Tracheal intubation without the use of muscle relaxants is commonly used in pediatric anesthesia. It is especially suitable for patients with neuromuscular diseases, for patients who are scheduled for minor craniomaxillofacial surgery, and for patients at risk for malignant hyperthermia.
In a previous study, administration of propofol (3 mg/kg) and remifentanil (2 μg/kg) was successful and associated with excellent conditions in 69% and 35% of pediatric patients, respectively.1 Intubation conditions have been found to influence the incidence of postoperative laryngeal injury.2 In particular, excellent conditions are associated with a lower incidence of hoarseness and sore throat. Although intubation conditions could be improved by increasing the doses of remifentanil or propofol that are administered, a corresponding increase in the incidence of bradycardia or hypotension may occur.3 Thus, an ideal regimen for the induction of IV anesthesia would provide satisfactory intubation conditions with minimal perturbation of hemodynamics. Distinct from the mechanisms of propofol or remifentanil, dexmedetomidine is a highly selective α2-adrenergic agonist. Dexmedetomidine has been found to significantly decrease the requirement for anesthetics and analgesics and to reduce the hemodynamic response to nociceptive stimuli.4 A slow IV infusion of dexmedetomidine (e.g., 1 μg/kg over 10 minutes) does not significantly affect hemodynamics, whereas a bolus injection of dexmedetomidine (0.5 μg/kg) produces a transient increase in systemic blood pressure (BP).5 Moreover, in a rat model, dexmedetomidine did not enhance the hemodynamic effects of opiates.6 The hypothesis of the present study was that a rapid infusion of dexmedetomidine (1 μg/kg) would improve intubation conditions without causing hemodynamic compromise in children after induction with propofol (3 mg/kg) and remifentanil (2 μg/kg). Consequently, intubation conditions and hemodynamic changes were the primary and secondary outcome measures for the present study.
This study was approved by the Ethics Committee of the Plastic Surgery Hospital, Peking Union Medical College (2013019), and written informed consent was obtained from each patient’s parent or guardian. This study was registered with the Chinese Clinical Trial Registry (ChiCTR-TQR-14004833) on February 9, 2014. On the basis of the results of previous studies,1 the incidence of successful intubations after induction with propofol and remifentanil was 69% and the incidence of successful intubations after induction with muscle relaxants was assumed to be 99.9%. Accordingly, the difference in the incidence of successful intubations between these 2 groups was hypothesized to be 31%. Under these circumstances, a power analysis indicated that 30 patients would be required for each group to achieve 90% power (α = 5%).
This study was conducted at a plastic surgery hospital in Beijing, China, between June 10, 2013, and March 14, 2014. There were 130 patients aged 5 to 10 years that were scheduled for tracheal intubation under general anesthesia, and 70 patients were excluded. The latter included children with upper respiratory tract infections 3 weeks before intubation, children with pulmonary or cardiac disease, children with difficult airways, or morbidly obese children (e.g., weight/height ratio >20%). Therefore, 60 ASA physical status I children aged 5 to 10 years scheduled for elective plastic surgery under general anesthesia were enrolled.
This randomized, double-blinded, and placebo- controlled study included a dexmedetomidine group (group D) and a placebo group (group P). Patients in group D received dexmedetomidine (1 μg/kg) + propofol (3 mg/kg) + remifentanil (2 μg/kg) (n = 30), whereas patients in group P received normal saline + propofol (3 mg/kg) + remifentanil (2 μg/kg) (n = 30). The assignment of patients to each group was determined randomly by a computer program. The results of the randomization process were only known to the nurse who was responsible for the preparation of research drugs. All research drugs were prepared using 20 mL syringes for their convenient administration via an injection pump. However, dexmedetomidine (1 μg/kg) and remifentanil (2 μg/kg) were each prepared in a volume of 10 mL in sodium chloride (0.9%). Syringes containing dexmedetomidine for group D (or normal saline for group P) were labeled drug 1. Syringes containing propofol and remifentanil for both groups were, respectively, labeled drug 2 and drug 3. Administration of anesthesia was performed by 2 anesthesiologists who were unaware of group assignment for each patient. One researcher (a senior resident) was responsible for administration of drugs and collection of data during induction of anesthesia, whereas the second (an attending physician) performed laryngoscopy and tracheal intubations and further assessed intubation conditions.
Induction of Anesthesia
Upon arrival at the operating room, each patient was monitored using a Datex-Ohmeda S/5 anesthesia-monitoring device that continuously measures BP, using pulse oximetry and with electrocardiography. An IV cannula 22 was inserted into a vein at the dorsum of the hand, and atropine (0.01 mg/kg) was administered. Anesthesia was then induced with an IV infusion of drug 1 (dexmedetomidine [1 μg/kg] for group D or normal saline for group P) for 2 minutes. Drug 2 (3 mg/kg propofol) was subsequently injected over 20 to 30 seconds, followed by infusion of drug 3 (2 μg/kg remifentanil) for 1 minute. One minute later, a laryngoscopy and tracheal intubation were performed using a Macintosh laryngoscope. After successful intubation, anesthesia was maintained with 2% sevoflurane and 50% nitrous oxide in oxygen, and the patients’ lungs were ventilated using a mechanical ventilator. All patients were administered oxygen for 3 minutes before induction of anesthesia. Assisted ventilation was administered manually to maintain end-tidal carbon dioxide partial pressure (PetCO2) between 35 and 40 mm Hg, when necessary, during induction of anesthesia.
Scoring of Intubation Conditions
Intubation conditions were evaluated using a previously described scoring system (Table 1),7 which includes 5 factors: ease of performing the laryngoscopy, vocal cord condition, coughing, limb movement, and jaw relaxation. Excellent conditions received a score of 1 for all the 5 factors, whereas acceptable conditions received a score of 2 for any of the 5 factors and poor conditions received a score >2 for any of the 5 factors. Both excellent and acceptable conditions were defined as successful intubations. Poor conditions were defined as failed intubations. If any of the following conditions occurred in either group: closed vocal cords, a rigid jaw that made it impossible to insert a laryngoscope, excessive limb movement, or severe coughing during the laryngoscopy or intubation, rocuronium (0.8 mg/kg) was administered to facilitate intubations. Propofol (1–2 mg/kg) was also administered before rocuronium if a child’s BP increased >20% compared with baseline. Anesthesia was maintained identically for all study patients.
Noninvasive measurements of BP, heart rate (HR), and pulse oxygen saturation (SpO2) were made at baseline, after injection of dexmedetomidine, after injection of remifentanil, before intubation, and 1, 3, and 5 minutes after intubation. Side effects were recorded during the induction of anesthesia. Hypotension (≤30% baseline) and bradycardia (HR ≤60 beats/min) were treated with IV administration of ephedrine (5 mg) and atropine (0.01 mg/kg). Hypertension (≥20% baseline for >1 minute) and tachycardia (≥20% baseline for >1 minute) were managed by increasing the depth of anesthesia or with the administration of vasoactive drugs, nicardipine (2–10 μg/kg/min), or nitroglycerin (3–6 μg/kg/min). Other events such as hypoxemia, laryngospasm, and pharyngolaryngeal injury were also recorded.
Data were analyzed using Statistical Package for the Social Sciences (SPSS, Chicago, IL) 10.0 and are expressed as the mean ± SD. Scoring of intubation conditions was analyzed using Mann-Whitney U tests. The incidence of successful intubations and excellent intubation conditions between groups was compared using the Fisher exact test. The Student t test was used to analyze demographic variables such as age and weight, and a χ2 test was applied to analyze gender differences between groups.
Hemodynamic variables (such as HR, systolic BP [SBP], and diastolic BP [DBP]) were analyzed by repeated measures of analysis variances (ANOVAs). The Kolmogorov-Smirnov Z test and the Levene test were applied to assess the normality of the distribution and homogeneity of variance of our data, respectively. These tests identified P values > 0.110, thereby confirming the normality of distribution and homogeneity of variance of the present data. The Mauchly test of sphericity was used to validate the correlation of the repeated measures, and tests of within-subject and between-subject effects were applied by repeated measures of ANOVA in a general linear model. An independent samples t test was used to compare the means between group P and group D at each timepoint. To compare the means between 2 different timepoints within each group, the Bonferroni test/Repeated measures/General Linear Model was applied. Briefly, the data were first divided according to group. Next, using the process of repeated measures analysis, the mean HR, SBP, and DBP values between each set of timepoints were compared. According to the results of the Mauchly Test of Sphericity, each factor of epsilon-corrected test for SBP, DBP, and HR was <0.7. Therefore, the Bonferroni test was used to reduce the incidence of type I error. A t test was applied 7 times to compare the mean values at each of the following timepoints with baseline: after the injection of dexmedetomidine, after the injection of remifentanil, before intubation, immediately after intubation, and 1, 3, and 5 minutes after intubation. Thus, the denominator for the Bonferroni adjustment was 7, and the α value was corrected to 0.05/7 for the significance level.
The P values for the main effects of group and the interaction effect between group and time for DBP were 0.1846 and 0.4085, respectively. The P value for the main effect of time for DBP was <0.0001. On the basis of a level of significance of P > 0.05, there was no significant interaction effect observed between time and group for DBP. A P value <0.01 for the main effect of time indicated that DBP significantly changed with time. A P value >0.05 for the main effect of group indicated that there was no difference in DBP between the 2 groups.
The P values for the main effects of group, and the interaction effect between group and time, for SBP were 0.0087 and 0.0058, respectively. The P value for the main effect of time for SBP was <0.0001. The P value for the main effect of group for HR was 0.1148. Each P value for the main effects of time and interaction effect between group and time for HR was <0.0001. On the basis of the interaction effect observed between group and time for SBP and HR, the main effects of group and time on SBP and HR could not be determined using overall repeated measures of ANOVA. Therefore, repeated measures of ANOVA were individually applied to each group for SBP and HR. Each P value was <0.0001 for the tests of within-subject effects, thereby indicating that SBP and HR significantly differed at various timepoints in each group. Moreover, an independent samples t test was used to compare the mean SBP and HR values between the 2 groups at each of the timepoints.
There were no statistically significant differences in the demographic data between group P and group D (Table 2). However, 2 patients in group D and 7 patients in group P, respectively, were administered nondepolarizing muscle relaxants for poor intubating conditions. Consequently, these 9 patients were excluded from statistical analysis of hemodynamic variables after intubation.
Tracheal intubations were successful in 90% (27/30) and 53% (16/30) of group D and group P patients, respectively (P = 0.0034). Excellent conditions were present in 22 of 27 and 8 of 16 of group D and group P intubations, respectively, resulting in an overall incidence of excellent conditions of 73% (22/30) and 27% (8/30), respectively (P = 0.0007; Table 3). In group D, 3 patients experienced failed intubations 1 each because of jaw rigidity that prevented insertion of the laryngoscope, severe coughing during insertion of the tube into the trachea, and severe limb movement during laryngoscopy. Two of those patients were administered rocuronium (0.8 mg/kg) and propofol (1.5 mg/kg) to facilitate intubation. There were 14 failed intubations in group P due to severe coughing and limb movement, and muscle relaxants were administered to 7 of 14 of these patients. In group D, coughing occurred during tube insertion for all 5 patients that had acceptable intubating conditions (e.g., a score of 2; Table 4).
Hemodynamic responses to intubation for groups D and P are shown in Figures 1 and 2. For group D, significant decreases in the mean differences in HR were observed after injection of dexmedetomidine (P = 0.0001), after injection of remifentanil (P = 0.0173), and before intubation (P = 0.0010), with differences and confidence intervals (CIs) of (13 [9, 16]), (10 [6, 15]), and (14 [10, 18]), respectively. Similarly, for group P, significant decreases in the mean differences in HR were observed after injection of remifentanil (P < 0.0001) and before intubation (P < 0.0001), with differences and CIs of (12 [9, 14]) and (13 [10, 16]), respectively. Compared with group P, a slower HR was observed in group D after injection of dexmedetomidine (P < 0.0001).
In group D, after injection of dexmedetomidine, the mean differences in SBP and DBP increased by (12 [7, 17]) and (12 [6, 18]), respectively, compared with values obtained at baseline (Fig. 2). The Bonferroni correction revealed statistically significant differences in group D for the mean SBP (P = 0.0118, CI = 2–22 mm Hg) and mean DBP (P = 0.0454, CI = 2–24 mm Hg) after injection of dexmedetomidine compared with baseline. A significant difference in mean SBP between group P and group D was also observed after injection of dexmedetomidine (P = 0.0242). Moreover, for group P, decreases in SBP were observed before intubation, immediately after intubation, and 1, 3, and 5 minutes after intubation (P < 0.0001 in each case).
For both groups, BP and HR values before intubation were comparable with those obtained immediately after intubation. In 3 patients, hypertension occurred transiently during the infusion of dexmedetomidine. However, after receiving propofol and remifentanil, both SBP and DBP decreased to baseline levels for these patients. There were no episodes of hypotension, bradycardia, hypoxemia, or laryngospasm reported during the induction of anesthesia for both groups.
In the postanesthesia care unit, 4 patients in group D and 7 patients in group P reported a sore throat. The average visual analog scale (VAS) score for each group was 4.0 and 4.6, respectively. There was no significant difference in the incidence of sore throat between the 2 groups according to a χ2-corrected test. Moreover, the intubating conditions score for these patients was ≥2. Only 1 patient in group P with a VAS score of 6 for a sore throat required oral tramadol (1.5 mg/kg) after intubation without muscle relaxant. All postintubation patients were treated with a nebulizer (α-chymotrypsin [5 mg] and dexamethasone [5 mg] in 20 mL saline). No hoarseness was observed, and laryngeal edema did not occur within 4 hours after operation. For patients intubated with rocuronium, a sore throat with a VAS score <5 was reported for 2 patients in group D and for 3 patients in group P. These patients received standard nebulizer inhalation treatment, and no additional special treatment was needed.
The results of this study demonstrate that administration of dexmedetomidine (1 μg/kg) effectively improved intubating conditions and inhibited a hemodynamic response to intubation in children after induction with propofol (3 mg/kg) and remifentanil (2 μg/kg).
In general, the intubation conditions were scored as excellent, acceptable, or poor based on the ease of performing a laryngoscopy, jaw relaxation, vocal cord condition, coughing, and limb movement. Postoperative pharyngolaryngeal complications also occurred less frequently in patients with excellent intubation conditions. An investigation by Blair et al.1 demonstrated that the rates of successful intubations after induction with propofol (3 mg/kg) and various doses of remifentanil (1, 2, and 3 μg/kg) were 50%, 69%, and 82%, respectively, and the rates of excellent conditions were 29%, 35%, and 48%, respectively. In contrast, lower rates of successful intubations and excellent intubation conditions were observed in the present study for group P (53% and 27%, respectively), whereas in group D, the rates increased to 90% and 53%, respectively, in combination with dexmedetomidine (1 μg/kg). Moreover, the latter increases were greater than those reported for induction with propofol (3 mg/kg) and remifentanil (3 μg/kg) for anesthesia induction performed by Blair et al.1 On the basis of these results, it appears that intubation conditions after induction with propofol (3 mg/kg) and remifentanil (2 μg/kg) could be improved with the addition of dexmedetomidine (1 μg/kg) rather than a higher dose of remifentanil.
Dexmedetomidine is increasingly used in perioperative management of pediatric patients. For example, dexmedetomidine has been administered as premedication both orally (2.6 μg/kg 30 minutes before a procedure)8 and intranasally (3 μg/kg 1 hour before the induction of anesthesia).9 In both cases, dexmedetomidine was found to provide effective sedation and anxiolysis, thereby facilitating separation of the patient from the parents. As a general anesthesia adjuvant, IV administration of dexmedetomidine (1 μg/kg) has also been found to decrease the target effect-site concentration of propofol and remifentanil that is required for suspension laryngoscopy by 1.29 μg/mL and 0.64 ng/mL, respectively.10 A vial of dexmedetomidine (200 μg per vial, produced by Jiangsu Hengrui Medicine, Co., Ltd., Nanjing, Jiangsu, China) currently costs $31.31 (USD), and this vial can provide a dose of 1 μg/kg per patient (the concentration used in the present study). Moreover, dexmedetomidine could potentially decrease the requirement for sedatives and analgesics during operation, as well as significantly decrease the incidence of emergence agitation and postoperative nausea and vomiting in children under sevoflurane anesthesia. Thus, dexmedetomidine (1 μg/kg) is an easily administered and economical adjuvant.11
Traditionally, it has been recommended that dexmedetomidine (1 μg/kg) be administered via IV infusion for 10 minutes. However, Bloor et al.12 demonstrated that a rapid infusion of 0.25, 0.5, 1.0, or 2.0 μg/kg dexmedetomidine over 2 minutes was well tolerated in healthy volunteers with a biphasic hemodynamic effect observed. Arterial BP initially transiently increased, while SBP reached its peak 3 minutes after the administration of dexmedetomidine because of the stimulation of α2-adrenoceptors present on vascular smooth muscle cells. This was followed by a long-lived reduction in arterial BP that was mediated by activation of α2-adrenoceptors in the central nervous system. A study by Snapir et al.13 also demonstrated that dexmedetomidine can mediate a significant increase in BP when the plasma concentration of dexmedetomidine increases from 0.5 to 3.2 ng/mL. The pressor effect of dexmedetomidine presumably correlates with the rate of IV infusion and plasma concentration of the drug.
In this study, both SBP and DBP increased after the injection of dexmedetomidine and both returned to baseline levels after administration of propofol and remifentanil. Three patients experienced hypertension that resolved soon after administration of propofol and remifentanil without the need for additional vasoactive drugs. In addition, there were no significant changes between the BP readings before and after intubation for both groups. It should also be noted that 2 patients from group D and 7 patients from group P that received failed intubation scores were excluded from statistical analysis of hemodynamic data after intubation because muscle relaxants were administered to these patients.
A common concern is the negative chronotropic effect of both dexmedetomidine and remifentanil. A significant decrease in HR may be caused by sympatholysis in the central nervous system and stimulation of the central vagus nerve and peripheral μ-opioid receptors by dexmedetomidine and remifentanil, respectively.14 Consequently, in this study, atropine (0.01 mg/kg) was administered to prevent bradycardia, although it is not routinely administered to pediatric patients that are scheduled for inhaled induction of general anesthesia in our department. Nevertheless, HRs for group D and group P were found to decrease by 15% and 13%, respectively, after the induction of anesthesia compared with baseline.
It is also important to note that all the children enrolled in the present study were categorized as ASA physical status I. Thus, it remains to be determined whether the results of this study can be applied to critically ill patients. Moreover, because the main objective of the present study was to evaluate intubation conditions, and this was the objective that the original power analysis was based on, the resulting smaller sample size (n = 30/group) may have influenced the accuracy of the hemodynamic analysis performed. Therefore, this is a limitation of the present study that was not addressed in the original design of our study protocol.
In conclusion, a single dose of dexmedetomidine (1 μg/kg) improved intubation conditions in children after induction with propofol (3 mg/kg) and remifentanil (2 μg/kg) without muscle relaxants. Dexmedetomidine did not affect the hemodynamic response to intubation.
Name: Lingxin Wei, MD.
Contribution: This author helped design the study, conduct the study, and prepare the manuscript.
Attestation: Lingxin Wei attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Xiaoming Deng, BS Med.
Contribution: This author helped design the study.
Attestation: Deng Xiaoming has approved the final manuscript.
Name: Jinghu Sui, MD.
Contribution: This author helped conduct the study and collect the data.
Attestation: Jinghu Sui attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Lei Wang, MD.
Contribution: This author helped collect the data and analyze the data.
Attestation: Lei Wang is the archival author.
Name: Juhui Liu, MD.
Contribution: This author helped analyze the data.
Attestation: Juhui Liu attests to the integrity of the original data and the analysis reported in this manuscript.
This manuscript was handled by: James A. DiNardo, MD.
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