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Effect of remifentanil on tracheal intubation conditions and haemodynamics in children anaesthetised with sevoflurane and nitrous oxide.

Neuromuscular blocking drugs are commonly used to improve the quality of conditions for tracheal intubation. There are several reports of intubation without neuromuscular blocking drugs while using sevoflurane (1-6). Sevoflurane is a non-irritating inhalational anaesthetic agent with low blood gas solubility and has been used frequently for inhalational induction and recommended for tracheal intubation in children without additional neuromuscular blocking drugs (2). To achieve good tracheal intubating conditions, high inspired sevoflurane concentrations for more than four minutes were necessary3. Muzi et al found that the time required to reach an adequate depth of anaesthesia with sevoflurane for tracheal intubation in adults was 5.7 minutes when 66% nitrous oxide was used and 7.7 minutes when 100% oxygen was used (4).

Opioid agents significantly reduce the minimum alveolar concentration of potent inhaled anaesthetics required to facilitate intubation and improve overall intubating conditions during sevoflurane anaesthesia (5,6). Remifentanil is a short-acting opioid that undergoes rapid metabolism by tissue and plasma esterases (7). Speed of onset is rapid (one to two minutes) and is similar to that of alfentanil (8). The improvement of intubating conditions is probably due to the apnoeic, analgesic and antitussive effect of opioids (9).

Inhaled anaesthetics and opioids can be used in combination. The tracheal intubating conditions after sevoflurane, nitrous oxide and remifentanil administration could be affected by the sequence of drug administration and the timing of tracheal intubation in relation to the time of peak drug effect. The present study was designed to investigate whether a bolus dose of remifentanil, given simultaneously with initiation of sevoflurane and nitrous oxide in paediatric patients, could produce good intubating conditions at two minutes.


After obtaining approval from the Institutional Review Board, 96 paediatric patients with ASA physical status I or II (aged between one and seven years) undergoing elective surgery were recruited into this study. Informed consent was obtained from their parents. Patients who had a history of upper respiratory tract infection within the previous 14 days or were suspected to have a difficult airway were excluded from the study.

Patients were randomly assigned to three groups: Group S was treated with sevoflurane, nitrous oxide and saline; Group R1 was treated with sevoflurane, nitrous oxide and remifentanil 1 [micro]g/kg and Group R2 sevoflurane, nitrous oxide and remifentanil 2 [micro]g/kg. All patients were premedicated with glycopyrrolate 0.004 mg/kg given intramuscularly 30 minutes before anaesthesia, to prevent bradycardia and salivary secretion and received ketamine 1 mg/kg intravenously just before being transferred into the operating room to facilitate separation from their parents. Drummond demonstrated that ketamine 1 mg/kg was not likely to reduce airway muscle activity (10). In the operating room, non-invasive measurements of electrocardiogram, oxyhaemoglobin saturation (Sp[O.sub.2]), heart rate and mean arterial pressure were performed. General anaesthesia was induced with a semi-closed anaesthetic circuit prefilled with 8% sevoflurane in 50% nitrous oxide and 50% oxygen (5 lpm nitrous oxide: 5 lpm oxygen) for two minutes and ventilation was assisted with positive pressure ventilation to keep end-tidal C[O.sub.2] at 35 to 40 mmHg. Simultaneous with the commencement of the inhaled agents, saline (Group S, n = 32), remifentanil 1 [micro]g/kg (Group R1, n = 32) or remifentanil 2 [micro]g/kg (Group R2, n = 32) was administered in 5 ml of 0.9% normal saline over 30 seconds. Ninety seconds after completion of saline or remifentanil administration, laryngoscopy was attempted.

Intubation and evaluation of intubating conditions was performed by an experienced anaesthesiologist blinded to the treatment groups, applying the scoring system described by Helbo-Hansen et al (Table 1) (11). Laryngoscopy, jaw relaxation, vocal cord movement, coughing and limb movement were evaluated using a four-point scale. Coughing was considered slight if no more than two coughs in sequence occurred, moderate if three to five coughs occurred and severe if more than five coughs occurred. Overall intubating condition scores were recorded using the highest score in any of the individual categories assessed. The intubating condition was judged as acceptable when the score was 2 or less. If any one of the individual category score was 3 or more, the intubating condition was judged as unacceptable. After intubation, ventilation was gently assisted and anaesthesia was maintained with age-adjusted 0.5 minimum alveolar concentration (12) end-tidal sevoflurane and 50% nitrous oxide and 50% oxygen. In all groups, heart rate, mean blood pressure and Sp[O.sub.2] were measured before induction (Tbase), immediately after injection of remifentanil (Tinj), immediately after intubation (Tintu0) and two and four minutes following intubation (Tintu2, Tintu4). The study ended at this point and anaesthesia was maintained at the discretion of the anaesthesiologist. Occurrence of bradycardia (60 beats per minute), hypotension (systolic blood pressure <70 mmHg), hypoxaemia (Sp[O.sub.2] <90%), muscle rigidity making ventilation difficult or other complications were recorded.

The sample-size calculation was based on the results of a previous pilot study. A power analysis was performed using acceptable intubating conditions as the primary outcome measure, with alpha = 0.05 and beta = 0.20 (power of 0.80). The sample size calculation indicated that 32 patients in each group would be required to detect an improvement of 30%. One-way analysis of variance or the chi-square test was performed to assess differences of patient characteristics and physiologic values among the three groups. A Kruskal-Wallis test was performed to assess differences in intubating condition score among the three groups. Two patients not intubated on the first attempt were excluded in the analysis of haemodynamic variables, because mean blood pressure and heart rate after intubation were clearly affected by this variation in airway management. Repeated measures analysis of variance was used to examine how continuous variables (mean arterial pressure, heart rate) differed over the study period among the groups, with the groups compared for between-subject (group) differences and analysed over time as the within-subject (group) factor and for interaction effects between differences in groups by time. Hypotensive episodes were compared using the chi-square test. Results were considered statistically significant if the P value was <0.05.


Ninety-six paediatric patients enrolled in the study were randomly allocated to the three groups (Group S, R1, R2). There were no statistically significant differences in patient characteristics among the three groups (Table 2).

Intubation in all patients was successful at the first attempt except for two children in Group S. These two children were intubated after additional ventilation for two more minutes. Only 18 of 32 patients (56.3%) in Group S were judged to have acceptable intubating conditions compared with 31 of 32 patients (96.9%) in Group R1 and 32 of 32 patients (100%) in Group R2 (P <0.001) (Figure 1). Slightly more patients in Group R1 had high intubating condition scores compared with Group R2, but there was no statistical difference.

Mean blood pressure and heart rate responses during induction of anaesthesia are presented in Figure 2. There were statistically significant within-subjects (i.e. within the groups) effects of time on mean blood pressure (P <0.01). The difference in mean blood pressure across time was statistically significant between subjects (P <0.01). Mean blood pressure was higher in Group S than in Groups R1 and R2 (P <0.01) and higher in Group R1 than in Group R2 but this was not statistically significant. There was a statistically significant interaction effect between differences in groups by time (P <0.01).

There were statistically significant within-subjects effects of time on heart rate (P <0.01). The difference in heart rate across time was not statistically significant between subjects (P >0.05). There was a statistically significant interaction effect between differences in groups by time (P <0.01).



The incidence of post-intubation hypotension was zero (0%) for Group S, two (6.3%) for Group R1 and five (15.6%) for Group R2 (P <0.05). All patients in Group R1 who developed hypotension immediately after intubation had subsequently recovered. Hypotension persisted for two minutes in one patient (3.1%) in Group R2. There was no hypotension four minutes after intubation. No patient developed a heart rate of less than 60 beats per minute, no patient had muscle rigidity affecting manual controlled ventilation and oxyhaemoglobin saturation remained greater than 95% in all patients throughout the study.


The present study demonstrated that a bolus dose of remifentanil given simultaneously with sevoflurane and nitrous oxide produced acceptable intubating conditions at two minutes in healthy premedicated paediatric patients without the use of neuromuscular blocking drugs.

Inhalational induction with sevoflurane has been a useful technique employed by paediatric anaesthesiologists for intubating children without the need for a neuromuscular blocking drug (1,2,13-15). In some previous studies, tracheal intubation was performed without neuromuscular blocking drugs after establishing and maintaining the end-tidal concentration of sevoflurane for 10 and 15 minutes in children (2,14). This long induction time is not clinically practical. Some studies used a more rapid induction sequence without a long stabilising period. Politis et al reported that the induction times needed to achieve 80% successful intubation were 137 and 187 seconds for children of one to four years and four to eight years of age, respectively (16). Inomata et al reported that the time to end-tidal sevoflurane concentrations of 4.5% (95% effective dose, 4.68%) was 213 seconds (15). In several reports, induction time (the time to loss of eyelash reflex) of anaesthesia with sevoflurane was comparable to intravenous agents (17-20). Nevertheless, the time for tracheal intubation with sevoflurane, over three minutes in previous reports, was longer than with traditional intravenous induction agents with neuromuscular blocking drugs. In the present study, anaesthesia was induced with 50% nitrous oxide and 8% sevoflurane, because nitrous oxide and sevoflurane suppress the response to tracheal intubation in a linear and additive fashion in children (14). Blair et al reported that with 8% sevoflurane in 60% nitrous oxide in oxygen for three minutes, overall intubating conditions are acceptable in 87.5% of children of three to 12 years old (21). In Group S of the present study, only 56.3% had acceptable intubating conditions, suggesting that other adjuvants would be required in paediatric patients to achieve acceptable intubating condition within two minutes with 8% sevoflurane and nitrous oxide.

Several clinical studies have demonstrated that remifentanil could reduce the end-tidal sevoflurane concentration required for successful tracheal intubation (22) and remifentanil 0.5 to 4 [micro]g/kg in combination with intravenous or inhaled anaesthetics allowed successful tracheal intubation in children (6,23-25). In Min's study, the ED95 of remifentanil for successful intubation in children following sevoflurane and nitrous oxide induction was 0.75 [micro]g/kg (25). In the present study, the remifentanil injection was commenced with the inhaled agents two minutes before intubation was attempted and completed 90 seconds before intubation. Laryngoscopy was performed at the time of the peak effect of remifentanil (90 seconds after intravenous administration (26)). The results indicated that successful intubation was possible at two minutes. The remifentanil doses in our study were higher than the ED95 identified in Min's study (25). Our results showed that remifentanil 1 [micro]g/kg together with sevoflurane and nitrous oxide was effective for tracheal intubation in paediatric patients, and remifentanil 2 [micro]g/kg was not significantly better than the 1 [micro]g/kg dose.

Several reports have shown that ketamine assists tracheal intubation when it is used together with neuromuscular blocking drugs (27-29). It is possible that the cardiovascular stimulating property of ketamine may contribute to a fast distribution of neuromuscular blocking drugs (28). Drummond showed that ketamine 1 mg/kg did not reduce airway muscle activity (10). This would suggest that the ketamine used to facilitate separating the patients from the parents in our study was unlikely to have directly affected airway muscle activity as neuromuscular blocking drugs were not used. We would acknowledge that there is still a possibility that the ketamine may have influenced the responses to intubation in the present study.

The administration of remifentanil following sevoflurane induction has been associated with severe bradycardia and even asystole (30). Previous studies have shown an unacceptable incidence of bradycardia associated with the use of remifentanil in the absence of a vagolytic drug (31). Speed of injection is a predisposing factor (32) and the presence of beta-adrenergic or calcium-channel blockade is another predisposing factor (33). Beta blockers are rarely used in children. Opioid-induced hypotension is most likely caused by a centrally mediated decrease in sympathetic tone and vagally induced bradycardia (33). Glycopyrrolate is a synthetic anticholinergic agent abolishing the bradycardiac effects of bolus remifentanil (8), and ketamine causes a rise of blood pressure of about 25% (on average the systolic pressure rises by 20 to 30 mmHg) and increase of heart rate by about 20% (34). In the present study, mean blood pressure and heart rate measured before induction were higher than those in previous studies (35). We used the ketamine 1 mg/kg intravenously to facilitate separation of the children from the parents as this has been shown to be effective sedation (36). The higher mean blood pressure and heart rate in our patients compared with previous studies was most likely due to our routine use of ketamine and glycopyrrolate. Both drugs may have contributed to the minimisation of significant hypotension and bradycardia in our patients. In the present study, blood pressure after anaesthetic induction was decreased in a dose-related fashion. The remifentanil 2 [micro]g/kg group had a greater incidence of hypotension than the remifentanil 1 [micro]g/kg group (15.6 vs 6.3%). Usually, hypotension was transient and was easily treated by decreasing the depth of anaesthesia. Remifentanil 2 [micro]g/kg provided no advantage with respect to haemodynamic changes compared with 1 [micro]g/kg. There was no incidence of bradycardia or hypoxaemia during the induction of anaesthesia. There was no incidence of muscle rigidity which interfered with positive pressure ventilation in our study. As rapid intravenous infusion of large doses of potent opioids is often associated with an incidence of muscle rigidity (37), remifentanil should be administered only by persons specially trained in the use of potent opioids.

In conclusion, a bolus dose of remifentanil in combination with sevoflurane and nitrous oxide induction for two minutes in paediatric patients, who were premedicated with glycopyrrolate and ketamine, can produce acceptable intubating conditions. This technique provides an alternative pharmacological approach to facilitating tracheal intubation to the use of traditional intravenous induction agents and neuromuscular blocking drugs in paediatric patients.

Accepted for publication on January 26, 2009.


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K. S. PARK *, S. Y. PARK *, J. Y. KIM *, J. S. KIM [subsection], Y. J. CHAE *

Department of Anesthesia and Pain Medicine, Ajou University Hospital, Suwon, Korea

* M.D., Assistant Professor.

[subsection] Ph.D., Professor.

Address for reprints: Dr Y. J. Chae, Department of Anesthesia and Pain Medicine, Ajou University Hospital, San 5, Won-cheon-dong, Young-tonggu, Suwon 442-721, Korea.

Intubating condition score

 1 2 3 4

Jaw relaxation Complete Slight tone Stiff Rigid

Laryngoscopy Easy Fair Difficult Impossible

Vocal cords Open Moving Closing Closed

Coughing None Slight Moderate Severe

Limb movement None Slight Moderate Severe

Intubating conditions were assessed on the basis of the scoring
system devised by Helbo-Hansen et al (11) with unacceptable
conditions defined as any component of the score being greater
than 2.


Patient characteristics and baseline physiological values

 Group S Group R1
 (n=32) (n=32)
Age (y) 4.4 [+ or -] 2.0 3.9 [+ or -] 2.0
Gender: male/female 21/11 20/12
Body weight (kg) 17.2 [+ or -] 6.2 14.8 [+ or -] 4.2
MAP (mmHg) 95.7 [+ or -] 9.5 94.1 [+ or -] 13.4
HR (beats/min) 120.3 [+ or -] 20.0 123.6 [+ or -] 23.3

Patient characteristics and baseline physiological values

 Group R2
Age (y) 4.0 [+ or -] 2.2
Gender: male/female 16/16
Body weight (kg) 16.1 [+ or -] 5.8
MAP (mmHg) 93.3 [+ or -] 13.0
HR (beats/min) 122.2 [+ or -] 27.1

Data are mean [+ or -] SD. MAP=mean arterial pressure, HR=heart
rate, baseline=on arrival in the operating room.
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Author:Park, K.S.; Park, S.Y.; Kim, J.Y.; Kim, J.S.; Chae, Y.J.
Publication:Anaesthesia and Intensive Care
Article Type:Report
Geographic Code:9SOUT
Date:Jul 1, 2009
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