A general anesthetic must provide adequate hypnosis and analgesia as well as block motor and sympathetic responses at the level of the spinal cord or peripheral nerves. This can be achieved by volatile anesthetics, local anesthetics acting on peripheral nerves, or an opioid acting on the spinal cord, midbrain, thalamus, and higher centers (1). Moreover, the ideal anesthetic should suppress the hemodynamic responses to surgery without causing significant cardiovascular depression.
The concept of an inhalation bolus used in this study, both for the induction and maintenance of anesthesia, is an adaptation of the traditional concept of overpressure (2). Inhalation bolus may be defined as the dynamic use of the vaporizer and fresh gas flow to control the hemodynamic responses to stress caused during surgery. There is usually a delay between a change in the vaporizer setting and the onset/offset of the desired clinical effect (3). An inhalation bolus minimizes this hysteresis through optimal use of the anesthesia apparatus, vaporizer setting, and fresh gas flow. To reach a desired anesthetic concentration without affecting normocapnia, the anesthesiologist may increase the inspired drug concentration, and if working with a circular circuit, the fresh gas may also be increased. Low blood/gas solubility, absence of airway irritation, ease of titration, and cardiovascular stability make sevoflurane suitable for use when considering an inhalation bolus (4,5). In this study, sevoflurane was used for the induction as well as maintenance of anesthesia.
The unique pharmacokinetic properties of remifentanil (i.e., rapid onset of action and an effect site equilibration half life t1/2ke0 of 1.2 min, and lack of significant hemodynamic effects when administered at doses <2 μg · kg−1 · min−1) make it a very versatile drug for hemodynamic control during surgical stress (6,7).
The similar pharmacokinetic properties and beneficial pharmacodynamic features of sevoflurane and remifentanil make them dynamic anesthetics and have enabled us to design an anesthetic model to compare the efficacy of a bolus administration of these two drugs for control of hemodynamic responses during surgery.
Materials and Methods
After obtaining approval of the IRB of the Hospital La Princesa and informed consent from each patient, a study was commenced with 120 patients. The patients consisted of both men and women aged between 28 and 77 yr, ASA class I–III, scheduled for elective major thoracic or abdominal surgery. Patients with a history of esophageal reflux or hiatus hernia, alcohol or drug abuse, morbid obesity, regular use of vasoactive drugs, history of adverse reaction to any of the study drugs, or history of malignant hyperthermia were excluded.
The patients were randomized to 1 of 2 groups: a Sevoflurane group (n = 63) and a Remifentanil group (n = 57). All patients fasted for approximately 8 h before surgery and received premedication with midazolam 0.03 mg/kg IV. Patients in the Sevoflurane group received an inhaled induction with 8% sevoflurane, fresh gas flow 6 L/min, and Fio2 100%. At loss of eyelash reflex, a bolus dose of cisatracurium 0.1 mg/kg was administered. Manually assisted ventilation was maintained with 8% sevoflurane for 3 min and then the trachea was intubated. In the Remifentanil group, anesthesia was induced with 8% sevoflurane, fresh gas flow 6 L/min, and Fio2 100% until loss of eyelash reflex. Subsequently, the concentration of sevoflurane was reduced to 1% and a bolus dose of cisatracurium 0.1 mg/kg was administered. A bolus dose of remifentanil 2 μg/kg was administered over 2 min followed by intubation of the trachea. Maintenance of anesthesia in both groups was the same. The vaporizer was adjusted to maintain the sevoflurane end-tidal concentration at 1% (fresh gas flow 2 L/min, semi-closed circuit), and remifentanil and cisatracurium were infused at 0.1 μg · kg−1 · min−1 and 0.1 mg · kg−1 · h−1, respectively. The cisatracurium infusion was discontinued 30 min before the end of surgery. Sevoflurane 1% and remifentanil infusion were maintained until the first skin suture, after confirming reversal of neuromuscular relaxation (the train-of-four ratio approximately 0.9).
The lungs of the patients were mechanically ventilated with a Dräger Julian ventilator (Dräger, Lübeck, Germany), a Quick Fil™ Dräger Vapor® 19.n vaporizer was used (Dräger), and body temperature was maintained above 35.5°C. Fluid replacement was done according to the type of surgery: in major abdominal surgery, 15 mL · kg−1 · h−1 for the first hour and then 10 mL · kg−1 · h−1; in thoracic surgery, 6 mL · kg−1 · h−1. Heart rate (HR), pulse oxymetry, capnography, and mean arterial pressure (MAP) were monitored (Siemens Marquette Hellige Eagle 4000 patient monitor; Siemens AG, Munich, Germany) in both groups. HR and MAP are indicative of sympathetic response to surgical stress. Neuromuscular block was monitored by train-of-four stimulation of the ulnar nerve (TOF Guard INMT, Turnhout, Belgium), and sevoflurane end-tidal concentration was monitored by using an infrared gas anesthesia analyzer (Dräger Julian side stream).
Baseline HR and MAP were taken before the induction of anesthesia after midazolam administration. A positive sympathetic response to surgical stress was defined as a 15% increase in HR or MAP above the baseline measurements. When a positive sympathetic response occurred, patients in the Sevoflurane group were administered 8% sevoflurane as an inhalation bolus (fresh gas flow 6 L/min semi-closed circuit), until the MAP and HR returned to baseline measurements during 1 min. When a positive sympathetic response occurred in the Remifentanil group, the infusion rate was increased from 0.1 to 1 μg · kg−1 · min−1 and this was maintained until the MAP and HR returned to baseline measurements during 1 min. If the response was inadequate (MAP and/or HR did not return to baseline values), in the Sevoflurane group, after 5 min of continuous 8% sevoflurane, a rescue bolus dose of remifentanil 1 μg · kg− 1 · min−1 was administered. Also, if no clinical response was seen in the Remifentanil group or if the response was inadequate after 5 min of remifentanil 1 μg · kg−1 · min−1, 8% sevoflurane was administered until the MAP and HR returned to baseline measurements during 1 min. The end-tidal concentration of sevoflurane was monitored at the time the bolus became effective. If, after the administration of a bolus dose of sevoflurane or remifentanil, a decrease in MAP and/or HR of >15% occurred with respect to baseline values, the response to the drug was considered to be excessive. If MAP was <50 mm Hg, IV fluids and ephedrine were given. If HR was <40 bpm, atropine was given. In both cases, the patient was excluded from analysis.
The following data were collected from all patients: demographic characteristics, ASA, type and duration of surgery, associated disease, and usual medication. The hemodynamic response to tracheal intubation 1 min after the induction bolus was evaluated in both groups. In addition, the number of bolus doses required during surgery to control the hemodynamic response, the duration in minutes of each bolus administration, the MAP and HR before and at the end of the bolus doses, the sevoflurane end-tidal concentration at the end of each bolus dose, and the total dose of remifentanil in each bolus were recorded. The number of times a rescue bolus dose was required and the number of excessive responses were also recorded. The trachea was extubated when the spontaneous respiratory rate exceeded 12 breaths/min and end-tidal carbon dioxide was <45 mm Hg. The time interval between the last skin suture until extubation of the trachea was recorded. Recovery from anesthesia was evaluated by using a 4-point scale (patient agitated, conscious, not conscious only responds to verbal commands, or not conscious only responds to pain) 1 and 5 min after extubation. Postoperative pain was evaluated by a simple questionnaire in which the patient selected one of four items (no pain, slight pain, moderate pain, and severe pain). The analgesic requirements were analyzed during the first hour after surgery, although the Acute Pain Unit protocol for major thoracic and abdominal surgery was followed for all patients (8).
A thoracic epidural catheter (T4-8 for thoracic surgery and T6-10 for abdominal surgery) was inserted in the preoperative period. After a test dose of 2 mL of 0.25% bupivacaine with epinephrine 1:200000, standard analgesia was commenced from the first minute after extubation by using an 8-mL epidural bolus of 0.25% bupivacaine and a postoperative continuous infusion of 0.125% bupivacaine with 5 μg/mL fentanyl. Any postoperative complications during the first hour after surgery were recorded.
Our primary variable was the need of rescue (ineffective bolus) of both drugs, so to detect a 10%–15% difference between groups with 80% statistical power and a significance level (α) of 0.05 (two-tailed), we calculated a sample size of 60 patients by using the GraphPad StatMate program (GraphPad Software, Inc.). For the statistical analysis, the Mann-Whitney U-test, χ2 test, or Fisher’s exact test, and unpaired Student’s t-tests were used as appropriate. P values < 0.05 were considered statistically significant. The demographic data were expressed as mean ± sd and range, and categorical data as n and percentage (%). All statistical tests were performed by using the Systat 8.0 program (SPSS Inc, Chicago, IL).
Of the 63 patients in the Sevoflurane group, two were excluded because of hypotension that required ephedrine. A patient undergoing gastrectomy who sustained a splenic tear during surgery requiring splenectomy was also excluded. Sixty patients were analyzed. Of the 57 patients in the Remifentanil group, two were excluded because of hypotension. Two additional patients were excluded because of bradycardia (HR < 40 bpm) that occurred during the administration of remifentanil for induction; therefore, 53 patients were analyzed. There were no significant differences between the groups with respect to age, body weight, sex, ASA class, and type and duration of surgery (Table 1).
Anesthesia Induction Bolus
MAP before the induction bolus in the Sevoflurane group was 95 ± 12.1 (66–125) mm Hg, and 95.2 ± 12.3 (70–125) mm Hg in the Remifentanil group. HR before induction in the Sevoflurane group was 77 ± 14.8 (52–111) bpm, and 75.3 ± 12.6 (50–111) bpm in the Remifentanil group. The end-tidal sevoflurane concentration after the induction bolus in the Sevoflurane group was 4% ± 0.3% (3.2%–5%) and 2.2% ± 1.1% (1%–4.3%) in the Remifentanil group (see Fig. 1). The MAP and HR values after intubation were 93.4 ± 35.8 (50–165) mm Hg and 85 ± 19.8 (44 - 115) bpm, respectively, for the Sevoflurane group, and 73.7 ± 25.8 (50–132) mm Hg and 69.7 ± 22.2 (40–136) bpm, respectively, for the Remifentanil group (see Table 2).
We found statistically significant differences (P < 0.05) in the values of both MAP and HR recorded after intubation. We administered a rescue bolus of remifentanil (MAP and/or HR after intubation >15% of baseline values) to 26 patients (43.3%) in the Sevoflurane group, and a rescue bolus of sevoflurane to 8 patients (15%) in the Remifentanil group (P < 0.05). After the induction bolus, the MAP and/or HR values decreased with respect to baseline values by >15% (excessive effect) in 17 patients in the Sevoflurane group (28.3%), and in 29 patients in the Remifentanil group (54.7%) (P < 0.05, Table 2).
Intraoperative Maintenance Bolus
A bolus of sevoflurane was administered on 253 occasions to patients in the Sevoflurane group, i.e., 4 ± 2 (1–10) bolus doses/patient. In the Remifentanil group, 268 bolus doses of remifentanil were administered, i.e., 4.8 ± 2.9 (1–11) bolus doses/patient. The mean duration of the bolus doses in the Sevoflurane group was 2.8 ± 1 (1–5) min and 3 ± 1.3 (1–5) min in the Remifentanil group. There were no statistically significant differences between the two groups (Table 3).
MAP before the bolus maintenance dose in the Sevoflurane group was 116 ± 15 (87–165) mm Hg, and 115.5 ± 19.1 (85–175) mm Hg in the Remifentanil group. HR before the maintenance bolus was 84.2 ± 18.5 (73–120) bpm in the Sevoflurane group and 84.4 ± 19.2 (70–137) bpm in the Remifentanil group. There were no statistically significant differences between the two groups (Table 3).
The end-tidal sevoflurane concentration after the bolus doses in the Sevoflurane group was 4.6% ± 1% (2.2%–6%), and 1% ± 0.1% (0.9%–1.5%) after the remifentanil bolus doses in the Remifentanil group (Fig. 1). The MAP and HR values after the maintenance bolus were 90.8 ± 14 (54–130) mm Hg and 78.8 ± 16.9 (47–118) bpm for the Sevoflurane group. Similarly, the MAP and HR for the Remifentanil group were 88.5 ± 20 (51–155) mm Hg and 76.4 ± 18.5 (44–126) bpm. There were no statistically significant differences in these values either.
The bolus dose was considered ineffective when the MAP and/or HR were not restored to within 15% of the baseline values after 5 min of maintenance with the bolus. This occurred in 10 patients and on 12 occasions (4.8%) in the Sevoflurane group and in 18 patients on 48 occasions (17.8%) in the Remifentanil group, both number of patients and total number of ineffective boluses were statistically significant (P < 0.05). When a rescue bolus of sevoflurane was administered to patients in the Remifentanil group, the end-tidal sevoflurane concentration at the end of the rescue bolus was 2.9% ± 1.3% (1.4%–4.3%).
In the Sevoflurane group, an excessive hemodynamic effect occurred after the administration of a bolus dose of sevoflurane in 17 patients on 30 occasions (12%), and in 26 patients on 72 occasions (26.8%) in the Remifentanil group after the administration of a bolus dose of remifentanil. The differences between the two groups in number of patients that had excessive hemodynamic effect and number of excessive hemodynamic events were also statistically significant (P < 0.05) (Table 3).
Extubation Time and Recovery Profile
The time that elapsed from the beginning of skin suturing to tracheal extubation (TE) of the patients in the Sevoflurane and Remifentanil groups was 11.7 ± 6.6 (2–30) min and 10.7 ± 5.7 (3–25) min, respectively. There were no statistically significant differences between the two groups. No statistically significant differences were found in postoperative pain and sedation scores at 1 and 5 min after extubation (Table 4).
There were no relevant postoperative complications in either of the groups. In the Sevoflurane group, two patients had nausea and three had postoperative shivering. In the Remifentanil group, one patient had two episodes of vomiting, two patients had nausea, and two patients had postoperative shivering. None of the patients in either group had intraoperative awareness when questioned at 24 h after surgery.
The results suggest that the inhalation bolus technique with sevoflurane does not prevent the hemodynamic response to tracheal intubation despite the large end-tidal sevoflurane concentration (4%). Previous studies have shown that sevoflurane concentration requirements for lack of movement in 50% of patients during laryngoscopy and tracheal intubation ranged from an end-tidal concentration of 3.5%(9) to 4.5%(10). Muzi et al. (11) observed that up to 6.4 minutes of manual hyperventilation with an inspired concentration of 6%–7% sevoflurane and an end-tidal concentration of 4.5% sevoflurane were required to obtain acceptable conditions for tracheal intubation. In our study, in the Remifentanil group, remifentanil in combination with a mean sevoflurane end-tidal concentration of 2% prevented a hemodynamic response to tracheal intubation. These findings are similar to those reported by Cros et al. (12).
We defined an excessive hemodynamic response as a decrease in MAP or HR of ≥15% below baseline values in both groups. In >50% of the patients in the Remifentanil group, there was an excessive hemodynamic response. This excessive effect began to appear at doses of 0.5 μg · kg−1 · min−1(13). Based on previously reported “ideal” remifentanil dosing to prevent hemodynamic responses to tracheal intubation without subsequent excessive hemodynamic effect (14), we used a dose of 2 μg/kg over 2 minutes. Findings from another study suggest that not even doses of 3–5 μg · kg− 1 · min−1 do not completely block a hemodynamic response to intubation (15). However, in our study, the excessive hemodynamic effect was significantly less in the Sevoflurane group, and we did not observe the transient hyperdynamic response reported in other studies (16), possibly because of the different inhaled induction technique used, combined with the use of a continuous infusion of remifentanil 0.1 μg · kg−1 · min−1. Other authors have reported that a rapid modification of the sevoflurane alveolar concentration is not associated with stimulation of the airways or sympathetic nerve activity, and only causes mild tachycardia or hypertension (17). Our results (as well as those in the literature referenced) suggest that the induction technique that would best control the hemodynamic response to tracheal intubation (without the occurrence of an excessive hemodynamic effect) would include induction with sevoflurane to reach an end-tidal concentration of at least 4.5%, in combination with a bolus dose of remifentanil ranging from 0.5 to 1 μg · kg−1 · min−1(7).
Maintenance of hemodynamic variables during the intraoperative period show a significant advantage of the Sevoflurane group over the Remifentanil group. Although both the sevoflurane bolus and the remifentanil bolus seemed to be effective in preventing a hemodynamic response to a surgical stimulus (without producing a hemodynamic effect after discontinuation of the stimulus), sevoflurane was significantly more effective. Inhaled anesthetics, at a given minimum alveolar anesthetic concentration, block the adrenergic response to a surgical incision in 50% of patients (MACBAR). After surgical stimulus, a sevoflurane end-tidal concentration of 4.6% corrected the hemodynamic response in >95% of the occurrences and resulted in an excessive hemodynamic effect on discontinuation of the stimulus in only 12% of the cases. Our results are in disagreement with those of Ura et al. (18), who reported the MACBAR of sevoflurane as 8%. However, this may be explained by the different method used, because they took the MAP obtained 30 seconds before surgical incision as the baseline value. This value is approximately 36% less than the MAP obtained before induction, which is the one used in this study. Katoh et al. (19) determined the sevoflurane MACBAR at 4.1%, much more in accordance with our results. Glass et al. (7) recommended limiting the dose of remifentanil to <2 μg · kg−1 · min−1 to minimize the excessive hemodynamic effects of the drug. Our results, obtained after a bolus dose of remifentanil, are similar to those reported in other previous studies, that found an excessive hemodynamic effect at an infusion rate of 1 μg · kg−1 · min−1(20). However, Guignard et al. (21) found increased postoperative pain with a fast rate of intraoperative remifentanil infusion. However, a faster infusion rate in our study might have shown better results to control the surgical response. The duration of the effective bolus doses for the control of hemodynamic response to surgical stress was similar for both groups, which confirms the similar pharmacokinetic versatility of sevoflurane (5) and remifentanil (6) to rapidly reach the biophase. Control of the hemodynamic response to stress provided by sevoflurane may not only be attributed to a traditionally accepted depression of the cardiovascular system, but may also be a consequence of inhaled anesthetic effects within the spinal cord, on both immobility and blunting nociceptive transmission (22).
There were no statistically significant differences between the two groups with respect to extubation times. TE for the Remifentanil group was similar to results obtained in previous studies (23). The awakening sevoflurane MAC is 0.66%(19), therefore it is reasonable to expect that after two decrement times (as occurs with two context-sensitive half-times with remifentanil), patients will be able to breathe spontaneously, be awake, and can be extubated (24), as occurred in our study. Finally, the results obtained with respect to quality of recovery and postoperative pain are similar in both groups.
In conclusion, the inhalation bolus of sevoflurane is not sufficient for the induction of anesthesia, but seems more effective than a remifentanil bolus during maintenance. Sevoflurane was associated with superior control of hemodynamic responses to surgical stress and this was accomplished without appreciable delay in TE or effect in the quality of recovery.
1. Glass PS. Anesthetic drug interactions: an insight into general anesthesia—its mechanism and dosing strategies. Anesthesiology 1998; 88: 5–6.
2. Eger EI II. Uptake and distribution. In: Miller RD, ed. Anesthesia. Philadelphia: Churchill Livingstone, 2000: 74–95.
3. Carpenter RL, Eger EI II, Johnson BH, et al. Pharmacokinetics of inhaled anesthetics in humans: measurements during and after the simultaneous administration of enflurane, halothane, isoflurane, methoxyflurane, and nitrous oxide. Anesth Analg 1986; 65: 575–82.
4. Strum DP, Eger EI II. Partition coefficients for sevoflurane in human blood, saline, and olive oil. Anesth Analg 1987; 66: 654–6.
5. Smith I, Nathanson M, White PF. Sevoflurane: a long-awaited volatile anaesthetic. Br J Anaesth 1996; 76: 435–45.
6. Glass PS, Hardman D, Kamiyama Y, et al. Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (GI87084B). Anesth Analg 1993; 77: 1031–40.
7. Glass PS, Gan TJ, Howell S. A review of the pharmacokinetics and pharmacodynamics of remifentanil. Anesth Analg 1999; 89 (4 Suppl):S7–14.
8. Pérez-Hernández C, Matute E, González F, et al. Continuous postoperative epidural analgesia for major abdominal and thoracic surgery. Rev Soc Esp Dolor 1999; 6 (2 Suppl):31.
9. Katoh T, Nakajima Y, Moriwaki G, et al. Sevoflurane requirements for tracheal intubation with and without fentanyl. Br J Anaesth 1999; 82: 561–5.
10. Kimura T, Watanabe S, Asakura N, et al. Determination of end-tidal sevoflurane concentration for tracheal intubation and minimum alveolar anesthetic concentration in adults. Anesth Analg 1994; 79: 378–81.
11. Muzi M, Robinson BJ, Ebert TJ, et al. Induction of anesthesia and tracheal intubation with sevoflurane in adults. Anesthesiology 1996; 85: 536–43.
12. Cros AM, Lopez C, Kandel T, et al. Determination of sevoflurane alveolar concentration for tracheal intubation with remifentanil, and no muscle relaxant. Anaesthesia 2000; 55: 965–9.
13. Hall AP, Thompson JP, Leslie NA, et al. Comparison of different doses of remifentanil on the cardiovascular response to laryngoscopy and tracheal intubation. Br J Anaesth 2000; 84: 100–2.
14. Barclay K, Kluger MT. Effect of bolus dose of remifentanil on haemodynamic response to tracheal intubation. Anaesth Intensive Care 2000; 28: 403–7.
15. Stevens JB, Wheatley L. Tracheal intubation in ambulatory surgery patients: using remifentanil and propofol without muscle relaxants. Anesth Analg 1998; 86: 45–9.
16. Vakkuri AP, Lindgren L, Korttila KT, Yli-Hankala AM. Transient hyperdynamic response associated with controlled hypocapneic hyperventilation during sevoflurane-nitrous oxide mask induction in adults. Anesth Analg 1999; 88: 1384–8.
17. Ebert TJ, Muzi M, Lopatka CW. Neurocirculatory responses to sevoflurane in humans: a comparison to desflurane. Anesthesiology 1995; 83: 88–95.
18. Ura T, Higuchi H, Taoda M, Sato T. Minimum alveolar concentration of sevoflurane that blocks the adrenergic response to surgical incision in women: MACBAR. Eur J Anaesthesiol 1999; 16: 176–81.
19. Katoh T, Kobayashi S, Suzuki A, et al. The effect of fentanyl on sevoflurane requirements for somatic and sympathetic responses to surgical incision. Anesthesiology 1999; 90: 398–405.
20. Elliott P, O’Hare R, Bill KM, et al. Severe cardiovascular depression with remifentanil. Anesth Analg 2000; 91: 58–61.
21. Guignard B, Bossard AE, Coste C, et al. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000; 93: 409–17.
22. Antognini JF, Carstens E. Macroscopic sites of anesthesia action: brain versus spinal cord. Toxicol Lett 1998:100–101:51–8.
23. Camu F, Royston D. Inpatient experience with remifentanil. Anesth Analg 1999; 89 (4 Suppl):512–21.
24. Bailey JM. Context-sensitive half-times and other decrement times of inhaled anesthetics. Anesth Analg 1997; 85: 681–6.