Korean J Anesthesiol 2009 Jul; 57(1): 13-9 □ Clinical Research Article □ DOI: 10.4097/kjae.2009.57.1.13

Comparison of intubating conditions and hemodynamic responses to with different effect-site concentrations of remifentanil without muscle relaxants during target-controlled infusion of propofol

Department of and Pain Medicine, Chonnam National University Medical School, Gwangju, Korea

Seok Jai Kim, Kyung Yeon Yoo, Byoung Yun Park, Woong Mo Kim, and Cheol Won Jeong

Background: We compared the effects of different remifentanil effect-site concentrations on intubating conditions, and cardiovascular and bispectral index score (BIS) responses to intubation at a fixed effect-site concentration of propofol without muscle relaxants. Methods: Sixty-four patients were randomly assigned to one of three groups: remifentanil 2 (group R2, n = 22), 4 (group R4, n = 21), or 6 ng/ml (group R6, n = 21). was induced using target-controlled infusion of propofol 5 μg/ml and each concentration of remifentanil. Laryngoscopy and intubation was attempted at 2.5 min following induction. Intubating conditions were assessed as excellent, good or poor using a standard scoring system. Mean arterial pressure (MAP), heart rate (HR), and BIS values were assessed. Results: Excellent or good intubating conditions were obtained in 91% of group R4 and 95% of R6, both of which are higher compared with 32% of R2 (P ＜ 0.01). MAP and HR decreased significantly after induction in all groups. After intubation, they recovered to baseline value in group R2 and R4 but were significantly less than baseline values in R6. BIS response to intubation was attenuated in group R4 and R6 but not R2. Hypotension was more frequent in group R6 than R2. Conclusions: Remifentanil target concentrations of 4 or 6 ng/ml combined with 5 μg/ml propofol provided good or excellent conditions for tracheal intubation and prevented cardiovascular and BIS response during induction without muscle relaxants. However, the use of 6 ng/ml dose was associated with frequent occurrence of hypotension and bradycardia requiring treatment. (Korean J Anesthesiol 2009; 57 13∼9)

Key Words: Intubating conditions, Propofol, Remifentanil, Target controlled infusion.

ade and anaphylactic shock [1]. Several studies have suggested INTRODUCTION that the use of propofol and adjuvants such as short-acting opioids, sympatholytics, , and agents Muscle relaxants are generally used to facilitate laryngoscopy may provide adequate conditions for laryngoscopy and tracheal and endotracheal intubation during induction of general ane- intubation without the need for neuromuscular blocking agents sthesia. In some situations, the use of muscle relaxants is un- [2,3]. desirable or contraindicated because they may have adverse ef- Remifentanil is a selective μ-opioid receptor agonist with a fects such as delayed paralysis, residual neuromuscular block- rapid onset, short duration, and a short blood/effect-site equili- bration half-time [4]. Stevens et al [5] have shown that propo- Received: March 24, 2009. fol 2 mg/kg and remifentanil 3 μg/kg co-administration pro- Accepted: May 14, 2009. vided adequate intubation conditions in healthy patients without Corresponding author: Kyung Yeon Yoo, M.D., Ph.D., Department of Anesthesiology and Pain Medicine, Chonnam National University Medical neuromuscular relaxants. Laryngoscopy and tracheal intubation School, 8, Hak-1dong, Dong-gu, Gwangju 501-757, Korea. Tel: 82-62- may cause cardiovascular changes, which can have adverse ef- 220-6893, Fax: 82-62-232-6294, E-mail: [email protected] fects [6,7], and arousal responses on the electroencephalogram Copyright ⓒ Korean Society of Anesthesiologists, 2009 during induction of anaesthesia [8]. Remifentanil has been re- ｃｃ This is an open-access article distributed under the terms of the Creative ported to attenuate these responses when combined with Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. propofol. The use of a target-controlled infusion (TCI) using a

13 Vol. 57, No. 1, July 2009 Korean J Anesthesiol computer-driven infusion device has been demonstrated to be After preoxygenation for 3 min, anesthesia was induced with Ⓡ more effective in controlling concentrations and in main- propofol (Fresofol 2%, Fresenius Kabi, Austria) of 5 μg/ml Ⓡ taining cardiovascular stability as compared with traditional using a TCI system (Orchestra Base Primea , Fresenius Vial, weight-adjusted infusions [9]. Because of its unique pharmaco- France). At the same time, remifentanil was started using the kinetic and pharmacodynamic profile, remifentanil is ideally same TCI system as in propofol. Propofol was administered 5 suited for continuous IV infusion [4]. However, the optimal ef- μg/ml at the effect site concentration in Marsh model [10] fect-site concentration of remifentanil required for intubation and remifentanil 2, 4, or 6 ng/ml in Minto model [11]. The without muscle relaxants while maintaining stable hemodynamic target and effect-site concentrations in each group had reached stability has not been determined using a steady effect-site within 90 s after start of TCI system, and then these concen- concentration of propofol. We therefore conducted this pro- trations were maintained for 60 s before intubation. spective, randomized, double-blind study to compare the differ- When the patients became unconscious, patients’ lungs were ent effect site concentrations of remifentanil on intubating con- ventilated manually with 100% oxygen through an anesthesia ditions, and hemodynamic and bispectral index (BIS) responses face mask connected to a semiclosed anesthesia circuit. Two to induction and endotracheal intubation without muscle relax- and half min following induction of anesthesia, laryngoscopy ants in patients receiving a propofol anesthesia. and endotracheal intubation was performed by an experienced anesthesiologist using a Macintosh 3 laryngoscope blade and a MATERIALS AND METHODS 7.0 or 8.0 mm endotracheal tube followed by slow inflation of the tracheal cuff between 25−30 mmHg with cuff pressure Ⓡ After approval from the Institutional Review Board of the gauge (VBM Cuff Pressure Gauge , VBM Medizintechnik University Hospital, informed written consent was obtained GmbH, Germany). After intubation, anesthesia was maintained from 69 American Society of Anesthesiologist physical status I with propofol 2−3 ug/ml, remifentanil 2−3 ng/ml. Intubating or II patients, aged 25−60 yrs. Patients with known car- conditions were evaluated by using a scoring system. Ease of diovascular, pulmonary, or renal disease, drug or alcohol abus- ventilation, jaw relaxation, ease of laryngoscopy, opening of ers, obesity greater than body mass index 30 kg/m2, and pa- vocal cords, degree of coughing and patient movement were tients with predicted difficult intubation (Mallampati classi- used to score overall intubating conditions as excellent (all cri- fication of airway anatomy higher than II) were excluded. teria scored as 1), good (mask ventilation scored as 1 and the All patients were premedicated with midazolam 0.1 mg/kg other criteria as 1 or 2) or poor (one of the criteria scored as orally 60 min before the induction of anesthesia. Before arrival 3) (Table 1) [12]. Patients who developed muscle rigidity and in the operating room, an IV catheter was placed to allow the thus could not be ventilated with face mask were given ro- administration of fluids and medications. Additionally, a 20- curonium 0.6 mg/kg IV to facilitate endotracheal intubation. gauge catheter was inserted into a radial artery connected to a These cases were excluded from data analysis. pressure transducer to measure blood pressure and to collect Mean arterial blood pressure (MAP), heart rate (HR), and blood samples. consisted of invasive arterial blood BIS values were recorded by an independent investigator be- pressure, electrocardiogram, pulse oximetry, capnometry and fore induction of anesthesia (baseline), just before laryngoscopy BIS. A standard BIS electrode montage (BIS Sensor-Aspect and intubation, and at 1 min intervals up to 5 min thereafter. Medical Systems, Inc., Natick, MA, USA) was applied to the BIS values were recorded as the maximum value displayed forehead before induction of anesthesia, and BIS was measured within each minute. These values were confirmed by down- Ⓡ continuously throughout the study using an Aspect A-2000 BIS loading data from the electronic memory of the monitor at the Ⓡ monitor (BIS XP, software version 3.31; Aspect Medical end of surgery. Arousal response (defined by an increase in Systems, Natick, MA, USA). HR was determined from electro- BIS to intubation) was determined by calculating the difference cardiogram traces. Patients were randomized to one of three of highest BIS value observed after intubation (for 5 min after groups, each to receive one of the following effect site con- intubation) and BIS value measured just before starting laryn- centrations of remifentanil in a double-blind manner; 2 ng/ml goscopy. Hypotension was defined as MAP ＜ 55 mm Hg, (R2 group, n = 22), 4 ng/ml (R4 group, n = 21), and 6 ng/ml and intravenous ephedrine 8 mg was administered for hypo- (R6 group, n = 21). tension of more than 60 s. Bradycardia was defined as HR ＜

14 Kim et al：Intubating conditions and remifentanil

Table 1. Scoring Criteria at Tracheal Intubation Table 2. Demographic Data

R2 (n = 22) R4 (n = 21) R6 (n = 21) R2 (n = 22) R4 (n = 21) R6 (n = 21)

Mask ventilation Sex (M/F) 12 / 10 8 / 13 12 / 9 1. Easy 19 (86.4%) 19 (90.6%) 20 (95.3%) Age (yr) 44 ± 13 47 ± 9 41 ± 13 2. Difficult 3 (13.6%) 2 (9.4%) 1 (4.7%) BMI (kg/m2) 23.6 ± 2.8 22.9 ± 2.4 22.9 ± 3.0 3. Impossible 0 (0%) 0 (0%) 0 (0%) Height (cm) 162 ± 9 163 ± 6164 ± 6 Jaw relaxation Values are means ± SD or number of patients. BMI: body mass 1. Complete 19 (86.4%) 19 (90.6%) 21 (100%) index, R2: remifentanil 2 ng/ml, R4: remifentanil 4 ng/ml, R6: re- 2. Slight tone 2 (9.0%) 2 (9.4%) 0 (0%) mifentanil 6 ng/ml. There were no statistically significant differ- 3. Stiff 1 (4.6%) 0 (0%) 0 (0%) ences among the groups. 4. Rigid 0 (0%) 0 (0%) 0 (0%) Laryngoscopy 1. Easy 19 (86.4%) 19 (90.6%) 20 (95.3%) variance. A P value ＜ 0.05 was considered statistically signi- 2. Fair 2 (9.0%) 2 (9.4%) 1 (4.7%) 3. Difficult 1 (4.6%) 0 (0%) 0 (0%) ficant. 4. Impossible 0 (0%) 0 (0%) 0 (0%) Vocal cords RESULTS 1. Open 11 (50%) 18 (85.9%)a) 19 (90.6%)a) 2. Moving 5 (22.7%) 1 (4.7%) 0 (0%) 3. Closing 1 (4.6%) 0 (0%) 1 (4.7%) There were no significant differences among groups with re- 4. Closed 5 (22.7%) 2 (9.4%) 1 (4.7%) spect to sex ratio, age, body mass index, or height (Table 2). Coughing Excellent conditions for intubation were observed in 3 (13.6%), 1. None 4 (18.0%) 16 (76.5%)a) 18 (85.9%)a) 2. Slight 5 (22.1%) 4 (18.8%) 2 (9.4%) 18 (85.7%), and 19 (90.5%) patients whereas good conditions 3. Moderate 7 (32.5%) 1 (4.7%) 1 (4.7%) 4 (18.2%), 1 (4.8%), and 1 (4.8%) patients in groups R2, R4 4. Severe 6 (27.4%) 0 (0%) 0 (0%) and R6, respectively. Thus overall intubating conditions ach- Limb movement ieved in groups R4 and R6 were better than those in group 1. None 14 (64.0%) 17 (80.5%)a) 20 (95.3%)a) 2. Slight 2 (9.0%) 3 (14.8%) 0 (0%) R2 (P ＜ 0.05) (Fig. 1). Muscle rigidity occurred in 2 each in 3. Moderate 4 (18.0%) 0 (0%) 1 (4.7%) groups R2 (8.3%) and R4 (8.7%), and 1 (4.5%) of the group 4. Severe 2 (9.0%) 1 (4.7%) 0 (0%) R6 during induction of anesthesia. These 5 patients were ex- Values are number of patients (%). R2: remifentanil 2 ng/ml, R4: cluded from data analysis. Remaining patients were all success- remifentanil 4 ng/ml, R6: remifentanil 6 ng/ml. These criteria were fully intubated and thus data from 64 patients were analyzed. used to score overall intubating conditions as excellent (all criteria MAP and HR before and after induction and endotracheal scored as 1), good (mask ventilation scored as 1 and the other criteria as 1 or 2) or poor (one of the criteria scored as 3). intubation are shown in Figs. 2 and 3. Baseline MAP and HR a)P ＜ 0.05 versus R2 group. were not significantly different among the three groups. After induction of anesthesia, there were significant decreases in 50 bpm and intravenous atropine 0.02 mg/kg was administered MAP (30, 35, and 39% in groups R2, R4 and R6, re- for bradycardia of more than 60 s. A dysrhythmia was defined spectively, P ＜ 0.05) and HR (12, 21 and 19%, P ＜ 0.05) as any ventricular or supraventricular premature beat or any compared to baseline values but these changes were not stat- sustained rhythm other than sinus. istically different between the groups. After intubation, MAP Statistical analysis was performed by using program SPSS and HR recovered to baseline values in the groups R2 and R4 15.0 (LEAD Technologies, Chicago, USA). All results are ex- but remained below baseline values in the R6 group, and thus pressed as means ± SD or number of patients. The differences they were significantly lower in the group R6 than in the R2 in hemodynamic varibles and BIS score were performed by group (P ＜ 0.05). Hypotension was more frequent in the R6 two-way repeated measures analysis of variance. The differ- group than in the R2 group (28.5% vs. 4.6%, P ＜ 0.05). The ences in complication rates among the group and nonparametric incidence of bradycardia increased as the effect site concen- data were performed by one-way analysis of variance. The trations of remifentanil increased but there was no difference Scheffe's test was used for multiple pairwise comparisons among the groups (9.2, 14.1, and 33.3% in R2, R4 and R6 when a significant difference was indicated with analysis of groups, respectively). In the R6 group, 3 patients required

15 Vol. 57, No. 1, July 2009 Korean J Anesthesiol

Fig. 3. Heart rate (HR) before and after laryngoscopy and endo- tracheal intubation. Values are expressed as means ± SD or num- Fig. 1. Overall intubating conditions. R2: remifentanil 2 ng/ml, R4: a) ber of patients. Baseline: before induction of anesthesia, Pre-int: remifentanil 4 ng/ml, R6: remifentanil 6 ng/ml. P ＜ 0.05 versus b) immediately before intubation, Post-int: immediately after in- baseline value, P ＜ 0.05 versus group R2. tubation, 3 and 5 min: 3 and 5 min after intubation. a)P ＜ 0.05 versus baseline value, b)P ＜ 0.05 versus group R2.

Table 3. Incidence of Adverse Effects

R2 (n = 22) R4 (n = 21) R6 (n = 21)

Hypotension 1 (4.6%) 2 (9.4%) 6 (28.5%)a) Bradycardia 2 (9.2%) 3 (14.1%) 7 (33.3%) Dysrhythmia 0 0 0

Values are number of patients (%). R2: remifentanil 2 ng/ml, R4: remifentanil 4 ng/ml, R6: remifentanil 6 ng/ml. a)P ＜ 0.05 versus R2 group.

mained unchanged in groups R4 and R6. However, peak BIS Fig. 2. Mean arterial pressure (MAP) before and after laryngo- scopy and endotracheal intubation. Values are expressed as means values after intubation did not differ among the groups. The ± SD or number of patients. Baseline: before induction of anes- maximal increase in BIS was noted within the first 2 min in thesia, Pre-int: immediately before intubation, Post-int: immediately all cases. after intubation, 3 and 5 min: 3 and 5 min after intubation. a)P ＜ 0.05 versus baseline value, b)P ＜ 0.05 versus group R2. DISCUSSION ephedrine for hypotension and 2 patients did atropine for bra- Our results demonstrated that remifentanil 4 or 6 ng/ml at dycardia, whereas no one required ephedrine or atropine in R2 the effect site concentration, administered with a TCI of 5 μg/ml and R4 group. Dysrhythmia did not appear in either group propofol reliably provides good or excellent conditions for tra- throughout the experiment (Table 3). cheal intubation in most healthy, premedicated patients with fa- BIS values before and after induction and endotracheal in- vorable airway anatomy. In addition, the combination of two tubation are shown in Fig. 4. Baseline BIS values did not dif- prevented pressure and tachycardiac responses to laryngo- fer among the groups. There was a significant decrease in BIS scopy and tracheal intubation, and remifentanil 4 and 6 ng/ml values after the induction of anesthesia with propofol and re- prevented intubation BIS response. However, the highest dose mifentanil in all groups, the degree of which was comparable of 6 ng/ml was associated with serious cardiovascular depres- among the groups. In response to tracheal intubation, BIS val- sion such as severe hypotension and bradycardia. ues increased significantly in group R2 (P ＜ 0.05) but re- Using TCI techniques, a few studies have demonstrated an

16 Kim et al：Intubating conditions and remifentanil

fect-site concentration of propofol in order to speed up the procedure and to reduce intraoperative recall. Troy et al [13] performed intubation 12 min and Leone et al [14] 4 min after the induction of anesthesia, whereas we performed intubation 1 min after reaching the effect site concentrations of both drugs. In a busy clinical setting, this rapid technique may have prac- tical advantages. The beneficial effect of remifentanil in attenuating the pres- sure response to intubation has been studied. O’Hare et al [18] studied the effect of single bolus dose of remifentanil with thi- opental and concluded that 1 μg/kg effectively attenuated car- Fig. 4. Bispectral index score (BIS) before and after laryngoscopy diovascular responses after endotracheal intubation. In our and endotracheal intubation. Values are expressed as means ± SD study, the lowest concentration of remifentanil 2 ng/ml did not or number of patients. Baseline: before induction of anesthesia, achieve satisfactory conditions for intubation but did attenuate Pre-int: immediately before intubation, Post-int: maximum value within 2 min after intubation, 3 and 5 min: 3 and 5 min after the pressor response to intubation, suggesting that smaller dose intubation. a)P ＜ 0.05 versus baseline value, b)P ＜ 0.05 versus of remifentanil is required to attenuate hemodynamic intubation group R2. response than to provide satisfactory condition for intubation. The most frequent drug-related adverse events in the present effect-site concentration of remifentanil along with propofol for study were transient hypotension and bradycardia. Decreases in use in induction and intubation without the use of muscle re- arterial blood pressure and bradycardia have also been ob- laxants [13,14]. Troy et al [13] found that an effect-site con- served with opioids in previous studies [19-21]. Remifentanil centration of remifentanil 8 ng/ml when administered with an has no effects on myocardial contractility and does not cause effect-site concentration of propofol 3 μg/ml provided sat- histamine release [22]. Propofol has many cardiovascular ef- isfactory conditions for intubation. Similarly, required target ef- fects including hypotension [23,24]. The degree of the decrease fect-site concentration of remifentanil to provide acceptable in- in systolic blood pressure in group R2 or R4 in the present tubating conditions without muscle relaxants was 10 ng/ml study after anesthesia induction (30−35% decrease from base- with a TCI of propofol 3.5 μg/ml in a previous study [14]. line) was similar to that reported three minutes after the ad- In the present study, a target concentration of 4 or 6 ng/ml ministration of 2 mg/kg of propofol (28%) [22]. In group R6, provided satisfactory intubating conditions in more than 90% however, the magnitude of hemodynamic depression after anes- of the patients. The discrepancy in dose of remifentanil neces- thesia induction was so severe that 5 patients (23.7%) required sary to provide satisfactory intubating conditions between the ephedrine or atropine. Sebel et al [25] observed that decreases previous two studies [13-15] and ours may not be readily in arterial pressure and heart rate after remifentanil, on average explained. Propofol has been shown to reduce remifentanil re- 20%, were independent of the given dose escalating from 2 to quirements to suppress responses to laryngoscopy, intubation 30 μg/kg in patients pretreated with glycopyrrolate. Without a and intra-abdominal surgical stimulation in a synergistic manner concurrent anticholinergic agent, instead, remifentanil was asso- [16]. They used target of propofol 3 or 3.5 μg/ml which is ciated with bradycardia or hypotension, or both, in 50% of in agreement with the reported propofol concentration at which healthy, ASA I-II patients during anesthetic induction and in- 50% of the patients lost , 3.4 μg/ml [17], tubation [26]. Thus, our results show that stable hemodynamics whereas we used a target of 5 μg/ml. Therefore, the differ- during induction of anesthesia are achieved with remifentanil 2 ence in the dose of remifentanil to provide satisfactory con- or 4 ng/ml in relatively healthy patients, and that the highest ditions for intubation may be due to differences in study de- dose is associated with severe cardiovascular depression, sug- sign, such as using the effect-site concentration of propofol, gesting that this dose is not clinically acceptable without anti- using premedication, or different definitions for opti- cholinergic drugs. Nevertheless, the actual response might be mal intubation condition. As compared with the previous stud- quite different in another patient population. Therefore, this ies [13,14], we tried to maintain a relatively higher target ef- technique should not be applied for elderly, compromised pa-

17 Vol. 57, No. 1, July 2009 Korean J Anesthesiol tients or those with clinically significant cardiovascular or cere- airway anatomy can be reliably intubated with good or ex- brovascular diseases, who may not tolerate decrease in MAP. cellent conditions without hyperdynamic cardiovascular and BIS Other intraoperative adverse events, such as muscle rigidity, intubation response 2.5 min after the administration of re- were observed in 5 (7.2%) of all patients involved in the pres- mifentanil 4 or 6 ng/ml with 5 μg/ml propofol using a TCI ent study. After remifentanil, such muscle rigidity was demon- without muscle relaxants. However, the use of the 6 ng/ml strated in 11−32% of patients with target concentrations esca- dose was associated with frequent occurrence of hypotension lating from 2.0 to 16.0 ng/ml [27]. 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Tracheal in- In conclusion, healthy, premedicated patients with favorable tubating conditions using propofol and remifentanil target con-

18 Kim et al：Intubating conditions and remifentanil

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