Effect of ketamine versus alfentanil following midazolam in preventing emergence agitation in children after sevoflurane anaesthesia: A prospective randomized clinical trial

Abstract

Objective

To investigate the effect of intranasal ketamine versus alfentanil in addition to oral midazolam for the prevention of emergence agitation in children.

Methods

Children undergoing urological surgery with sevoflurane anaesthesia received oral midazolam 40 min before induction and were then randomly assigned to receive 2 mg/kg ketamine, 10 µg/kg alfentanil or 1 ml isotonic saline intranasally. Parental separation status and mask acceptance were assessed preoperatively. Emergence agitation was evaluated using a paediatric anaesthesia emergence delirium (PAED) score.

Results

Data from 78 children were evaluated in the study. There were no significant differences between the groups in demographic characteristics, recovery times or parental separation scores. Mask acceptance was significantly better in the ketamine group than in the saline group. The mean PAED score in the ketamine group was significantly better than in the other two groups, but was similar in the saline and alfentanil groups. The incidence of emergence agitation was 3.8%, 36.0% and 40.7% in the ketamine, alfentanil and saline groups, respectively.

Conclusions

The addition of intranasal ketamine to oral midazolam significantly improved the quality of induction and reduced sevoflurane-induced emergence agitation, in children undergoing urological surgery.

Keywords

Child sevoflurane emergence delirium general anaesthesia premedication

Introduction

Anaesthesia induction with sevoflurane is frequently used in children. Although sevoflurane is a popular, well-accepted and easily manageable anaesthetic for the induction and maintenance of anaesthesia (in addition to having a good safety profile), recovery may be complicated by emergence agitation in paediatric patients, even in the absence of surgery.¹ Cravero et al.¹ reported that, depending on whether a high or low threshold was used to define agitation, 33% or 80%, respectively, of patients receiving sevoflurane anaesthesia developed emergence delirium.

Several studies have evaluated the ability of premedication to decrease the incidence of emergence agitation. Midazolam is the most frequently used premedication drug in paediatric patients;^2–4 however, there are ongoing debates concerning its efficacy in preventing emergence agitation.⁵ Ketamine and alfentanil are other premedication drugs that are used in paediatric patients.^6–8 Combining different premedication drugs has offered promising results in terms of improved sedation scores and anxiolysis.^9,10

The present study evaluated the effects on emergence agitation of adding intranasal ketamine or intranasal alfentanil to oral midazolam as premedication in children undergoing urological surgery.

Patients and methods

Patients

Children aged between 1 and 8 years undergoing general anaesthesia with sevoflurane for urological surgical procedures at Yeditepe University Hospital, Istanbul, Turkey, between February and August 2012, who were American Society of Anesthesiologist status I–II, were enrolled in the study. Exclusion criteria included cardiac, pulmonary, hepatic or renal disease, and psychological or emotional disorders.

Written informed parental consent was obtained for all study participants. The study was registered with the ClinicalTrials.gov protocol registration system (NCT02022488) and was approved by the Ethics Committee of Yeditepe University Hospital, Istanbul, Turkey.

Premedication and anaesthesia

All patients received oral midazolam 0.5 mg/kg as preanaesthetic medication ∼40 min before the induction of anaesthesia. Children were randomly assigned to one of three groups using a computer-generated random number table by an anaesthesiologist who did not participate in the study. Children in the ketamine group (group MK) received 2 mg/kg ketamine intranasally, those in the alfentanil group (group MA) received 10 µg/kg alfentanil intranasally and those in the saline group (group MS) received 1 ml isotonic saline intranasally, 8–10 min before the induction of anaesthesia. The intranasal drugs were given while patients were in the supine position; if the volume of drug required exceeded 1 ml, the dose was divided between both nostrils. Each patient’s parents, the anaesthesiologists (with the exception of S.B.), the statistician and all observers were blinded to the study groups.

Heart rate, noninvasive blood pressure and oxygen saturation on pulse oximetry were routinely monitored and recorded before anaesthesia induction and every 5 min during surgery. Anaesthesia was induced with 7% sevoflurane and 60% nitrous oxide in oxygen, then maintained with 0.75 minimum alveolar concentration of sevoflurane in 60% nitrous oxide in oxygen. After anaesthesia induction and intravenous cannulation, a laryngeal mask airway was inserted. Before the first surgical incision, caudal block was performed using 0.25% bupivacaine at a dose of 0.8 ml/kg. Adequacy of caudal block was assessed with the absence of an increase in heart rate with the skin incision; the block was deemed inadequate if the heart rate increased > 20% within 60 s of the incision. At the end of surgery, inhaled agents were discontinued and the oxygen concentration was increased to 100%.

Patient evaluation

For each patient, age, weight, duration of surgery and anaesthesia, and spontaneous eye opening time (emergence duration) were recorded.

Parental separation status was measured in the preoperative period using a four-point scale (1, asleep; 2, good separation, awake, calm; 3, awake, anxious, can be easily reassured; 4, crying, cannot be reassured).¹¹ Similarly, a four-point scale was also used to assess the ease of mask acceptance (1, excellent – asleep or awake, calm, co-operative, accepting mask; 2, slight fear but can be easily reassured; 3, moderate fear, reassured with difficulty; 4, crying, needs restraint).¹¹

Emergence agitation was measured using a paediatric anaesthesia emergence delirium (PAED) score,¹² in which five attributes (the child makes eye contact with the caregiver; the child’s actions are purposeful; the child is aware of the surroundings; the child is restless; the child is inconsolable) are scored between 0 and 4. Eye contact, purposeful actions and awareness of surroundings were scored as: 0, extremely; 1, very much; 2, quite a bit; 3, just a little; 4, not at all. Restlessness and inconsolability were scored as: 0, not at all; 1, just a little; 2, quite a bit; 3, very much; 4, extremely. The maximum score overall is 20. The degree of agitation was recorded at 0, 15, 30, 45, 60 and 120 min after entering the postanaesthesia care unit, and the highest recorded values during the first 30 min and the following 90 min were used for evaluation. Patients with a PAED score > 12 at any time during the first 120 min postoperatively were considered to be agitated¹³ and were treated with 1 µg/kg intravenous fentanyl.

At the same time points as the PAED score was recorded, pain was assessed using the Modified Children’s Hospital of Eastern Ontario Pain Scale (Modified CHEOPS),¹⁴ which is based on scores for cry, facial expression, verbal expression and movement. Each child with a pain score ≥ 4 was treated with 1 µg/kg intravenous fentanyl in the postanaesthesia care unit.

The modified Aldrete score¹⁵ was measured every 5 min to determine readiness for discharge from the postanaesthesia care unit, with a score of ≥ 9 being required for discharge.

After discharge from the postanaesthesia care unit, children with a Modified CHEOPS score ≥ 4 or higher received oral paracetamol at a dose of 15 mg/kg.

Adverse events s(including laryngospasm, bronchospasm and postoperative respiratory depression, hypoxaemia, and nausea or vomiting) were noted. In addition, the time to discharge from hospital was recorded for each patient.

Statistical analyses

On the basis of reference data,⁵ G*Power 3.1.5 (http://www.gpower.hhu.de/en.html) was used to calculate that a sample size of 28 would be needed in each group to detect a 25% difference in PAED scores with a significance level of 0.05 and a power of 80% (one-sided test). Variables were analysed using the Kolmogorov–Smirnov test to determine whether or not they were normally distributed.

Data for continuous variables were presented as mean ± SD. Data for categorical variables were presented as frequencies and percentages. χ²-test was used to compare categorical variables in the different groups. One-way analysis of variance was used to compare normally distributed variables between groups. The Levene test was used to assess the homogeneity of the variances. When overall significance was observed, pairwise post-hoc tests were performed using Tukey’s test. The Kruskall–Wallis test was used to compare non-normally distributed variables between the groups. The Mann–Whitney U-test was performed to test the significance of pairwise differences using the Bonferroni correction to adjust for multiple comparisons. A P-value < 0.05 was considered to be statistically significant. Apart from the calculation of sample size, all statistical analyses were performed using IBM SPSS® Statistics software, version 21 (IBM, Somers, NY, USA).

Results

A total of 84 children were enrolled in the study; six children were excluded due to deviation from the protocol (Figure 1), leaving 78 patients for evaluation. Of these, 26 were in group MK, 25 were in group MA and 27 were in group MS. There were no significant differences in age, weight, duration of surgery and anaesthesia or emergence time between the three groups (Table 1).

Figure 1.

Flow chart of patients enrolled in a study investigating intranasal ketamine versus alfentanil, in addition to oral midazolam, for the prevention of emergence agitation in children.

Table 1.

Demographic and operative data for children receiving premedication with midazolam and saline (group MS), midazolam and alfentanil (group MA) or midazolam and ketamine (group MK).

Parameter	Group MS n = 27	Group MA n = 25	Group MK n = 26
Age, years	4.7 ± 2.7	5.6 ± 2.6	5.4 ± 2.2
Weight, kg	20.0 ± 8.7	24.0 ± 10.6	23.0 ± 8.0
Duration of surgery, min	39.2 ± 42.8	26.5 ± 16.6	27.0 ± 19.6
Duration of anaesthesia, min	63.0 ± 42.6	51.0 ± 16.0	50.0 ± 20.7
Spontaneous eye opening time (emergence time), min	11.0 ± 6.2	10.0 ± 4.4	15.0 ± 10.2

Data presented as mean ± SD.

No statistically significant between-group differences; (P ≥ 0.05; one-way analysis of variance).

Parental separation scores were not significantly different among the three groups (Table 2). The mask acceptance score was lower, indicating better acceptance, in group MK compared with group MS (P = 0.004); all other differences in mask acceptance score between the groups were not statistically significant (Table 2).

Table 2.

Parental separation score, mask acceptance score and paediatric anaesthesia emergence delirium (PAED) scores in children undergoing urological surgery and receiving premedication with midazolam and saline (group MS), midazolam and alfentanil (group MA) or midazolam and ketamine (group MK).

Parameter	Group MS n = 27	Group MA n = 25	Group MK n = 26
Parental separation score	2.1 ± 0.6	2.4 ± 0.7	2.1 ± 0.4
Mask acceptance score	1.9 ± 1.0	1.4 ± 1.0	1.2 ± 0.7^a
Highest PAED score during first 30 min	9.0 ± 7.0	9.0 ± 6.0	3.0 ± 4.0^b
Highest PAED score during following 90 min	3.3 ± 4.4	1.6 ± 2.4	1.9 ± 2.7

Data presented as mean ± SD.

P < 0.001 versus group MS and

P < 0.001 versus groups MA and MS; Kruskall–Wallis test.

The highest PAED score during the first 30 min was significantly lower in group MK than in group MS or group MA (P < 0.001 for both; Table 2), but there was no significant difference between groups MS and MA (Table 2). There were no significant differences between the groups in the highest PAED score during the rest of the postoperative period (Table 2). The number of children with a PAED score > 12 during the postoperative period was one (3.8%) in group MK, nine (36.0%) in group MA and 11 (40.7%) in group MS. The frequency of emergence agitation and subsequent fentanyl use was significantly lower in group MK compared with groups MA and MS (P = 0.004 for both) (Table 3).

Table 3.

Incidence of nausea and vomiting, use of fentanyl rescue medication during the postoperative period and the time to discharge from hospital in children undergoing urological surgery and receiving premedication with midazolam and saline (group MS), midazolam and alfentanil (group MA) or midazolam and ketamine (group MK).

Parameter	Group MS n = 27	Group MA n = 25	Group MK n = 26
Nausea or vomiting	3 (11.1)	6 (24.0)	8 (30.8)
Fentanyl use	11 (40.7)	9 (36.0)	1 (3.8)^a
Time to hospital discharge, h	3.86 ± 0.5	3.76 ± 0.4	3.82 ± 0.35

Data presented as n (%) of patients or mean ± SD.

P = 0.004 versus groups MS and MA; χ²-test.

No adverse events such as laryngospasm, bronchospasm and postoperative respiratory depression or hypoxaemia were noted during the study. The incidences of nausea or vomiting in groups MA and MK were higher than in group MS, but these differences were not statistically significant (Table 3). The times to hospital discharge were similar for all three groups (Table 3).

Modified CHEOPS pain scores were < 4 throughout the study in all patients, therefore additional fentanyl use for pain relief was not required.

Discussion

In the present study, addition of intranasal ketamine to oral midazolam as a premedication significantly improved the quality of anaesthetic induction and reduced sevoflurane-induced emergence agitation, without delaying emergence or affecting the time to discharge from hospital.

A number of factors affect emergence agitation, including: preoperative anxiety;¹⁶ pain;¹⁷ type of anaesthesia used.^1,18 Although emergence agitation in children after sevoflurane anaesthesia can occur in those who are not in pain,¹ postoperative pain is a well-known contributing factor.¹⁷ In the present study, caudal analgesia ensured that all participants were pain free.

The incidence of sevoflurane-induced emergence agitation has been reported to be 33–80%, with the wide range in incidence being related to the definitions used.¹ A number of scales have been devised to evaluate emergence agitation in children. The PAED scale has been shown to be reliable and valid.¹² In the present study, patients were considered to be agitated if the PAED score was > 12 at any time during the postoperative period; using this definition, the incidence of agitation was 3.8% in group MK, 36.0% in group MA and 40.7% in group MS.

Different strategies have been recommended to decrease the incidence of emergence agitation. The level of preoperative anxiety has been shown to be related to emergence delirium and postoperative behavioural changes.^16,19 Chorney and Kain²⁰ demonstrated that 42% of children displayed distress during anaesthesia induction. Premedication is widely used in paediatric patients in order to provide sedation, reduce preoperative anxiety and improve the quality of induction. Lapin et al.²¹ observed that children anaesthetized with sevoflurane without prior premedication had a 67% incidence of postoperative agitation. McMillan et al.²² demonstrated that 0.5 mg/kg midazolam orally was effective premedication that offered a good safety profile. In the present study, all three groups were given 0.5 mg/kg midazolam orally. Midazolam has been shown to provide amnesia, reduce anxiety and decrease the incidence of postoperative behavioural changes.²³ However, there is an ongoing debate concerning its efficacy; some studies have shown that it does not prevent emergence agitation.^24,25 The use of a single drug may not be sufficient for the prevention of emergence agitation;²⁶ in such cases, treatment with additional analgesics or sedatives may be required. The serum concentration of oral midazolam peaks at 53 min after oral ingestion.²⁷ Considering the length of the operation and the time taken for patient transfer, the sedation period of midazolam may not cover the postoperative period and therefore may not prevent emergence agitation.

Several studies have evaluated the effects on emergence agitation of combining midazolam with other sedative drugs.^10,22,28 Nasal administration of premedication drugs may be an alternative route to intravenous, subcutaneous, oral or rectal administration in paediatric patients and may offer advantages such as ease of administration and rapid onset.^6,29 In the present study, the incidence of emergence agitation following premedication with midazolam alone was higher than when midazolam was combined with intranasal ketamine.

Ketamine is an N-methyl-d-aspartate receptor antagonist with opioid receptor activity. It is highly lipid soluble and is rapidly absorbed after intranasal administration.⁷ Ketamine has been shown to be effective in reducing anxiety only when administered in combination with midazolam.⁹ Warner et al.¹⁰ reported that a midazolam/ketamine mixture is more effective for parental separation and mask acceptance than midazolam or ketamine alone. Weksler et al.⁶ reported that 6 mg/kg ketamine provides effective premedication in children without delaying recovery time. However, premedication with 3 mg/kg ketamine intranasally was reported to cause brief desaturation periods in children.³⁰ In the present study, a low dose of nasal ketamine was combined with midazolam to prevent emergence agitation and minimize adverse effects. The reason for the success of this combination is probably related either to the prolongation of the elimination half-life of ketamine³¹ or a simple additive effect as a result of the interaction between midazolam and ketamine.²⁸

Intranasal administration of fentanyl during sevoflurane anaesthesia has been reported to be associated with decreased agitation, without an increase in the total hospital stay.³² Alfentanil, a rapid- and short-acting synthetic analogue of fentanyl, appears to offer some clinically significant advantages over fentanyl during outpatient anaesthesia.³³ The use of alfentanil is associated with fewer intraoperative side effects, such as respiratory depression and muscular rigidity, and a more rapid recovery time compared with fentanyl.³³ The maximal plasma concentration with intranasal alfentanil is reached within 9 min and the elimination half-life is short.³⁴ The short half-life of nasal alfentanil may explain why it did not prevent emergence agitation in the present study. However, the terminal half-life of nasal alfentanil (59.4 min) is similar to that of intravenous alfentanil (60 min).³⁴ The administration of 10 µg/kg alfentanil intravenously after induction of anaesthesia in children undergoing adenotonsillectomy reduced the incidence of emergence agitation without delaying the recovery time.³⁵ Furthermore, the combination of midazolam and alfentanil has been reported to significantly decrease the expected median effective dose required for hypnosis of both drugs by 46%.³⁶ In contrast, despite using a dose of 10 µg/kg, alfentanil did not decrease emergence agitation in the present study; this is probably due to the reduced bioavailability (64.9%) of alfentanil when given via the nasal route.³⁴

In the present study, nausea or vomiting were more common in groups MA and MK than in group MS, but these differences were not statistically significant. However, both alfentanil and ketamine have the potential to cause nausea and vomiting, which may explain the numerically higher incidence with the combination therapies, compared with midazolam alone.

The present study has a number of limitations. During the first 30 min of anaesthesia emergence only three consecutive PAED measurements were made, whereas other studies have performed six measurements within this time period. In the present study children were continuously monitored in the postanaesthesia care unit; the PAED score was measured three times and the highest value was used for statistical evaluation.

Another limitation is the lack of knowledge about changes in the median effective doses of the drugs employed when used in combination to control emergence agitation.

In conclusion, intranasal ketamine, in addition to oral midazolam premedication, significantly reduced sevoflurane-induced emergence agitation without delaying emergence or affecting the time to hospital discharge, in children undergoing urosurgical procedures.

Footnotes

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

Cravero

Surgenor

Whalen

. Emergence agitation in paediatric patients after sevoflurane anaesthesia and no surgery: a comparison with halothane. Paediatr Anaesth 2000; 10: 419–424.

Kain

Mayes

Bell

. Premedication in the United States: as status report. Anesth Analg 1997; 84: 427–432.

Haas

Nenniger

Yacobi

. A pilot study of the efficacy of oral midazolam for sedation in pediatric dental patients. Anesth Prog 1996; 43: 1–8.

Kain

Caldwell-Andrews

Krivutza

. Trends in the practice of parental presence during induction of anesthesia and the use of preoperative sedative premedication in the United States, 1995–2002: results of a follow-up national survey. Anesth Analg 2004; 98: 1252–1259.

Köner

Türe

Mercan

. Effects of hydroxyzine-midazolam premedication on sevoflurane-induced paediatric emergence agitation: a prospective randomised clinical trial. Eur J Anaesthesiol 2011; 28: 640–645.

Weksler

Ovadia

Muati

. Nasal ketamine for paediatric premedication. Can J Anaesth 1993; 40: 119–121.

Hosseini Jahromi

Hosseini Valami

Adeli

. Comparison of the effects of intranasal midazolam versus different doses of intranasal ketamine on reducing preoperative pediatric anxiety: a prospective randomized clinical trial. J Anesth 2012; 26: 878–882.

Özcengiz

Akman

Özbek

. Çocuklarda ıntranasal alfentanıl premedıkasyonu. Türk Anest Rean Cem Mecmuasi 1996; 24: 15–18. [in Turkish, English abstract].

Funk

Jakob

Riedl

. Oral preanaesthetic medication for children: double-blind randomized study of a combination of midazolam and ketamine vs midazolam or ketamine alone. Br J Anaesth 2000; 84: 335–340.

10.

Warner

Cabaret

Velling

. Ketamine plus midazolam, a most effective paediatric oral premedicant. Paediatr Anaesth 1995; 5: 293–295.

11.

Ghai

Grandhe

Kumar

. Comparative evaluation of midazolam and ketamine with midazolam alone as oral premedication. Paediatr Anaesth 2005; 15: 554–559.

12.

Sikich

Lerman

. Development and psychometric evaluation of the pediatric anesthesia emergence delirium scale. Anesthesiology 2004; 100: 1138–1145.

13.

Bajwa

Costi

Cyna

. A comparison of emergence delirium scales following general anesthesia in children. Paediatr Anaesth 2010; 20: 704–711.

14.

Splinter

Semelhago

Chou

. The reliability and validity of a modified CHEOPS pain score. Anesth Analg 1994; 78: S413–S413.

15.

Aldrete

Kroulik

. A postanesthetic recovery score. Anesth Analg 1970; 49: 924–934.

16.

Kain

Caldwell-Andrews

Maranets

. Preoperative anxiety and emergence delirium and postoperative maladaptive behaviors. Anesth Analg 2004; 99: 1648–1654.

17.

Weldon

Bell

Craddock

. The effect of caudal analgesia on emergence agitation in children after sevoflurane versus halothane anesthesia. Anesth Analg 2004; 98: 321–326.

18.

Kuratani

. Greater incidence of emergence agitation in children after sevoflurane anesthesia as compared with halothane: a meta-analysis of randomized controlled trials. Anesthesiology 2008; 109: 225–232.

19.

Aono

Mamiya

Manabe

. Preoperative anxiety is associated with a high incidence of problematic behavior on emergence after halothane anesthesia in boys. Acta Anaesthesiol Scand 1999; 43: 542–544.

20.

Chorney

Kain

. Behavioral analysis of children’s response to induction of anesthesia. Anesth Analg 2009; 109: 1434–1440.

21.

Lapin

Auden

Goldsmith

. Effects of sevoflurane anaesthesia on recovery in children: a comparison with halothane. Paediatr Anaesth 1999; 9: 299–304.

22.

McMillan

Spahr-Schopfer

Sikich

. Premedication of children with oral midazolam. Can J Anaesth 1992; 39: 545–550.

23.

Rosenbaum

Kain

Larsson

. The place of premedication in pediatric practice. Paediatr Anaesth 2009; 19: 817–828.

24.

Viitanen

Annila

Viitanen

. Midazolam premedication delays recovery from propofol-induced sevoflurane anesthesia in children 1--3 yr. Can J Anaesth 1999; 46: 766–771.

25.

Cohen

Drewsen

Hannallah

. Propofol or midazolam do not reduce the incidence of emergence agitation associated with desflurane anaesthesia in children undergoing adenotonsillectomy. Paediatr Anaesth 2002; 12: 604–609.

26.

Abu-Shahwan

Chowdary

. 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.

27.

Payne

Mattheyse

Liebenberg

. The pharmacokinetics of midazolam in paediatric patients. Eur J Clin Pharmacol 1989; 37: 267–272.

28.

Beebe

Belani

Chang

. Effectiveness of preoperative sedation with rectal midazolam, ketamine, or their combination in young children. Anesth Analg 1992; 75: 880–884.

29.

Dale

Hjortkjaer

Kharasch

. Nasal administration of opioids for pain management in adults. Acta Anaesthesiol Scand 2002; 46: 759–770.

30.

Abrams

Morrison

Villasenor

. Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures. Anesth Prog 1993; 40: 63–66.

31.

Morgan

Mikhail

. Nonvolatile anesthetic agents. In: Clinical anesthesiology, 2nd ed. Stamford: Appleton & Lange, 1996, pp. 143–143.

32.

Galinkin

Fazi

Cuy

. Use of intranasal fentanyl in children undergoing myringotomy and tube placement during halothane and sevoflurane anesthesia. Anesthesiology 2000; 93: 1378–1383.

33.

White

Coe

Shafer

. Comparison of alfentanil with fentanyl for outpatient anesthesia. Anesthesiology 1986; 64: 99–106.

34.

Schwagmeier

Boerger

Meissner

. Pharmacokinetics of intranasal alfentanil. J Clin Anesth 1995; 7: 109–113.

35.

Kim

Chang

Lee

. Post-induction alfentanil reduces sevoflurane-associated emergence agitation in children undergoing an adenotonsillectomy. Acta Anaesthesiol Scand 2009; 53: 678–681.

36.

Short

Plummer

Chui

. Hypnotic and anaesthetic interactions between midazolam, propofol and alfentanil. Br J Anaesth 1992; 69: 162–167.