Sevoflurane is now the standard inhaled induction drug for children.1–6 It has a pleasant smell, does not irritate the airways, and has a low blood gas solubility coefficient.7,8 These properties result in fast and pleasant induction of anesthesia.
If administered in sufficient concentration for a long enough period, sevoflurane can produce relaxation of mandibular and laryngeal muscles to allow for laryngoscopy and intubation without the use of a muscle relaxant.9 This can be particularly advantageous when an anesthesiologist working without assistance (single-handed) prefers to intubate a child’s trachea before establishing IV access to administer adjuvant drugs.
Although the hemodynamic responses during inhaled induction with inspired concentrations of 59 and up to 7% sevoflurane have been unremarkable in healthy children,4,5 the effects of these high concentrations in children who may be hypovolemic because of prolonged fasting are not known. High concentrations (8%) of sevoflurane were reported to induce epileptiform electroencephalogram activity in children.10–12 These changes are reversed when inspired sevoflurane concentrations are decreased. Several authors recommend 5% sevoflurane as a safe inspired concentration after loss of eyelash reflex in children.12
The ability to perform laryngoscopy and tracheal intubation under “light” sevoflurane anesthesia is often facilitated by the use of IV adjuncts, such as opioids and propofol, or neuromuscular blocking drugs.
Remifentanil hydrochloride is a potent ultrashort-acting opioid analgesic that undergoes rapid metabolism by tissue and plasma esterases. The mean half-life in children has been found to be similar across age groups, with means of 3.4–5.7 min.13 Remifentanil has been used IV to obtund the airway response to tracheal intubation after sevoflurane induction in adults.14 In children, it has been shown to provide acceptable tracheal intubating conditions without neuromuscular blocking drugs when combined with IV propofol induction.15,16
The use of the intranasal route to administer lipophilic opioids is well established. The absorption is very rapid because of the large surface area and vascularity of the nasal mucosa. Fentanyl has been used nasally to control pain and/or irritability after bilateral myringotomy tube surgery in children with good results.17,18 The effective dose is approximately twice that used IV.
Our hypothesis was that remifentanil, administered intranasally at a dose of 4 mcg/kg, 2 and 3 min before laryngoscopy, would increase the percentage of patients with acceptable intubation conditions after a 5% sevoflurane induction when compared to patients who received no remifentanil.
We conducted a double-blind, randomized, controlled trial using a 2-level factorial design to compare intubating conditions and airway response to intubation as primary outcomes, and hemodynamic response, chest wall compliance and oxygen saturation as secondary outcomes. Included were 188 ASA physical Status I or II pediatric patients, aged 1–7 yr, undergoing elective surgical procedures that require tracheal intubation. Excluded were children with a history of upper respiratory tract infection in the previous week, reactive airway disease requiring daily treatment, or in whom a difficult intubation was anticipated. At level 1, participants were randomly allocated to receive nasally either remifentanil (4 mcg/kg) or placebo (equal volume of saline). At level 2, each level 1 group was randomly allocated to have either 2 or 3 min intubating times. In addition, blood samples were obtained from 17 patients to determine the pharmacokinetics of nasally administered remifentanil in children. The IRB approval, and parental consent were obtained in all cases.
As per our routine practice, no premedication was given and all the children were accompanied during induction by a parent or guardian. Anesthesia was induced using nitrous oxide/oxygen (60:40 mixture) and sevoflurane. A Mapleson-D system with a fresh gas flow of 6 L/min through a Sevotec-5 vaporizer was used. Depending on the child’s cooperation, sevoflurane was started with mask application at 8%, or introduced initially at a lower concentration that was quickly increased to 8% as tolerated. IV access was then established. Sixty seconds after 8% sevoflurane had been administered, nasal remifentanil (4 mcg/kg) or placebo (equal volume of saline) was administered, and nitrous oxide was discontinued. The study drug was prepared as a 100 mcg/mL solution in a 1-mL syringe for each patient by a member of the research team who was not involved in the care or observation of the patient being studied. The nasal solution was dripped through the nares half in each nostril using a blunt plastic cannula (B-D, Franklin Lakes, NJ 07471, Part # 303345) with the child’s head turned to the side so that the liquid would stay in contact with the lateral surface of the nasal cavity and not drip into the nasopharynx. Anesthesia induction continued with 5% sevoflurane in oxygen as (almost) equal to minimum alveolar anesthetic concentration for endotracheal intubation for these age groups,9 with respirations assisted or controlled as needed to maintain end-tidal CO2 of 35 ± 3 torr.
Patients were randomized to 2 or 3 min intubating times after nasal drug administration (3–4 min after sevoflurane induction). A randomization table was computer-generated and the assignment to a particular arm was determined by opening a sealed envelope at the time of induction. An investigator, blinded to the duration of time from nasal drug administration (being outside the room during induction), attempted laryngoscopy and intubation, and scored the response19 (Table 1). Laryngoscopy was started 5 s earlier than the randomized intubation time, using a MacIntosh curved laryngoscope blade. If laryngoscopy was successful, tracheal intubation was attempted at the predetermined intubation time with an appropriate size uncuffed tracheal tube without neuromuscular blockade or other adjuvants. Care was taken to avoid touching the carina during intubation.
Patients who could not be intubated because of excessive movement during attempted laryngoscopy, and those who coughed vigorously after tracheal intubation were given an IV bolus dose of muscle relaxant (rocuronium) or propofol (2–3 mg/kg) and were regarded as having unacceptable intubating conditions. Good or excellent scores were counted as acceptable and poor scores were counted as unacceptable (Table 1).
Inspired/end-tidal sevoflurane and CO2 concentrations were measured with a Datex anesthesia gas monitor, and recorded immediately before and after tracheal intubation in each patient. Accuracy of end-tidal measurements was maximized by confirming the return of the end-tidal CO2 trace to zero, and by gas sampling from a flexible cannula (an IV catheter) positioned adjacent to the nares. After tracheal intubation, gases were sampled through the angled elbow piece near the proximal end of the tracheal tube.
Monitoring consisted of heart rate, arterial blood pressure (BP), respiratory rate, oxygen saturation, and end-tidal sevoflurane. End-tidal CO2 was also monitored and maintained at 35 ± 3 torr. Any evidence of chest wall rigidity, such as difficulty in ventilation, wheezing, changing compliance or any change in the slope of the end-tidal CO2 waveform was noted.
The study was considered complete once spontaneous respirations resumed, or if IV muscle relaxants were administered, whichever occurred first. Anesthesia was then continued in any manner selected by the anesthesiologist in charge of the case.
Blood samples for assay of remifentanil were drawn from 17 patients at baseline when possible, and at 2, 3, 4, and 10 min after drug administration. Because remifentanil is highly susceptible to endogenous esterase activity, blood samples (2 mL) were collected in heparinized Vacutainer® tubes and immediately transferred to culture tubes that already contained 40 μL of 50% citric acid to preserve remifentanil from esterase activity. The tubes were tightly capped, inverted several times to ensure sample homogeneity, and immediately frozen at −80°C. Analysis was performed using the gas chromatograph, a Hewlett-Packard Model 5890 II equipped with a 5972A mass selective detector, 7673 liquid automatic sampler, split-splitless capillary inlet system, and electronic pressure control system.20
Statistical and Analytical Methods
The Bonferroni-corrected sample size estimate of 168 (42 per ea. of four comparison groups) was derived to achieve 80% power, in two-tailed testing at a P = 0.5, to detect a clinically important difference of 50% in the rate of acceptable intubations in remifentanil-treated (95%) compared with the saline-treated (45%) patients at 2 and/or 3 min. The number was increased by 10% to 188 to cover anticipated losses.
To address the primary aim, we compared intubation conditions and airway response to intubation in those administered remifentanil (4 mcg/kg) to those administered placebo, both overall and by time of intubation. To address the main outcome, we compared the proportion of patients who in each of the four groups achieved good-to-excellent conditions for intubation using a test of difference in proportions. For the secondary outcomes, we used repeated measures analysis of covariance models to perform these analyses. Covariates included age, sex, race, and weight. Variance estimates were adjusted to account for the correlation between measurements on the same patient. From the model, we estimated means by treatments: remifentanil or saline overall and by time of intubation, 2 or 3 min. All statistical analyses were performed by using the Statistical Analysis Software Institute SAS/STAT Software 6.12; 1997 package.21 PK analysis was implemented using WinNonLin software developed by Pharsight.
One hundred eighty-eight patients completed the study. Participants were similar in age, weight, sex, and race between the remifentanil and saline groups for either the 2-min or 3-min subgroups (Table 2). All patients who had pharmacokinetics sampling had detectable remifentanil blood levels at 2 min after intranasal administration (Fig. 1). The mean remifentanil plasma concentrations (±sd) at 2, 3, 4, and 10 min were 1.0 (0.60), 1.47 (0.52), 1.70 (0.46), and 1.16 (0.36) ng/mL, respectively. The observed peak plasma concentration was at 3:47 min.
Good or excellent intubating conditions were achieved at 2 min in 68.2% and at 3 min in 91.7% of the children who received intranasal remifentanil versus 37% and 23% in children who received placebo (P < 0.01) (Fig. 2). Differences of end-tidal CO2 and sevoflurane concentrations immediately before and after intubation were not statistically significant among the four groups (Table 3).
No patient developed clinically significant (>20%) bradycardia or hypotension. However, at 3-min, the systolic BP, diastolic BP, and heart rate were statistically significantly lower in the remifnetanil versus saline groups (P = 0.002, 0.002, and 0.015 respectively) (Fig. 3). There were no episodes of laryngeal spasm or chest wall rigidity associated with the use of intranasal remifentanil.
Our results show that the use of nasal remifentanil in this study resulted in better intubating conditions in children during light sevoflurane anesthesia than placebo. In fact, good or excellent intubating conditions at 2 min in the children who received intranasal remifentanil (68.2%) were significantly better than the same conditions at 3 min in children who received placebo (23.8%) P = 0.006. This approach, therefore, can allow for earlier laryngoscopy and intubation under light sevoflurane anesthesia. The use of nasal opioids as adjuncts to sevoflurane during laryngoscopy can be particularly advantageous for the anesthesiologist who performs an inhaled induction and needs to concentrate on managing the airway of the anesthetized child. Normally, he/she must seek help to establish an IV to administer a neuromuscular blocking drug or an opioid to facilitate laryngoscopy16,22 or to establish a deeper level of inhaled anesthesia to perform laryngoscopy and intubation without the use of muscle relaxants.9,22 Nasal remifentanil offers an additional option to facilitate tracheal intubation in these children.
The concept of tracheal intubation without neuromuscular blockade is not new. A survey of members of the Society for Pediatric Anesthesia found that tracheal intubation using an inhaled anesthetic without muscle relaxation (IAWMR) was used in children by 44% of the respondents.23 In that study, the most commonly stated reason for using IAWMR was the lack of need for a muscle relaxant during intubation or maintenance of anesthesia. Difficulty with pediatric venous access, because of either technical challenge or lack of an assistant able to place an IV, were other reasons many survey responders used IAWMR. Anesthesiologists who most often used IAWMR had three times the odds of working most cases alone without an assistant to start an IV line.
The use of sevoflurane for induction and tracheal intubation has been widely investigated in children.24 Inomata and Nishikawa25 suggested an ED95 (95% effective dose) end-tidal sevoflurane concentration of 4.68% for tracheal intubation that can be obtained by breathing an inspired concentration of 5% sevoflurane in oxygen for an average of 3.5 min. The average induction time required for smooth tracheal intubation in 95% of children breathing sevoflurane 5% in oxygen has been found to be 3 min 14 s.26 However, we acknowledge that although the end-tidal sevoflurane concentrations in our study were 4% or more at the time of laryngoscopy, they do not represent steady-state values.25
Although not addressed in the current study, it is possible that the use of 8% sevoflurane without any adjuncts would have resulted in similar intubating conditions to those achieved with a 5% concentration and nasal remifentanil.27
IAWMR technique is sometimes facilitated by the use of adjuvants, such as topical lidocaine,28 or IV administration of an opioid, to blunt the airway response to laryngoscopy and intubation. Remifentanil, an ultrashort-acting opioid with very fast onset has been studied. Crawford et al.16 showed that, after propofol induction in infants, an IV dose of 3 mcg/kg of remifentanil was effective in achieving adequate intubation conditions 90 s after remifentanil administration, and that the dose response of remifentanil for tracheal intubation was similar in infants and children. Crawford et al.16 calculated the ED50 and ED95 doses of IV remifentanil, that are required to achieve acceptable intubating conditions after 4 mg/kg IV propofol induction, to be 1.7 ± 0.1 mcg/kg and 2.88 ± 0.5 mcg/kg, respectively.
The intranasal route of opioid administration is an effective and rapid method of achieving analgesia in adults and children when IV access is not available.17,18,29–31 As long as the drug is not pushed very quickly down the nose, it does not reach the larynx, and the risk of inducing coughing is minimal.
The choice of a 4 mcg/kg dose of nasal remifentanil was based on an assumption that blood levels of nasally administered drugs are about half that obtained after IV dosing.32,33 The optimal dose of IV remifentanil for tracheal intubation under sevoflurane anesthesia in adults was found by Joo et al.14 to be 2 mcg/kg, hence our 4 mcg/kg dosing.
It is noted that the blood levels of remifentanil in our patients were on the low side. One study examining intubation conditions with IV remifentanil in children used 3 mcg/kg, which is a higher dose than we used in our study.15 Other authors reported that an IV dose of 4–5 mcg/kg of remifentanil may be even more reliable in achieving good intubating conditions after 2 mg/kg of IV propofol in adults.34 Remifentanil at 3.3 ng/mL combined with sevoflurane at 1-minimum alveolar anesthetic concentration provided excellent conditions for intubation without muscle relaxants in 50% of adult patients.35 During propofol anesthesia, a target remifentanil blood concentration of 5–15 ng/mL provided good intubating conditions and absence of cough about 75% of the time.36 Future studies should examine the intubating conditions and the possible side effects of using a higher remifentanil dose nasally.
We conclude that intranasal administration of remifentanil 4 mcg/kg after sevoflurane induction in children decreases the incidence of coughing and movement during intubation.
The authors are grateful to Robert McCarter, ScD, for statistical consultation after the unexpected death of our primary statistician, Kantilal M. Patel, PhD. Remifentanil assays were performed by Sang Park, PhD, Analytical Facility, Department of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195; www.uwanesthesiology.org/assays.
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