Premedication with oral midazolam with or without
parental presence
Zuleyha Kazak, Gul B. Sezer, Ali A. Yılmaz and Yesim Ates
Background and objectiveIn this study, we aimed toinvestigate whether the combination of low-dose (0.25 mg kg1) midazolam premedication with parental presence can effectively reduce anxiety at induction as well as provide a smoother emergence.
MethodsInstitutional ethics committee approval and informed consent from one of the parents were obtained prior to the study. Sixty ASA grade I or II children undergoing surgery were enrolled in the study. Children were randomized to receive either 0.5 mg kg1midazolam orally (group M) or 0.25 mg kg1 midazolam orally with parental presence (group MP) or parental presence alone (group P). The child’s anxiety and sedation scores were evaluated as 1–4 points on the Anxiety Scale and as 0–4 points on the University of Michigan Sedation Scale (UMSS), respectively, at the entrance to the operating room and for tolerance to the face mask. Heart rate, the mean arterial blood pressure and O2saturation (%) were assessed at repeated
intervals before and after induction. At the end of surgery, the child’s Anxiety Scale score, UMSS score, Observer’s Pain Scale (OPS) score and FLACC score were also assessed.
ResultsThere were no differences between groups in demographic variables and duration of surgery or anaesthesia. Mean blood pressure changes were similar between groups at measured intervals, but the heart rate was higher in group M before and after induction of anaesthesia (P < 0.05). UMSS
score was greater in both midazolam groups (groups M and MP) in the preoperative period (P < 0.05). Anxiety Scale scores for anxiolysis were higher in groups M and MP than in group P (less anxious and more sedated) at 20 min after premedication, at the entrance to the operating room and at mask tolerance time points (P < 0.05). During recovery there was no significant difference in sedation, recovery scores or behavioural anxiety assessment between groups, Anxiety Scale score, UMSS score, FLACC score, Visual Analog Scale (VAS) score and Observer’s Pain Scale score in groups MP, M and P. ConclusionPreoperative administration of midazolam 0.5 mg kg1for premedication alone, without parental presence at induction, and that of low-dose midazolam 0.25 mg kg1for premedication with parental presence at induction are both equally effective in reducing separation anxiety and providing a smooth emergence. However, parental presence alone, without midazolam for premedication, is not an adequate approach for this outcome. If the environment for parental presence is convenient, the dose of midazolam may be reduced and induction and emergence conditions may still be of high quality. Eur J Anaesthesiol 2010;27:347–352
Keywords: midazolam, parental presence, smoother emergence
Received4 December 2008 Revised 11 May 2009
Accepted6 August 2009
Implications
This study shows that, when paediatric patients are accompanied by their parents at anaesthetic induction, the premedication dose of midazolam may be decreased; however, comparable induction and emergence charac-teristics may still be obtained as compared with a regular dose of the same agent.
Most children are anxious on separation from their parents at the entrance to the operating room and show
agitation at emergence.1,2Even though parental presence
with 0.5 mg kg1 midazolam has been used to obtain a
smoother induction, and emergence, results are
conflict-ing.3,4A lower dose of midazolam with parental presence
has been advocated to obtain better results both at
induction and at emergence from anaesthesia.3 So far,
there has been no study comparing midazolam alone with a combination of parental presence and low-dose
midazolam. Sedative and parental presence during induc-tion of anaesthesia (PPIA) is often used to treat anxiety in
children undergoing surgery and general anaesthesia.5
Although some anaesthesiologists use these two inter-ventions interchangeably, others use premedication and
PPIA simultaneously.6 Midazolam, in some instances,
may be associated with loss of balance as well as
respir-atory depression, hypnosis, dysphoria and blurred vision.7
Because of these potential side effects, it should be used in the lowest effective dose possible. The effect of PPIA combined with a low dose of midazolam premedication has not been evaluated previously.
The aim of this prospective, double-blind randomized study was to investigate whether PPIA combined with midazolam at a low dose can provide both smooth induc-tion and smooth emergence from anaesthesia.
Methods
Local institutional ethics committee approval was obtained for the planned study, and informed parental consent was obtained at least 24 h before the planned operation. Sixty healthy children of grade ASA I, aged between 2 and 6 years, were included in the study. All the From the Department of Anaesthesiology and Reanimation, Faculty of Medicine,
Ufuk University (ZK), Mesa Hospital (GBS) and Faculty of Medicine, Ankara University (AAY, YA), Ankara, Turkey
Correspondence to Zuleyha Kazak, Assistant Professor, MD, Faculty of Medicine, Department of Anaesthesiology and Reanimation, Ufuk University, Mevlana Bulvarı (Konya Yolu) No: 86-88, 06520 Balgat, Ankara, Turkey
operations were short routine procedures of less than 90 min and done in morning sessions; the study was performed on an outpatient basis.
Exclusion criteria were the use of sedatives or hypnotics within the last month, use of theophylline or hepatic enzyme-inducing drugs, presence of severe central ner-vous system (CNS) dysfunction or increased intracranial pressure, malformations of the cardiovascular system, hypertonus or hyperthyroidism. Children who refused to take the entire midazolam dose were not included in this study.
All inductions were performed in an induction room at the same time of the day (in the morning). Patients were randomly allocated into three groups by the sealed
envel-ope method: group M (n¼ 20), Dormicum (midazolam;
5 mg ml1, parenteral formulation, Roche, Basel,
Switzer-land) premedication; group MP (n¼ 20), midazolam
pre-medication and parental presence during anaesthetic
induction; group P (n¼ 20), parental presence during
induction without premedication. Midazolam was admi-nistered in 5 ml volume of sour cherry juice. Children
received 0.5 mg kg1 oral midazolam in group M,
0.25 mg kg1 oral midazolam in group MP and 5 ml of
sour cherry juice without midazolam in group P. All the children were transferred to the operating room 30 min after premedication. Children in group M were placed supine on the operating table, whereas, in other groups, parents were encouraged to sit on a straight-back chair and to hold their children during the induction of anaesthesia.
Demographic data including age and weight were recorded (Table 1). The University of Michigan Sedation
Scale (UMSS) (Table 2)8 and Anxiety Scales scores
(Table 3)9were assessed at baseline (before
premedica-tion), at 5, 10, 15 and 20 min after premedication and at induction of anaesthesia. Postoperative recovery was evaluated using the Face, Legs, Activity, Cry and
Con-solability (FLACC) scale (Table 4)10every 10 min. The
children in groups MP and P were taken to the operating room with their parents, and the children in group M were separated from their parents and were taken to the operating room 30 min after premedication.
Anaesthesia was induced with 7% sevoflurane in 100% oxygen. A 24 G cannula was then inserted into a
peripheral vein and intravenous rocuronium bromide
0.15 mg kg1was used to facilitate laryngeal mask airway
(LMA) insertion. After LMA insertion, sevoflurane was reduced to 2%. Anaesthesia was maintained with 1.5– 2.5% sevoflurane in 50% nitrous oxide and oxygen at an inspired concentration titrated to stabilize vital signs. No additional doses of rocuronium bromide were given; when the patients started breathing, frequency of con-trolled ventilation was increased (decreasing end tidal
CO2and increasing anaesthetic depth), and spontaneous
breathing was not allowed until the end of surgery. Heart rate (HR) and mean blood pressure (MBP) were measured during midazolam administration (baseline) and on application of the face mask on induction of
anaesthesia. HR, MBP and O2 saturation (%) were
assessed at 5 min intervals starting after premedication until 20 min after extubation.
At the end of surgery, all anaesthetic drugs were discon-tinued simultaneously. Muscle relaxants were antago-nized at the end of surgery. The LMAs were removed after recovery of spontaneous ventilation and gag reflex.
All the groups were given 15–20 mg kg1 paracetamol
rectally before surgery started. Perfalgan (paracetamol
intravenous formulation, 10 mg ml1, parenteral
formu-lation, Bristol-MS, UK) 15 mg kg1 was administered
when inadequacy of pain control was detected, that is, a VAS score above 4 or a FLACC score above 4. The children’s Anxiety Scale scores were evaluated according to the Anxiety Scale, and, at the end of the surgery, the child’s Anxiety Scale score, UMSS score, Observer’s Pain Scale (OPS) score and FLACC score (Table 3) were also assessed. Postanaesthetic recovery was evaluated by using the FLACC score, Anxiety Scale score, UMSS score, VAS score, OPS score every 10 min. The VAS score was evaluated by a physician in the postanaesthesia care unit blinded to the study groups.
Table 1 Patient characteristics (mean W SD or numbers of patients), anaesthesia and operation times, surgical data
Group M (n¼ 20) Group MP (n¼ 20) Group P (n¼ 20) P value
Age (months) 39 28 39 24 37 27 0.946
Weight (kg) 14 6.0 14 4.9 15 7.3 0.737
Female/male patient 5/15 4/16 9/11 0.819
Anaesthesia time (min) 62 26 52 34 59 68 0.780
Operation duration of (min) 51 24 41 32 48 66 0.784
Inguinal hernia 5 8 6 0.583
Circumcision 7 5 8 0.592
Strabismus 8 7 6 0.803
Table 2 University of Michigan Sedation Scale
0 Awake and alert
1 Minimally sedated: tired/sleepy, appropriate response to verbal conversation
and/or sound
2 Moderately sedated: somnolent/sleeping, easily aroused with light tactile
stimulation or a simple verbal command
3 Deeply sedated: deep sleep, arousable only with significant physical
stimulation
On the first day and 14 days after the operation, parents were interviewed personally or by telephone for changes in the child’s behaviour (eating, sleeping, dreaming and toilet training).
Sample size determination and statistical analysis A pilot study using 18 children showed the mean (SD) of the score of the child’s emergence behaviour to be 4 (0.9), 4.5 (0.6) and 3 (0.8) in the midazolam, PPIA and
midazolamþ PPIA groups, respectively. We assumed
that maternal presence during induction would improve the effect of oral midazolam on the score of the child’s emergence behaviour to at least one degree. Thus, a sample size of 17 was needed to show a difference of 1 (SD 0.8) in the score of the child’s emergence behaviour
with a significance level of 0.05 (a¼ 0.05) and a power of
80% (b¼ 0.20). Data are presented as mean standard
deviation or median and interquartile range. The data for the patients’ characteristics and scores were analysed using the one-way analysis of the variance (ANOVA) followed by the Tukey test for multiple comparisons (for the variables that are normally distributed) or the Kruskal–Wallis test followed by Dunn’s method for multiple comparisons (for the variables that were not normally distributed). Sex distributions were analysed
using the two degrees of freedom in x2test. A P value of
less than 0.05 was regarded as significant.
Results
There were no differences between groups in age, sex, weight and duration of surgery and anaesthesia. There
were no episodes of bradycardia, hypotension, brady-pnoea, abrady-pnoea, airway obstruction, emesis or arterial oxygen desaturation during premedication, induction and the recovery periods. None of the children were sedated to the extent that they failed to respond to stimulation or were unable to be aroused. Operative procedures were evenly distributed among the groups and included strabismus, inguinal hernia and circumci-sion. Mean blood pressure changes were similar between groups at measured intervals. Sedation UMSS scores were greater in both midazolam groups (groups M and MP) in the preoperative period (P < 0.05) (Fig. 1). For the Anxiety Scale score, the area under the curve (AUC) for group P was significantly lower than that for groups M and MP (P < 0.05) (Fig. 2). The Anxiety Scale score for anxiolysis was higher in group M at the 20 min after premedication and mask tolerance time points (less anxious). The Anxiety Scale scores for anxiolysis were higher in groups M and MP than in group P (less anxious)
Table 3 Anxiety Scale
1 Panicky
2 Moaning
3 Composed
4 Friendly
Table 4 Face, Legs, Activity, Cry and Consolability behavioural pain
assessment tool
Category Description Score
Face 0¼ No particular expression or smile 0
1¼ Occasional grimace/frown, withdrawn or disinterested
1
2¼ Frequent/constant quivering chin, clenched jaw 2
Legs 0¼ Normal position or relaxed 0
1¼ Uneasy, restless, tense 1
2¼ Kicking or legs drawn up 2
Activity 0¼ Lying quietly, normal position, moves easily 0
1¼ Squirming, shifting back and forth, tense 1
2¼ Arched, rigid or jerking 2
Cry 0¼ No cry 0
1¼ Moans or whimpers, occasional complaint 1
2¼ Crying steadily, screams or sobs, frequent complaints
2
Consolability 0¼ Content and relaxed 0
1¼ Reassured by occasional touching, hugging or being talked to, distractable
1 2¼ Difficult to console or comfort
Fig. 1 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 0 0 mi n 10 mi n 20 mi n Mas k t o le ra n c e p o s t 1 mi n p o s t 5 mi n p o s t 10 mi n p o s t 20 mi n p o s t 30 mi n Group M Group MP Group P Time UMSS (me d ia n ± in te r q u ar ti le r a n g e) * *
at the entrance to the operating room and at mask tolerance time points (P < 0.05) (Fig. 2). During recovery, there was no significant difference in sedation, recovery scores or behavioural anxiety assessment between groups, according to the UMSS score, FLACC score, OPS score, Anxiety Scale score and VAS score in groups MP, M and P (Figs 1–5).
There was no difference between the groups in parental satisfaction. In one patient in group P, dissatisfaction was reported. In another patient in group M, nutritional disturbance was observed, and in one patient in group P, enuresis was seen within 14 days after the operation.
Discussion
In this study, the combination of low-dose (0.25 mg kg1)
midazolam premedication with parental presence was
compared with the widely accepted 0.5 mg kg1 oral
premedication dose of midazolam or parental presence
alone in terms of induction and emergence characteristics of anaesthesia. The main outcome of this study was that
low-dose (0.25 mg kg1) midazolam with parental
pre-sence was equally effective as the regular dose of mid-azolam and superior to parental presence alone in provid-ing good anxiolysis in the induction room and smooth emergence from anaesthesia. So far, there has been no study comparing midazolam alone to a combination of parental presence and low-dose midazolam. In the pae-diatric age group, the premedication agent should be acceptable to the child, should have a short onset time as well as a low profile of side effects and must provide adequate anxiolysis and sedation.
Ghai et al.11 previously combined low-dose midazolam
with ketamine for premedication and compared it with
0.5 mg kg1 midazolam alone. They found the
combi-nation to be equally effective as midazolam alone in providing anxiolysis and keeping the children awake, Fig. 2 4.5 * * 4 3.5 3 2.5 2 1.5 1 0.5 0 0 mi n 10 mi n 20 mi n Mas k t o le ra n c e p o s t 1 mi n p o s t 5 mi n p o s t 10 mi n p o s t 20 mi n p o s t 30 mi n Group M Group MP Group P Time A S (me d ia n ± in te r q u ar ti le r a n g e)
Anxiety Scale scores were higher (less anxiety) in groups M and MP than in group P at the 20 min after premedication and at mask tolerance time points (P < 0.05). Fig. 3 9 8 7 6 5 4 3 2 1 0
10 min 20 min 30 min
Group M Group MP Group P Time UMSS (me d ia n ± in te r q u ar ti le r a n g e)
Face, Legs, Activity, Cry, Consolability for groups P, MP and M in the postoperative period. Fig. 4 6 5 4 3 2 1 0
10 min 20 min 30 min
Group M Group MP Group P Time OPS (me d ia n ± in te r q u ar ti le r a n g e)
Observer’s Pain Scale scores for groups P, MP and M in the postoperative period.
calm and in a quiet state so that they could be separated easily from parents. In this study, we used a dose of
0.5 mg kg1midazolam for the control group.
Some anaesthesiologists use sedative premedication and PPIA interchangeably or simultaneously in their daily
practice.3,4 However, to date, several studies have
reported that PPIA is not an effective intervention in
treating the preoperative anxiety of children.12,13
There-fore, in this study, midazolam was added as a premedica-tion agent to parental presence.
On the other hand, Blount et al.14reported that, among
children undergoing immunizations, parents who were taught to be active in distracting through conversation and reading or in reassuring their children through touch and eye contact were able to reduce the children’s distress. Both behavioural interventions of PPIA and pharmacological interventions (e.g. sedatives) are avail-able to treat preoperative anxiety and emergence beha-viour of children undergoing general anaesthesia. PPIA is suggested as an alternative to sedative premedication.
Recently, Arai et al.4reported that PPIA has no additive
effect on a child’s compliance during the induction process
when combined with oral midazolam (0.5 mg kg1).
How-ever, their study did not involve a decreased dose of midazolam. In this study, both midazolam groups (groups M and MP) were superior to group P in terms of induction characteristics. The results of this study indicate that, contrary to Arai et al., parental presence with a decrease in the midazolam dose at premedication results in the same quality of induction (e.g. mask tolerance).
The child, the parent and the anaesthesiologist must be assessed simultaneously to understand the factors influ-encing anxiety during induction of anaesthesia. The most
preferred agent for this purpose is oral midazolam.7Oral
midazolam has a low profile of side effects and provides adequate anxiolysis and sedation; therefore, it is the most preferred agent for oral premedication. However,
midazolam in some instances may be associated with loss of balance and head control as well as respiratory
depres-sion, hypnosis, amnesia, dysphoria and blurred vision.7
Although it is crucial to monitor all premedicated/sedated patients at all times due to a great variation in phar-macological effect produced by any given dose, a reduction in the effective dose for adequate sedation would be preferred. These potential side effects necessi-tate that it should be used in the most minimum dose
possible. McMillan et al.15reported that oral midazolam
0.5 mg kg1is a well tolerated and effective
premedica-tion and that 0.75 mg and 1 mg kg1, while offering no
additional benefit, may cause more side effects. There-fore, the recommended dose for oral midazolam
preme-dication is 0.5 mg kg1. In this study, a 0.5 mg kg1dose
of midazolam was used as the standard control group, and
the dose of midazolam was decreased to 0.25 mg kg1in
the comparison group. There may be some variation in the sedative effects of midazolam when given orally, particularly if fixed time points are used for observation. Therefore, similar studies can be performed with larger groups to verify the results of this study.
Kain et al.11found that premedication with oral
midazo-lam before surgery was a more effective intervention than either parental presence or no premedication – no parent present for managing a child’s and parent’s anxiety during the preoperative period. The same investigators reported that the anxiety of children in the standard midazolam premedication group was very low and an additional anxiolytic effect of parental presence seemed very diffi-cult to detect while a standard dose of midazolam pre-medication was used. They have also suggested that a different result may have been found if a lower dose of midazolam or a less satisfactory premedicant drug
had been used.3 In this study, the decreased dose of
midazolam combined with PPIA (group MP) has shown the same induction characteristics as with midazolam alone.
So far, the effect of premedication on the emergence characteristics of paediatric patients has been evaluated
in a limited number of studies.4Arai et al.4 found that
PPIA and midazolam at the regular dose (0.5 mg kg1)
were superior to midazolam alone in terms of emergence characteristics. In this study, none of our study groups involved a PPIA and regular dose midazolam induction; our results showed that the study groups were compar-able in terms of emergence characteristics.
It is known that inhalational anaesthetics such as sevo-flurane cause postoperative emergence agitation. This effect can be attenuated by intravenous agents such as
propofol and midazolam. Recently, propofol 1 mg kg1
was reported to prevent emergence agitation caused by inhalational anaesthetics, if administered before or at the end of surgery. In this study, the midazolam groups were found to be superior to the PPIA group at induction; Fig. 5 9 8 7 6 5 4 3 2 1 0
10 min 20 min 30 min
Group M Group MP Group P Time V A S (me d ia n ± in te r q u ar ti le r a n g e)
Visual Analog Scale scores for groups P, MP and M in the postoperative period.
however, there was no significant difference between groups at emergence. Even though we have not encoun-tered any patients requiring pharmacological interven-tion for this reason, propofol may be administered to prevent emergence agitation in patients if midazolam is not appropriate.
Conclusion
Preoperative administration of midazolam 0.5 mg kg1
for premedication alone, without parental presence at
induction, and low-dose midazolam 0.25 mg kg1for
pre-medication with parental presence at induction are both equally effective in reducing separation anxiety and providing a smooth emergence. However, parental pre-sence alone, without midazolam for premedication, is not an adequate approach for this outcome. If the environ-ment for parental presence is convenient, the dose of midazolam may be reduced and induction and emer-gence conditions may still be of high quality.
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