

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    Tables

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