Complications of sevoflurane–fentanyl versus midazolam–fentanyl anesthesia in pediatric cleft lip and palate surgery: a randomized comparison study


Careful choice of anesthetic agents in pediatric patients reduces the frequency of anesthesia-related complications. The frequency and type of intraoperative and postoperative complications of sevoflurane–fentanyl versus midazolam–fentanyl anesthesia were compared in 140 consecutive children (aged 3 months to 10 years) undergoing cleft lip and palate repair. Midazolam–fentanyl anesthesia was induced with midazolam (0.05 mg/kg), fentanyl (0.005 mg/kg) and vecuronium (0.1 mg/kg), and maintained with the same agents according to the defined parametars. Sevoflurane–fentanyl anesthesia was induced and maintained with sevoflurane (5–8 vol% and 0.8–1 vol%, respectively) in an oxygen/air mixture and supplemented with fentanyl (0.005 mg/kg). Both groups were comparable in basic demographic data, hemodynamic and respiratory parameters. Difficult intubation occurred in 6 of 76 children (midazolam–fentanyl group) and 4 of 64 children (sevoflurane–fentanyl group) ( P = 0.754). Ventricular extrasystole and bronchospasm occurred in one patient each in the sevoflurane–fentanyl group. Postoperatively, emergence agitation was observed in the sevoflurane–fentanyl group (17 cases; P < 0.001); postoperative nausea and vomiting occurred in 2 children (midazolam–fentanyl group) and 3 children (sevoflurane–fentanyl group) ( P = 0.660). Midazolam-based anesthesia in children is safer than sevoflurane-based anesthesia regarding occurrence of emergence agitation.

Anesthetic management of pediatric patients undergoing cleft lip and palate surgical repair is associated with a high rate (13%) of intraoperative and postoperative complications. Some complications, such as bleeding, changes in the endotracheal tube position during surgery, or postoperative swelling of the tongue, are attributed to the surgical procedure; others, such as those related to ventilation and intubation, postoperative nausea and vomiting, emergence agitation or pain, may be ascribed to the choice of anesthesia. Various anesthetic techniques have been proposed to reduce the incidence of these complications, but there is no consensus on the safest anesthetic agents for pediatric patients undergoing cleft lip and palate surgical repair. The choice of anesthetic differs from one hospital to another.

Pediatric anesthesia largely relies on inhalational anesthetics. Sevoflurane, as an inhalational anesthetic, has been routinely used since the 1990s for anesthesia in children undergoing different types of surgery, including pediatric cleft lip and palate repair. It induces fewer complications than other inhalational anesthetics, such as halothane or isoflurane, due to low solubility, but absolute safety of sevoflurane in pediatric patients has not been confirmed consistently.

In the authors’ institution, the choice of anesthetic agents for children undergoing cleft lip and palate repair mainly depends on the preference of the anesthesiologist. Two anesthetic techniques are commonly used. The older technique is predominantly based on the administration of intravenous anesthetics, with addition of fentanyl and vecuronium; the newer technique uses inhalational anesthesia with sevoflurane, supplemented with fentanyl. The aim of this study is to determine and compare the intraoperative and postoperative complication rates of midazolam-based anesthesia versus sevoflurane-based anesthesia in pediatric cleft lip and palate repair, to test the hypothesis that the complication rate would be lower in patients anesthetized with sevoflurane.

Patients and method


All pediatric patients scheduled for elective cleft lip and palate surgical repair at Dubrava University Hospital in Zagreb between January 2002 and May 2006 were considered eligible for the study. Those with contraindications for the surgery, infection, anemia, asthma, severe heart defects, or mental retardation, were excluded from the study ( Fig. 1 ). Of 150 consecutive patients in the study period, 140 were included after obtaining written parental consent and study approval from the Ethics Committee of Dubrava University Hospital. The study sample consisted of 81 boys and 59 girls with normal cardiovascular and pulmonary status, hematological parameters in the normal range, and American Society of Anesthesiologists (ASA) score I/II. The children were aged between 3 months and 10 years ( Table 1 ). Body weight ranged from 5.5 kg to 26 kg.

Fig. 1
Setting up the study.

Table 1
Demographic, surgical and anesthetic data of 140 children undergoing cleft palate and lip repair surgery*.
No. of patients
Parameter Midazolam fentanyl (n = 76) Sevoflurane fentanyl (n = 64)
Age group
<12 months 49 43
12 24 months 15 13
>24 months 12 9
Age (months) 6.7 (4.7–21.8) 6.9 (5.4–20.5)
Sex (male/female) 45/31 36/28
Weight (kg) 7.9 (6.3–14.0) 8.1 (6.6–10.0)
ASA I/II 70/6 58/6
Duration of surgery (min) 106.6 ± 25.6 106.8 ± 33.4
Duration of anesthesia (min) 128.7 ± 28.7 127.6 ± 31.2
Site of surgery (palate/lip) 48/28 36/28

*There was no significant difference between the groups. Age and weight are presented as medians with interquarile range (not normal data distribution), and duration of surgery and anesthesia as mean ± standard deviation (normal data distribution).


All children were premedicated with midazolam 0.05 mg/kg (Dormicum®, F. Hoffman-La Roche Ltd., Basel, Switzerland) administered orally 30 min before being transferred to an operating suite. On arrival at the operating suite, all children were immediately pre-induced with sevoflurane (5–8 vol%) (Sevorane ® , Abbott Laboratories S.A., Abbott Park, IL, USA) administered via face-mask breathing spontaneously to make the cannulation of a peripheral vein more convenient for the children and the staff. Once intravenous access was established, sevoflurane was switched off. After a few minutes the monitored minimal alveolar concentration of sevoflurane was zero.

The children were randomly assigned to receive either midazolam–fentanyl or sevoflurane–fentanyl (study group) anesthesia. Randomization was performed using a computer-generated random number list. A nurse anesthetist informed the anesthesiologist of the type of anesthesia immediately before administration.

In the midazolam–fentanyl group, which served as a control, anesthesia was induced with midazolam 0.05 mg/kg, fentanyl 0.005 mg/kg (Fentanyl ® , Janssen Pharmaceutica, Beerse, Belgium), and vecuronium 0.1 mg/kg (Norcuron ® , N.V. Organon, Oss, The Netherlands). In the same group, anesthesia was maintained with an intravenous bolus of midazolam, fentanyl or vecuronium, and oxygen/air mixture without inhalational anesthetics. An intravenous bolus of midazolam (0.025 mg/kg) was administrated every 45 min during the surgical procedure. An additional intravenous bolus of fentanyl (0.001 mg/kg) was added depending on heart rate. Vecuronium (0.01 mg/kg) was added every 40 min or if there was an increase in end-tidal carbon dioxide. Patients were mechanically ventilated to maintain end-tidal carbon-dioxide tension (P ET CO 2 ) to maintain normocapnia (4.5–5.0 kPa). At the end of surgery the effect of the paralytic agent, vecuronium, was reversed by neostigmine (0.04 mg/kg). Atropine (0.01 mg/kg) was co-administrated with neostigmine.

In the sevoflurane–fentanyl group, the study group, anesthesia was induced with sevoflurane 5–8 vol% (Sevorane ® , Abbott Laboratories S.A., Abbott Park, IL, USA) and maintained with sevoflurane 0.8–1.0 vol% in oxygen/air mixture, supplemented with fentanyl 0.005 mg/kg in an intravenous bolus. An additional intravenous bolus of fentanyl (0.001 mg/kg) was added in the same manner as in the midazolam–fentanyl group.

In both groups, before the surgical incision the surgeon infiltrated 2% lidocaine containing adrenaline solution (2 ml; i.e. 40 mg of lidocaine plus 0.025 mg epinephrine) (Lidokain-Adrenalin ®, Belupo, Croatia). Non-steroid anti-inflammatory drugs were not administered, because the authors avoid administering them routinely intraoperatively.

Anesthesia was always administered by one of two anesthesiologists experienced in both anesthetic techniques. During surgery, the children were monitored using standard three-lead electrocardiography, pulse oxymetry, capnometry and non-invasive blood pressure monitoring.

Data collection

Preoperative, intraoperative and postoperative data on oxygen saturation, heart rate, hemoglobin, and hematocrit were collected by the anesthesiologists who carried out the anesthesia. Preoperative data were collected 5 min before induction. Intraoperative and postoperative oxygen saturation and heart rate values were measured every 5 min during surgery and during the patient’s stay in the postanesthesia care unit (PACU); the average values were used for analysis. Intraoperative hemoglobin and hematocrit were measured at the end of surgery. Postoperative hemoglobin and hematocrit values were measured immediately before discharge from the PACU. Intraoperative and postoperative complications were recorded. Intraoperative complications included difficulty of intubation, presence of cardiac arrhythmias and bronchospasm. Difficulty of intubation was determined according to the number of intubation attempts. Easy intubation involved one attempt, moderately difficult intubation involved 2 attenpts, difficult intubation involved 3 or more attempts. Cardiac arrhythmias were recorded by type (supraventricular/ventricular) and frequency of appearance (once/more than once). Bronchospasm was recorded as present or absent. Postoperative complications were observed over 2 h in the PACU, including emergence agitation (0, child sleeps peacefully; 1, agitation), postoperative nausea and vomiting (0, absent; 1, present), and postoperative pain, which was measured using different scales depending on the child’s age. An objective scale was used in children aged < 3 years, the Smiley scale was used in children aged 3–5 years, and a numerical self-rating scale (from 0 to 10) was used in children aged >5 years. If pain was suspected, either paracetamol 20–30 mg/kg or diclophenac 1 mg/kg were administered per rectum and the degree of agitation reassessed after 30 min. Only cases in which agitation persisted after the administration of analgesics were included in the analysis; agitation that disappeared after the administration of analgesics was considered pain-related. Owing to the different pain-assessment scales used, pain intensity could not be analyzed and compared in more detail.

After 2 h in the PACU, the children were transferred to a department where specialized care is provided for patients after cleft lip and palate repair. Postoperative pain was treated according to a routine protocol including paracetamol 15 mg/kg every 6 h or diclophenac 1 mg/kg every 8 h per rectum.

Statistical analysis

The sample size was calculated from the data from a previous study. With α of 0.001 and a power of 90% to detect the differences, the authors calculated that 63 patients were needed per group. They included more patients per group to allow for possible exclusions. Distribution of continuous variables was determined with the Kolmogorov–Smirnov test of normality. Normally distributed data were expressed as mean ± standard deviation (SD). Non normally distributed data were presented as a median with interquartile range (IQR). Categorical data were expressed as frequencies and percentages. The association of categorical variables was assessed using the χ 2 test and Fisher’s exact test. Student’s t-test and the Mann–Whitney U-test were used for comparison of normally distributed variables and skewed data, respectively. Changes over time were tested with a two-way non-parametric repeated-measures analysis. P < 0.05 was considered statistically significant. Statistical analysis was performed with SPSS software for Windows, version 11.0 (SPSS Inc., Chicago, IL, USA).


Oxygenation was satisfactory (SpO 2 = 98–100%) throughout surgery in both groups and no significant changes in SpO 2 were observed over time either within or between the groups ( Table 2 ). Intraoperative heart rate, hemoglobin and hematocrit significantly decreased over time in both groups, but showed no difference between the groups ( Table 2 ). The postoperative values of these parameters were significantly lower than the preoperative ones in both groups, but did not significantly differ from the intraoperative values.

Feb 8, 2018 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Complications of sevoflurane–fentanyl versus midazolam–fentanyl anesthesia in pediatric cleft lip and palate surgery: a randomized comparison study
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