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Anesth Analg 2003;96:976-981 © 2003 International Anesthesia Research Society
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Abstract |
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In this randomized, double-blinded, placebo-controlled trial, we investigated whether clonidine lessened the requirements for isoflurane, fentanyl, and labetalol to provide controlled hypotension in children who underwent oromaxillofacial surgery. We also studied preoperative sedative effects, the hemodynamic response to nasotracheal intubation, and recovery characteristics. Thirty-nine healthy children, aged 10–16 yr, received clonidine 5 µg/kg or placebo on the night before surgery and 90 min before surgery. By self-assessment, children in both groups showed similar anxiety, whereas observers rated clonidine patients as more sedated (P < 0.01). Heart rate during induction remained significantly decreased in clonidine patients compared with placebo patients (P < 0.001), as did arterial blood pressure before induction (P < 0.01) and peak pressure after intubation (P < 0.001). Children who took clonidine required significantly less isoflurane to maintain a mean arterial blood pressure of 60 ± 4 mm Hg (mean isoflurane concentration, clonidine 0.99% versus placebo 1.33; P = 0.0004) and required less fentanyl than placebo patients (P = 0.002). Fewer treatment patients received labetalol (clonidine, n = 3 versus placebo, n = 13; P = 0.004). There was a trend toward faster recovery in the clonidine group, with a shortened recovery room stay (P = 0.03). We conclude that clonidine is a useful adjunct for controlled hypotension in children.
IMPLICATIONS: This study shows that adolescents having major jaw surgery are helped by the blood pressure-decreasing drug clonidine. This drug allows smaller doses of anesthetics, pain relievers, and blood pressure-decreasing drugs to be used; reduces changes in heart rate and blood pressure; and provides faster recovery from the anesthetic.
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Introduction |
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Adolescent children who undergo corrective maxillary or mandibular surgery for dentofacial abnormalities experience less blood loss when the anesthetic technique includes a moderate degree of controlled hypotension (1). Although there are numerous approaches to providing controlled hypotension, isoflurane has been an integral part of many reports. Isoflurane lends itself particularly well to the technique of controlled hypotension because of its favorable effects on the systemic and cerebral circulation (2–4) .
In recent years, the antihypertensive drug clonidine has generated considerable interest as an anesthetic adjuvant. Clonidine acts by a central 
2-adrenergic mechanism and reduces sympathetic nervous system output. Clonidine diminishes requirements for inhaled anesthetics and enhances the effects of sedative, anxiolytic, and analgesic drugs (5). Some of these findings have also been observed in children: clonidine provides for preoperative sedation, lessens the induction dose of thiamylal, and lessens the concentration of halothane required to provide anesthesia and maintain cardiovascular stability (6–8) . Similar to findings in the elderly, clonidine blunts the hemodynamic response to orotracheal intubation (9,10) . Moreover, clonidine has proven useful as an adjunct to controlled hypotension. These studies have included only adults (11–14) .
We conducted this study to determine whether the use of clonidine would benefit a population of adolescent children undergoing major corrective maxillofacial surgery under isoflurane anesthesia with controlled hypotension. We investigated whether clonidine reduced the amount of isoflurane, fentanyl, and labetalol required to provide controlled hypotension and whether it reduced the number of interventions necessary to maintain a given level of hypotension. In addition, we studied the sedative and anxiolytic effects of clonidine pre-medication, assessed the hemodynamic response to nasotracheal intubation, and examined whether cloni-dine premedication affected postoperative analgesic requirements.
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Methods |
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This study was approved by the institutional Research Ethics Board. After informed consent was obtained from the children and their parents, the patients were randomized to receive either clonidine or placebo. The randomization was performed by the hospital pharmacy by using a table of random numbers, and the patients, investigators, surgeons, and nurses involved in the patients’ care were blinded to the nature of the assignment. Consecutive healthy adolescent patients scheduled for orthognathic surgery were considered eligible for this study. Exclusion criteria were significant heart disease that contraindicated the use of controlled hypotension, medically important liver or kidney dysfunction, allergy to clonidine, allergy or contraindication to the use of labetalol or ß-blocking drugs, weight heavier than 80 kg, and inability to comply with the protocol, i.e., a language barrier. Clonidine 5 µg/kg or an identical-looking placebo was given by mouth at bedtime on the night before surgery and 90 min before surgery. The dose was rounded to the nearest multiple of 50, starting at 200 µg for patients weighing
40 kg, to a maximum of 400 µg. In addition, all patients received diazepam 0.15 mg/kg by mouth and had EMLA® cream (Astra Pharma Inc.) applied to the back of each hand 90 min before surgery. To assess the anxiolytic effect of the premedication, patients were asked to indicate their emotional state on a visual analog scale (10-cm length; range from 0 = completely calm to 10 = worst possible anxiety). The patients were instructed in the use of this measurement at the end of the preoperative interview. On the morning of surgery, before they received their preoperative medication, and again immediately before they were taken to the operating room (OR), they were asked to rate their anxiety on the visual analog scale. Furthermore, the patients’ perceived degree of sedation was rated by the anesthesiologist and the circulating OR nurse on a four-point scale: 1, awake and talkative; 2, awake but uncommunicative; 3, drowsy, quiet, and easily arousable; and 4, asleep, not easily arousable (15).
Standard noninvasive monitoring was used; it included a three-lead electrocardiogram, pulse oximeter, automated blood pressure (BP) cuff (Cardiocap 200; Datex), axillary temperature, and continuous respiratory gas analysis (Datex Ultima). The gas analysis data were stored digitally, allowing later retrieval and calculation of expired isoflurane concentration by using software called "Collect," which was provided by Nellcor Puritan Bennett.
All anesthetics were given by the same anesthesiologists (TH and MF) by using a standardized protocol for induction, maintenance, and recovery. After placement of an IV cannula, patients received a priming dose of vecuronium 1.0 mg, fentanyl 3.0 µg/kg, and droperidol 25 µg/kg. After preoxygenation for 3 min, thiopental 5 mg/kg was given, and vecuronium was given to achieve a total dose of 0.1 mg/kg. Manual ventilation with bag and face mask continued for 90 s, after which a nasogastric tube was passed and the trachea intubated by using a lubricated, warmed, preformed, nasotracheal RAE tube. The lungs were mechanically ventilated with a Bain circuit with an oxygen/nitrous oxide mixture of 30%:70% and an isoflurane vaporizer setting of 1% until the start of surgery. The fresh gas flows were set at 100 mL/kg, the respiratory rate ranged from 10 to 14 breaths/min, and the tidal volume was adjusted to maintain the end-tidal carbon dioxide concentration between 35 and 40 mm Hg. Lactated Ringer’s solution 10 mL · kg-1 · h-1 was given for the first hour of surgery by using an infusion pump. This was reduced to 5 mL · kg-1 · h-1 for the remainder of the operation. To aid in achieving a bloodless field, the patients were placed in a 15° Fowler position, and the surgeons injected 1% lidocaine with epinephrine 1:100,000 solution before tissue dissection.
The patients’ BP was recorded 3 times before surgery: on admission; at bedtime, when the study drug was given; and 90 min before surgery, when the study drug and diazepam were given. The preinduction BP and heart rate (HR) were taken in the OR before the patients received any medication. At the start of the injection of thiopental, BP and HR were recorded at 1-min intervals for 5 min. The smallest and largest values for each of these measurements (HR and systolic, diastolic, and mean BP) are reported.
The surgical time was defined as the time from the first injection of local anesthetic to the completion of mucosal closure. The hypotensive period commenced 10 min after the start of surgery and ended when the surgeons did not request hypotension any longer. After the intubation sequence, the noninvasive BP was recorded every 3 min. The target mean arterial BP (MAP) for the hypotensive period was 60 ± 4 mm Hg with a HR of 100 bpm. The vaporizer output for isoflurane was adjusted as follows: if MAP was more than 64 mm Hg but less than 70 mm Hg, the vaporizer setting was increased by at least 0.1% to a maximum of 0.25%. If MAP increased to 
70 mm Hg, the vaporizer output was increased by at least 0.25%, to a maximum of 0.5%. Similarly, if MAP was between 51 and 56 mm Hg, the isoflurane vaporizer setting was reduced by a minimum of 0.1%, to a maximum 0.25%, and if MAP was <51 mm Hg, the vaporizer setting was reduced by at least 0.25%, to a maximum of 0.5%. If HR was faster than 100 bpm, fentanyl 50 µg was given. This was repeated to a maximum dose of 7 µg/kg for the entire case. If HR remained increased, labetalol 5 mg was administered and repeated as necessary. To ensure amnesia, the isoflurane vaporizer was not reduced to less than 0.3% throughout the study. If hypotension persisted that did not correct by decreasing the isoflurane concentration to 0.3%, a fluid bolus of 250 mL was infused over 15 min. This was repeated if necessary. During the hypotensive period, the surgeons were asked every 30 min to rate the quality of the operative field on a five-point scale, the Surgeon’s Scale for Quality of Surgical Field, according to Fromme et al. (16): 5, massive uncontrollable bleeding; 4, bleeding, heavy but controllable, that significantly interfered with dissection; 3, moderate bleeding that moderately compromised surgical dissection; 2, moderate bleeding, a nuisance but without interference with accurate dissection; 1, bleeding, so mild it was not even a surgical nuisance; and 0, no bleeding, virtually bloodless field.
At the completion of surgery, nitrous oxide and isoflurane were discontinued, and the patients’ lungs were ventilated with 100% oxygen. This time marked the start of the recovery period, during which the following events were recorded: arrival in the postanesthetic care unit, spontaneous eye opening or body movement, patient response to verbal command, tracheal extubation, and the time for the patient to reach a recovery room score of 10. For postoperative pain control, the patients received IV morphine 0.05 mg/kg mg as needed in the recovery room and oral codeine 0.5 to 1.0 mg/kg on the surgical wards. In addition, naproxen 500 mg was given twice daily, starting on the morning of surgery.
On the basis of the data of Woodcock et al. (11), who reported a 40% reduction of isoflurane from a mean inspired concentration of 2.25% with a SD of 0.72, we calculated a study size of 40 patients with a of 0.05 and a ß of 0.1 for a two-tailed test. Data are expressed as mean ± SD unless otherwise stated. Parametric data were compared by using Student’s t-test, nonparametric data by using the Mann-Whitney ranked sum test, and nominal data by using the 
2 or Fisher’s exact test. Repeated-measures analysis of variance was used to compare preoperative BP measurements and BP and HR measurements during induction, followed by post hoc Student’s t-tests with the Bonferroni adjustment.
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Results |
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Of 46 consecutive eligible patients, 6 candidates were excluded because of patient refusal, language barrier, or weight heavier than 80 kg. One patient who had initially consented to participate refused to take the study drug, and his data were not included in the analysis. Thus, 19 patients were assigned to the clonidine group and 20 patients to the placebo group. Because of computer failure, the information on inspiratory and expiratory gases could not be collected for one patient in the clonidine group. In two patients, the induction sequence had to be modified because of nose bleeding. In these two patients, 1-min measurements of HR and BP were taken throughout the entire intubation period. Although placement of the nasogastric tube and endotracheal tube could not be achieved in one pass as planned, the smallest and largest recorded values for HR and BP were in the first 5-min observation period, and, therefore, these data are included in the analysis.
The two groups were comparable with regard to sex, age, and weight (Table 1). The children were almost equally divided among three surgeons; one surgeon had only one patient in each study arm (Table 1). Le Fort I osteotomy and bilateral sagittal split osteotomy, with or without a functional genioplasty, were performed in 34 patients; Le Fort osteotomy alone in 1 patient; bilateral sagittal split osteotomy in 4 patients; and a Le Fort osteotomy with an external mandibular osteotomy and temporomandibular joint arthroplasty in 1 patient.
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With respect to preoperative sedation, the children had similar ratings on the visual analog scales on the morning of surgery, on the ward, and before entering the operating rooms (ORs). However, the children in the clonidine group were rated markedly more sedated by both the anesthesiologist and the OR nurse (Table 2).
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The results of the BP measurements taken on the ward, on admission, at bedtime, and on the morning of surgery are shown in Figure 1. There were no differences between the groups with respect to systolic or diastolic BP, although on the morning of surgery systolic BP tended to be less in the clonidine patients than in the placebo ones (clonidine, 108 mm Hg versus placebo, 122 mm Hg; P = 0.054). Comparisons were made between the hemodynamic measurements taken in the OR before induction (Ind in Figure 1) and the lowest and highest recordings taken during the 5-min interval after the injection of thiopental. Typically, the smallest values occurred before the intubation (Min in Fig. 1) and the largest values after intubation (Max in Fig. 1). The HR was statistically significantly slower in treatment patients than in control patients at all of these points (P < 0.001). Within-group comparisons show that in the clonidine group, HR on induction was not significantly different from the smallest value (P = 0.3) or the largest (P = 0.4), whereas HR showed larger variability in the placebo group (Ind versus Min, P = 0.02; Ind versus Max, P = 0.07). Between-group comparisons for BP showed similar results. The systolic, mean, and diastolic BP of the clonidine group were significantly less than those of the placebo group before induction and at their peak (P < 0.001). At the nadir, however, no differences were observed between the two groups for systolic, mean, or diastolic BP (0.47 < P < 0.82). Thus, placebo patients experienced a larger decrease in BP than clonidine patients after induction, so the differences between the groups leveled out. Within the placebo group, comparisons showed highly significant differences for all BP measurements at all of the three intraoperative observation points (P < 0.001). This was similar for the clonidine group, except that the peak systolic BP after induction did not increase significantly (P = 0.6).
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; placebo group = 
.The durations of surgery and hypotension were similar in both groups (Table 1). During surgery, the two groups received similar volumes of IV fluid, and their estimated blood losses were of similar magnitude (Table 1). There was no difference in the amount of local anesthetic solution given (Table 1). Also, assessment of the surgical field by the surgeons showed no difference between the groups (score: clonidine 1.2 versus placebo 1.3; P = 0.629, Mann-Whitney U-test). Patients in the clonidine group received fewer anesthetics and less labetalol for control of BP (Table 1). The mean end-tidal isoflurane concentration was significantly less in clonidine patients than in the control group for the entire surgical time (P = 0.0003) and for the time of controlled hypotension (P = 0.0004). The amount of fentanyl given to control HR was significantly less in the clonidine group (86 versus 185 µg; P = 0.002), and clonidine patients received significantly less labetalol. Only three patients in the treatment group required labetalol, compared with 13 in the placebo group (P = 0.004). However, an equal number of adjustments were made in each group to maintain the BP and HR in the target range (Table 1). Four patients in the clonidine group and three in the control group required an extra fluid bolus when the BP remained less than the target range despite having reached the lowest vaporizer setting of 0.3% isoflurane.
On arrival in the recovery room, patients in the clonidine group were slightly colder than those in the placebo group (Table 3). Patients in both groups recovered at similar rates after the discontinuation of inhaled anesthetics (Table 3). However, the times to movement to command and tracheal extubation tended to be shorter in the treatment group, and the length of recovery room stay was significantly shorter in patients who had taken clonidine (P = 0.03). Patients in both groups received nearly the same amount of morphine in the recovery room, but patients in the clonidine group required larger amounts of codeine in the first 24 h after surgery for control of pain (P = 0.09).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Controlled hypotension effectively reduces surgical blood loss and improves surgical conditions in adolescents who undergo corrective orthognathic surgery (1). If inhaled anesthetics are used to decrease BP, larger inspired concentrations are used than are required to provide surgical anesthesia. In addition, ß blockade may be used to control unwanted tachycardia, regardless of whether nitroprusside or isoflurane forms the principal hypotensive drug. Although clonidine has been used successfully as an adjunct for hypotensive techniques in adults (11–14) , we are not aware of its application in the pediatric population. In this randomized, double-blinded study, we demonstrated that clonidine reduced the concentration of isoflurane required to produce a bloodless surgical field in a group of adolescents. The two groups of children in our study were well matched with regard to their demographic characteristics, surgeries, surgeons, and intraoperative conditions. The hemodynamic values for BP and HR were kept in a narrowly defined range, and, as a result, surgical blood loss and the surgeons’ assessment of the operative field were identical. Children who received clonidine required markedly less isoflurane, fentanyl, and labetalol to meet these conditions. Our findings are in agreement with the results of studies in adults that showed reduced requirements for isoflurane, narcotics, and other drugs, such as droperidol or labetalol. Most of these findings were reported in the elderly (9,15,17–19) . Earlier studies in adults implied greater hemodynamic stability when clonidine was used in conjunction with anesthesia. In both groups in our study, similar numbers of vaporizer adjustments or additional drug doses were necessary to maintain the BP and HR in the target range, probably because of the variability of surgical conditions encountered in this type of surgery.
We also observed a trend for a shortened recovery period in the children who were treated with clonidine, although not all of the comparisons in the recovery period achieved statistical significance, possibly because of the small sample size of the study. It appears that the narcotic-sparing effects of clonidine did not extend beyond the time of surgery, because children in both groups required similar amounts of morphine in the recovery room. Moreover, we observed a trend toward children in the clonidine group receiving larger amounts of codeine in the first 24 hours after surgery than their placebo counterparts. This differs from previous reports in adults and children (18,20) .
In younger children, 6–12 years of age, a dose of clonidine 4 µg/kg produced better sedation than diazepam 0.4 mg/kg and also facilitated separation from parents and acceptance of the face mask for anesthesia induction (6). In their teenage years, children develop greater self-awareness and often undergo periods of emotional instability, including anxiety (21). Adolescents especially have been noted to develop increased fear of dentistry compared with younger children or college students (22). This age group may particularly benefit from sedative premedication. In our study, the children who had received clonidine and diazepam clearly appeared more sedated to the observers than did the control group, who had taken diazepam only. However, in their self-assessment, children experienced similar degrees of anxiety regardless of their premedication. This may simply mean that an outwardly calm patient may not necessarily experience relief of anxiety and that our measurement tools, visual analog scale, and observer rating do not indicate the same thing. Interestingly, in a study of similar design of women undergoing breast surgery, the combination of clonidine and diazepam did not provide better sedation or anxiolysis than diazepam alone (19).
Placing an endotracheal tube during anesthesia may increase BP and HR. Numerous strategies, including pretreatment with clonidine, have been devised to minimize increases in HR and BP, which may be harmful to the elderly or to patients with limited cardiac reserve. Some have argued that such hemodynamic changes are of little consequence in otherwise healthy, young patients (23). Nasotracheal intubation takes longer to perform and is associated with increased hemodynamic changes and stress responses compared with orotracheal intubation (24). Our study indicates that hemodynamic changes after nasotracheal intubation show less fluctuation in the subjects who were treated with clonidine than in placebo-treated patients. This area may warrant further investigation in children who do not tolerate such changes, i.e., children with hypertension and renal disease.
In this study, we used a Bain circuit and high fresh gas flows to deliver anesthetic gases so that changes in vaporizer output would rapidly result in changes in inspired gas concentration, because we used isoflurane as the principal anesthetic for BP control. Although this study did not take into account the cost of drugs, it is conceivable that cost savings could be realized if less inhaled anesthetic, less narcotic, and less labetalol were used compared with the relatively small expense of clonidine (the hospital cost of one tablet of clonidine 100 µg is US$0.10 in this institution).
In summary, we have shown that adolescent children undergoing orthognathic surgery require considerably less isoflurane, fentanyl, and labetalol to achieve a moderate degree of controlled hypotension after pretreatment with clonidine. This may result in earlier extubation after anesthesia and lead to a shortened recovery period. Clonidine also minimizes HR and BP changes associated with nasotracheal intubation. The combination of clonidine with diazepam provides profound sedation in these children.
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Acknowledgments |
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Supported in part by a grant from the IWK Research Foundation.
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Footnotes |
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Presented in part at the International Anesthesia Research Society meeting, San Francisco, CA, March, 1997.
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References |
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