EMLA^® Cream coated on endotracheal tube with or without epidural lidocaine reduces isoflurane requirement during general anesthesia

Abstract

This study was designed to evaluate the effect of tracheal topical anesthesia using EMLA^® Cream (EC) coated on the endotracheal tube (ETT) with or without epidural anesthesia (EA) on isoflurane requirement during general anesthesia (GA) and investigate whether EC coated on the ETT with EA was associated with the additive effect compared with the effect when each anesthetic was administered independently. The prospective randomized, double-blinded, and controlled study included 60 ASA I–II patients scheduled for upper abdominal surgery requiring GA. Patients were randomly assigned to one of the following groups: group 1 received GA, group 2 received EC+ GA, group 3 received GA+ EA, and group 4 received EC+ GA+ EA. Isoflurane was administered at the required concentrations to maintain the mean arterial pressure at a level not exceeding 20% of preoperative values. The percentage mean expired concentration (%MEC) was used in calculating the isoflurane requirement. Emergence agitation, postoperative sore throat, and hoarseness were recorded. Groups 2, 3, and 4 exhibited a significant reduction on isoflurane requirement compared with group 1 (P<0.05). The isoflurane requirement evaluated by %MEC decreased by 12%, 38%, and 50% in groups 2, 3, and 4, respectively. The incidence of emergence agitation was significantly lower in groups 2 and 4 than those in groups 1 and 3 (P<0.05). Tracheal topical anesthesia using EC coated on ETT with or without EA reduced the isoflurane requirement during GA, indicating that EC combined with EA exhibited an additive effect on the requirement of general anesthetic.

Keywords

EMLA^® Cream / epidural anesthesia / general anesthesia / isoflurane / lidocaine

Introduction

The combination of epidural anesthesia with general anesthesia is widely used in abdominal or thoracic surgery and can reduce intraoperative general anesthetic requirements. Epidural local anesthetic administrations have demonstrated a 30% to 50% reduction in the doses of intravenous and inhaled anesthetics [1-9].

EMLA^® Cream (EC; Astra, Westborough, MA), a eutectic mixture of local anesthetics containing 2.5% lidocaine and 2.5% prilocaine, has been used as a topical anesthetic. We recently reported that EC coated on a rigid bronchoscope reduced the dosage of intravenous anesthetic agents for tracheobronchial foreign body removal in children [10]. To our knowledge, the effects of tracheal topical anesthesia using EC coated on the endotracheal tube (ETT) on the inhaled anesthetic requirements have not been reported. We hypothesized that tracheal topical anesthesia using EC coated on the ETT with or without epidural anesthesia might reduce the inhaled anesthetic requirements during general anesthesia. Therefore, we designed this study to evaluate the effect of the tracheal topical anesthesia on the isoflurane requirements using EC coated on ETT with or without epidural lidocaine during general anesthesia and investigate whether EC with epidural anesthesia is associated with the additive effect compared with the effect when each anesthetic was administered independently.

Materials and methods

This prospective study was approved by our institutional ethics committee, and informed consent was obtained from every study patient. Sixty ASA physical status I-II patients, aged 18 years to 65 years, scheduled for upper abdominal operations requiring general anesthesia were enrolled. Exclusion criteria included the followings: body mass index less than 18 or more than 28; cardiovascular, neurologic, or metabolic disease; known allergy to amide local anesthetics; history of substance abuse; and current prescription opioid or benzodiazepine use. Patients were randomly assigned to one of the following four treatment groups using a table of random numbers: group 1 received general anesthesia; group 2 received EC coated on the ETT and general anesthesia; group 3 received general anesthesia and 1.5% lidocaine epidural administration; and group 4 received EC coated on the ETT, general anesthesia and 1.5% lidocaine epidural administration. We did not establish the epidural saline control in groups 1 and 2 because several studies have shown a reduction in the isoflurane requirements in patients receiving epidural saline [5,11]. Thus, we may evaluate the pure effect of EC coated on the ETT or epidural lidocaine on isoflurane requirements during general anesthesia.

All patients received an intravenous premedication of 0.03 mg/kg midazolam approximately 30 min before the induction of general anesthesia. Non-invasive monitoring of blood pressure, electrocardiogram, pulse oximetry (SpO₂), temperature, and capnography (EtCO₂) were initiated upon arrival at the operating room. A large-bore intravenous line was established, and lactated Ringer’s solution (8 ml/kg) was administered. In groups 3 and 4, an epidural catheter was inserted through a 16-gauge Tuohy needle at T7 to T11 intervertebral spaces and advanced 3-4 cm. Then, a test dosage of 3 ml of 1.5% lidocaine was administered to exclude spinal anesthesia. A bolus of 5 ml of 1.5% lidocaine was administered to the patient in supine position. Motor and sensory blocks were assessed after 15 min using a Bromage scale and pinprick. The anesthesiologists-in-charge did not participate in this study.

Before induction of the anesthesia, 0.5-1.0 g EC was precoated on the surface of the 10 cm distal segment of ETT in groups 2 and 4 or the same amount of lubricant ointment in groups 1 and 3 by a nurse who did not participate in the study. General anesthesia with 2 µg/kg fentanyl, 2 mg/kg propofol, and 0.1 mg/kg vecuronium was administered in all patients. ETT was inserted by a resident who did not participate in the study. After endotracheal intubation, the epidural catheter was connected to an infusion pump that delivered 8 ml/h of the same solution as the bolus. General anesthesia was maintained with isoflurane and vecuronium by the anesthesiologist according to clinical signs. Controlled ventilation was instituted at tidal volumes of 8-12 ml/kg at a rate necessary to maintain an EtCO₂ of 30-35 mmHg. Esophageal temperature was maintained near 36°C. Investigators who recorded the expired concentrations of isoflurane and hemodynamic variables were absent from the operating room before the intubation and were blinded as to group allocation. During the study, the investigators were blinded to the epidural treatment by means of a sheet placed over the epidural catheter and infusion pump.

All patients received 1.2% to 2% isoflurane (fresh gas flow of 5 L/min) for 15 min to guarantee an adequate depth of anesthesia at surgical incision. The isoflurane was turned off (fresh gas flow decreased to 2 L/min) immediately after incision and administered at the required concentrations to maintain the mean arterial pressure (MAP) at a level not exceeding 20% of preoperative values. The end-point was achieved by increasing or decreasing the end-tidal isoflurane by 0.2%/min. Supplement of fentanyl (50 µg) was given in all groups by a sequential 0.2% increase in isoflurane concentration if hemodynamic control was not achieved within 5 min. The total dosage of fentanyl for induction and maintenance of anesthesia was noted. The end-tidal concentration of isoflurane was maintained above 0.6 minimum alveolar concentration (MAC) at least for all patients to decrease the likelihood of anesthesia awareness [12,13]. A fluid challenge of 250 ml of lactated Ringer’s solution followed by boluses of ephedrine (5 mg) was administered if hypotension persisted. Urapidil was used to treat hypertension. Tachycardia was defined as heart rate (HR)>100 bpm and was treated with esmolol. Atropine was given if the HR was lower than 50 bpm. At peritoneal closure, the epidural lidocaine was stopped and replaced with an infusion of 0.125% bupivacaine plus 2 µg/ml of fentanyl (5 ml/h), which was administered to provide postoperative analgesia in groups 3 and 4. By contrast, intravenous infusion of 10 µg/ml of fentanyl (2 ml/h) was given in groups 1 and 2. All anesthetics were discontinued at the end of surgery, and a fresh oxygen flow of 6 L/min was administered until extubation.

The expired concentrations of isoflurane were continuously measured by a gas analyzer (Spacelabs, Ultra View 1700, Miami, FL, USA), and values were recorded every 5 min. Individual values were used in calculating the isoflurane requirements. Results were expressed as percentage mean expired concentration (%MEC) of isoflurane. %MEC was calculated as %MEC= MAC-hours/the duration of anesthesia (isoflurane used), where MAC-hours is the expired concentrations (recorded every 2 min) of isoflurane as a fraction of MAC times the duration of anesthesia. MAC values of 1.15% were used for isoflurane. HR and SpO₂ were continuously monitored, whereas MAP was also recorded at 5 min intervals. We evaluated hemodynamic stability during the maintenance period using the average error and average absolute error of hemodynamic parameters, as described by Liu et al. [14]. Emergence agitation, postoperative sore throat, and hoarseness were assessed. All patients were interviewed regarding any intraoperative recall before and 48 h after discharge from the postanesthesia care unit.

Sample size was estimated using power analysis based on the variability observed in a preliminary study (SD= 0.2%). A minimal sample of 13 patients in each group would provide a power of 80% and α-level of 0.05 to detect a 30% decrease in the anesthetic requirement [7]. This study enrolled 15 patients in each group. All data are presented as means±SD or number (n). Patients’ characteristics were compared using one-way ANOVA. Comparisons between the groups were performed for the isoflurane requirements, fentanyl consumption, MAP, and HR by one-way ANOVA followed by a post hoc Newman-Keuls test. Categorical variables were analyzed using χ²-test. P<0.05 was considered statistically significant.

Results

The four groups exhibited comparable demographics and surgical characteristics (Table 1). No motor block in the lower extremities could be established 10 min after the epidural test dose bolus and the upper level of sensory block was observed in T4 to T7 in the groups that received 1.5% epidural lidocaine (groups 3 and 4).

Isoflurane requirements were evaluated in MAC-hours and %MEC in all groups (Table 2). The EC coated on the ETT (group 2) and/or epidural lidocaine (groups 3 and 4) induced a significant reduction in the isoflurane requirements compared with general anesthesia alone (group 1, P<0.05). The isoflurane requirements evaluated by %MEC decreased by 12%, 38%, and 50% in groups 2, 3, and 4, respectively. The average amounts of fentanyl consumption were not statistically different among the four groups (Table 2).

Intraoperative hemodynamic stability and vascular active drugs requirements are shown in Table 3. The average errors and absolute average errors in the MAP and HR values in groups 3 and 4 were significantly lower than those of the MAP and HR values in groups 1 and 2 (P<0.05). No significant differences in the average errors and absolute average errors of MAP and HR values between groups 1 and 2 were observed. The intraoperative hemodynamic variability in groups 3 and 4 was equal.

No patient reported intraoperative recall during the follow-up period. Postoperative complications are shown in Table 4. The incidence of emergence agitation in groups 1 and 3 was higher than that in groups 2 and 4 (P<0.05). No significant differences were found among the four groups with respect to the incidence obtained from the sore throat and hoarseness after surgery.

Discussion

We evaluated the effects of tracheal topical anesthesia using EC coated on ETT with or without the epidural anesthesia on the general anesthetic (isoflurane) requirements in patients under general anesthesia. This study revealed that tracheal topical anesthesia using EC coated on the ETT with or without epidural lidocaine decreased the isoflurane requirements during general anesthesia. Significant reduction in the isoflurane requirements for maintenance of anesthesia was observed in group 3 compared with that in group 1. Epidural lidocaine reduced the isoflurane requirements up to 38%MEC, in accordance with results described in three previous studies, that showed epidural anesthesia reduced 34%, 35%, and 42% requirements of volatile anesthetics, respectively [4-6]. However, the %MEC of isoflurane in our study was higher than that of the result observed in a study by Casati et al. [5] The main differences of the two studies include the type and dosage of the administration of the local anesthetic, in addition to the use of 2 µg/ml of fentanyl. Lidocaine is less potent than bupivacaine (approximately 10∶1) and has a shorter duration of action. Casati et al. [5] used a bolus of 5 mg followed by an infusion of 5 mg/h (0.0625% bupivacaine) or twice as much when they tested the effects of 0.125% bupivacaine. Thus, we used the dosage of local anesthetic between 0.0625% and 0.125% bupivacaine as described previously [5] to consider the potency ratio of the two drugs. Moreover, we did not administer epidural fentanyl in our study. Epidural fentanyl combined with local anesthetic induces synergistic interaction and a more significant isoflurane-sparing effect [5,15]. Epidural saline exhibits an analgesic effect and reduces the isoflurane requirement to some extent [5,11]. Thus, our study excluded the effect of epidural saline on the isoflurane requirement, resulting in higher %MEC (1.01%±0.11%) in patients who received general anesthesia alone (group 1).

Epidural blockade decreases general anesthetic requirements at the surgical site. However, a considerable depth of anesthesia is still needed to allow the patients to tolerate ETT and ventilation. The mechanical airway irritation elicited by intubation and ETT in place causes a very intensive stress during general anesthesia. Many drugs and techniques have been used to reduce irritation [16]. However, these studies have demonstrated several limitations, including short duration, less effect, or insecurity. In our study, the effect of tracheal topical anesthesia was obtained by precoating EC on the ETT to reduce irritation. The topical anesthesia applied by coating EC on the surface of the ETT exhibits several advantages, including simplified technique, no additional suffering, and prolonged duration (3-4 h). In our study, we found that tracheal topical anesthesia with EC reduced the isoflurane requirements by 12%MEC. We speculated that the possible mechanisms involve the paralysis of the airway along the ETT coated with EC that reduced the irritation and the elicited systemic effect from absorbed local anesthetics. In addition, lower incidence of emergence agitation is associated with the combination with EC topical anesthesia, suggesting excellent tolerance of the tracheal tube as opposed to inhalation-based anesthesia.

Moreover, the effects of the combined EC and epidural lidocaine on the isoflurane requirements were equal to the algebraic sum of their individual effect in %MEC, suggesting that tracheal topical anesthesia and epidural anesthesia exhibit an additive effect in reducing the isoflurane requirements. The exact mechanism of the phenomenon remains unclear. However, the nociceptive input blocked by local anesthetics originating from the local areas and the systemic effect from the absorbed local anesthetics may play major roles in this phenomenon.

Hypertensive and tachycardia episodes were the most common among the undesirable hemodynamic events observed in groups 1 and 2, whereas hypotensive and bradycardia episodes were mostly observed in groups 3 and 4. However, no significant differences among the four groups were observed, with respect to episodes of these disorders during the operation. Similarly, ephedrine and atropine were more commonly administered in groups 3 and 4, whereas esmolol and urapidil were more frequently administered in groups 1 and 2. However, the requirements for pharmacologic intervention did not differ significantly among the four groups. The average error and absolute average error of MAP and HR in the groups with epidural anesthesia (groups 3 and 4) were lower, indicating that the hemodynamic status is more stable.

We did not monitor the depth of anesthesia using an electroencephalographic monitor, such as bispectral index (BIS) or A-line ARX index (AAI) as described in previous studies [4-8], which sets a limitation to the present study. However, Casati et al. [5] suggested that isoflurane requirements evaluated by MAP or BIS exhibit similar results. In addition, some studies have also suggested that no reduction in anesthesia awareness associated with BIS monitoring was observed [17,18]. Thus, we were unable to evaluate anti-nociception directly. We used the isoflurane requirements evaluated by MAP as an indirect measurement of the depth of anesthesia. We maintained MAP within 20% from the baseline values that were routinely used in clinical practice although they were not very precise. We did not assume an intraoperative recall to occur in this study population because the end-tidal isoflurane concentration (above 0.6 MAC) that prevents learning and recall is similar to the average concentration of isoflurane (group 4) in our study. Thus, the absence of recall for all patients among the four groups without BIS monitoring was not a surprising result.

In summary, tracheal topical anesthesia using EC coated on the ETT with or without epidural lidocaine reduced the isoflurane requirements during general anesthesia, indicating that the combination manifested an additive effect on the general anesthetic requirements.

References

[1] Tverskoy M, Shifrin V, Finger J, Fleyshman G, Kissin I. Effect of epidural bupivacaine block on midazolam hypnotic requirements. Reg Anesth1996; 21(3): 209-213

[2] Hossain M, Hoq MF, Rahman MS, Yeasmeen S, Ahmed A, Huda MR, Rahman MM. Vecuronium and fentanyl requirement in abdominal surgery under combined epidural-general anaesthesia and general anaesthesia alone. Mymensingh Med J2012; 21(1): 55-59

[3] Li Y, Zhu S, Yan M. Combined general/epidural anesthesia (ropivacaine 0.375%) versus general anesthesia for upper abdominal surgery. Anesth Analg2008; 106(5): 1562-1565

[4] Hodgson PS, Liu SS. Epidural lidocaine decreases sevoflurane requirement for adequate depth of anesthesia as measured by the Bispectral Index monitor. Anesthesiology2001; 94(5): 799-803

[5] Casati L, Fernández-Galinski S, Barrera E, Pol O, Puig MM. Isoflurane requirements during combined general/epidural anesthesia for major abdominal surgery. Anesth Analg2002; 94(5): 1331-1337

[6] Lu CH, Borel CO, Wu CT, Yeh CC, Jao SW, Chao PC, Wong CS. Combined general-epidural anesthesia decreases the desflurane requirement for equivalent A-line ARX index in colorectal surgery. Acta Anaesthesiol Scand2005; 49(8): 1063-1067

[7] Reinoso-Barbero F, Martínez-García E, Hernández-Gancedo MC, Simon AM. The effect of epidural bupivacaine on maintenance requirements of sevoflurane evaluated by bispectral index in children. Eur J Anaesthesiol2006; 23(6): 460-464

[8] Zhang J, Zhang W, Li B. The effect of epidural anesthesia with different concentrations of ropivacaine on sevoflurane requirements. Anesth Analg2007; 104(4): 984-986

[9] Kim SH, Chun DH, Chang CH, Kim TW, Kim YM, Shin YS. Effect of caudal block on sevoflurane requirement for lower limb surgery in children with cerebral palsy. Paediatr Anaesth2011; 21(4): 394-398

[10] Yu H, Yang XY, Liu B. EMLA Cream coated on the rigid bronchoscope for tracheobronchial foreign body removal in children. Laryngoscope2009; 119(1): 158-161

[11] Samsó E, Vallés J, Pol O, Gallart L, Puig MM. Comparative assessment of the anaesthetic and analgesic effects of intramuscular and epidural clonidine in humans. Can J Anaesth1996; 43(12): 1195-1202

[12] Dwyer R, Bennett HL, Eger EI 2nd, Peterson N. Isoflurane anesthesia prevents unconscious learning. Anesth Analg1992; 75(1): 107-112

[13] Gonsowski CT, Chortkoff BS, Eger EI 2nd, Bennett HL, Weiskopf RB. Subanesthetic concentrations of desflurane and isoflurane suppress explicit and implicit learning. Anesth Analg1995; 80(3): 568-572

[14] Liu J, Klein KW, Griffin JD, White PF. Does monitoring end-tidal isoflurane concentration improve titration during general anesthesia? J Clin Anesth1995; 7(3): 186-191

[15] Maves TJ, Gebhart GF. Analgesic synergy between intrathecal opioids and local anesthetics. Anesth Analg1991; 73(3): 365-366

[16] Soltani HA, Aghadavoudi O. The effect of different lidocaine application methods on postoperative cough and sore throat. J Clin Anesth2002; 14(1): 15-18

[17] Sebel PS, Bowdle TA, Ghoneim MM, Rampil IJ, Padilla RE, Gan TJ, Domino KB. The incidence of awareness during anesthesia: a multicenter United States study. Anesth Analg2004; 99(3): 833-839

[18] Avidan MS, Zhang L, Burnside BA, Finkel KJ, Searleman AC, Selvidge JA, Saager L, Turner MS, Rao S, Bottros M, Hantler C, Jacobsohn E, Evers AS. Anesthesia awareness and the bispectral index. N Engl J Med2008; 358(11): 1097-1108

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