There are at least two components to the anesthetic state. First is the loss of consciousness and recall, which implies the inability to respond to or recall a non-noxious stimulus and has been found to correlate well with the bispectral index (BIS). The second component is obtundation of reflex responses (somatic or motor, hemodynamic, and endocrine) to a noxious stimulus, which occurs below the level of cortex and thus may be unrelated to the state of consciousness. During unconsciousness, a noxious stimulus may cause arousal/awakening depending on the intensity of the stimulus. To prevent arousal, the noxious stimulus needs to be kept from reaching higher centers which could be achieved by opiates, local anesthetics, and hypnotics. Varying degrees of synergistic interactions have been reported among the drugs used to achieve the anesthetic state. The relationship between the hypnotic component of anesthesia and BIS is independent of the presence of an opioid, but the level of consciousness, and therefore the BIS, is affected by a painful stimulus and this response is ablated by an opioid or an increasing concentration of propofol (1).
Local anesthetics used through different routes, i.e., IM, IV, and for neuraxial blockade have been found to reduce the induction and maintenance dosage of propofol and inhaled anesthetics (2–8). All of these studies were primarily aimed at establishing the interaction between these drugs evaluated either by a non-noxious or noxious stimulus. Clinical practice of anesthesia is a polypharmacy, wherein the anesthetic state is the net result of the action of different drugs and their interaction in the presence of a surgical stimulus.
It is common to combine epidural analgesia with general anesthesia, wherein epidural blockade will decrease the requirement for general anesthetic. However, a considerable depth of anesthesia is still needed so as to allow patients to tolerate an endotracheal tube and ventilation. Therefore, it is important to establish the effect of epidural analgesia on the drug requirement needed to produce the anesthetic state. In view of the synergistic interaction observed among hypnotics, opioids, muscle relaxants, and local anesthetics, this study was planned to determine the effect of epidural bupivacaine on the requirement of propofol, fentanyl, and vecuronium.
The institutional ethical committee approved this prospective, randomized, double-blind, placebo-controlled trial. Informed written consent was obtained from all patients who were randomized into 2 groups of 15 each with the help of a computer-generated table of random numbers. This study consisted of 30 consecutive patients, ASA physical status I and II, aged 18–50 yr, undergoing Whipple’s pancreaticoduodenectomy for periampullary carcinoma surgery, lasting >4 h.
Exclusion criteria were patients with cardiovascular or neurological disease, hypersensitivity reaction to local anesthetic (amide group), bleeding or coagulation disorders, and drug or alcohol abuse.
Patients were premedicated with tablet ranitidine 150 mg and lorazepam 2 mg at night and 2 h before surgery with sips of water. Patients were preloaded with 10 mL/kg normal saline (NS). An epidural catheter (Portex) was placed between T9-10. The control group received 0.9% NS and the bupivacaine group received 0.1% bupivacaine via the epidural route. Depending on the group allocation, 10 mL of drug was administered as a bolus via the epidural route 20 min before induction of anesthesia and then infusion was maintained at 6 mL/h. The anesthesiologist performing the epidural block and setting the epidural infusion was not aware of the group allocation. Another independent anesthesiologist prepared all epidural injections.
Intraoperative monitoring consisted of 5 lead electrocardiography, heart rate (HR), invasive arterial blood pressure, central venous pressure, end-tidal carbon dioxide, pulse oximetry, temperature, BIS (model A-2000, 3.1 software version; Aspect Medical Systems, Natick, MA), urine output, and neuromuscular junction monitoring. Neuromuscular transmission was monitored on the right arm by the electromyographic response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve (Myotest; Biometer International, Odense, Denmark). The right arm was wrapped in a protective towel. The train-of-four response to a supramaximal stimulus was obtained before the initial bolus dose of vecuronium. After recovery of T1/T0 to 10%, patients were administered one-fifth of the initial dose of vecuronium as top-up doses.
Induction of anesthesia was done with IV fentanyl 2 μg/kg and propofol. Propofol was administered via IV infusion at 4 mg/s (15–20 s). Once the BIS value reached 40–50, endotracheal intubation was facilitated by vecuronium 0.1 mg/kg. Ventilation was controlled (Siemens 900) with a tidal volume of 10 mL/kg and respiratory rate adjusted to maintain end-tidal carbon dioxide between 30–35 mm Hg. Lungs were ventilated with 66% nitrous oxide in oxygen. After endotracheal intubation, propofol 1% infusion was titrated to maintain BIS between 40–50. The doses of propofol required for induction were noted.
The mean of 3 consecutive systolic blood pressure (SBP) and HR taken 5 min after the arrival of the patient in the operating room was taken as the baseline reading. Inadequate analgesia was defined as an increase in SBP and/or HR by >20% of baseline value for >5 min in response to a surgical stimulus. In cases of inadequate analgesia, patients were given bolus doses of fentanyl 0.5 μg/kg. At the end of the study period (i.e., 4 h), maintenance dose requirements of propofol, fentanyl, and vecuronium were calculated by dividing the total amount of the individual drug used for maintenance by duration of the study period (4 h) and patient’s weight in kilograms, thus giving the individual drug consumption in mg · kg−1 · h−1. This did not consider the doses of these drugs, which were administered at the time of induction. Fentanyl and vecuronium were administered at induction in the standard prescribed doses.
IV colloids were administered at 10 mL · kg−1 · h−1 and packed red blood cells were administered only when hematocrit became <24 as per our departmental protocol. Bradycardia was defined as HR <40 bpm and hypotension as a decrease in SBP <20% of baseline. Hypotension was treated by infusion of NS and, if necessary, with ephedrine 5 mg IV. Intraoperative awareness was assessed by reciting a number to each patient four times at hourly intervals during anesthesia and the patients were questioned for the recall of this number in the postoperative period.
Assuming that epidural administration of bupivacaine will reduce the requirement of anesthetics by 30%, power analysis with α = 0.05, β = 0.8, showed that we would need to study 13 patients in each group. To exclude any dropouts, we included 15 patients in each group. The frequency of hypotension or bradycardia was recorded. Data were analyzed by using the Student’s t-test for equality of means between the two groups. P ≤ 0.05 was considered significant.
There was no difference in the demographic variables of all the patients (Table 1). Requirement of propofol for induction in the bupivacaine group was 1.3 ± 0.3 mg/kg compared with 2.4 ± 0.6 mg/kg in the control group (P < 0.05) (Table 2). However, propofol requirement for maintenance of anesthesia to achieve BIS between 40–50 in the bupivacaine group was 2.4 ± 0.9 compared with 4.4 ± 1.6 mg · kg−1 · h−1 observed in the control group (P < 0.05) (Table 2). The requirement of vecuronium for maintenance of muscle relaxation in the bupivacaine group was 0.023 ± 0.014 compared with 0.042 ± 0.021 mg · kg−1 · h−1 in the control group (P < 0.05). A significant reduction in the fentanyl requirement was observed in the bupivacaine group compared with the control group (0.1 ± 0.2 versus 0.9 ± 0.3 μg · kg−1 · h−1). Two patients in the bupivacaine group had hypotension, which was treated by additional NS infusion and IV ephedrine. However, no significant difference was observed in the requirement of colloids and blood in both groups. None of our patients had awareness, bradycardia, hypersensitivity reaction to bupivacaine, backache, or dural tap.
In the present study, significant reduction in the dose requirement of propofol for induction and maintenance of anesthesia was observed along with a reduction in maintenance doses of fentanyl and vecuronium in the patients who received epidural bupivacaine before the start of anesthesia.
The recommended doses of propofol for induction and maintenance of anesthesia are 1–2.5 mg/kg and 50–150 μg · kg−1 · min−1, respectively. This was similar to the dosage of propofol used for induction and maintenance of anesthesia in the control group (9). However, a significant reduction in the requirement of propofol for induction and maintenance of anesthesia was observed in the bupivacaine group. The requirement of fentanyl during maintenance of anesthesia in the control group was 0.9 ± 0.3 μg · kg−1 · h−1 which is within the recommended range of fentanyl infusion, i.e., 0.5–5.0 μg · kg−1 · h−1 (10). In the bupivacaine group, fentanyl requirement for maintenance of anesthesia was reduced to 0.01 + 0.2 μg · kg−1 · h−1 (P < 0.05). We administered vecuronium top ups (one-fifth) of the initial doses as guided by neuromuscular junction monitoring.
BIS directly correlates with the level of hypnosis and was kept between 40–50 to avoid any recall. In the present study, any increase in the BIS level during anesthesia and surgery could either be because of a reduction in the plasma concentration of propofol or because of inadequate suppression of the noxious stimulus. However, the latter also results in an increase in HR and SBP through autonomic reflexes. We administered fentanyl to suppress these reflexes and, at the same time, propofol infusion was adjusted to maintain BIS in the range of 40–50. In such a scenario, when blood concentration of these drugs is not available, it is possible that we might have used more propofol instead of fentanyl or vice versa. Therefore, the study data do not reflect the extent of reduction in the propofol and fentanyl consumption by epidural bupivacaine. Instead, they only show that epidural bupivacaine substantially reduces the requirement of these drugs used to achieve a predictable depth of anesthesia.
The interaction between propofol and fentanyl is well known and is more pronounced for suppression of reflexes for skin incision than for loss of consciousness (11). Furthermore, the concentration response of the interaction between opiates and volatile anesthetics or propofol observed for the prevention of purposeful movement on skin incision is remarkably similar (11–14). Epidural bupivacaine not only provides excellent analgesia at the surgical site but also adds to muscle relaxation which, in turn, depends on the level of neuraxial blockade and the concentration and type of drug used. Nevertheless, the presence of an endotracheal tube and positive pressure ventilation will certainly create a considerable need for propofol, fentanyl, and vecuronium. Therefore, any reduction in the requirements of these drugs is perhaps the result of interaction between these drugs and epidural bupivacaine.
Neuraxial anesthesia markedly potentiates the sedative effects of midazolam in humans, which suggests that neural blockade may itself have sedative properties (15,16). Several mechanisms may help to explain the interaction of local and general anesthetics. First, there might be inhibition of tonic afferent spinal nerve signaling to the brain and to the spinal cord above the level of neural blockade (5). Afferentation theory proposes that tonic sensory and muscles-spindle activity maintains a state of wakefulness (17). Eappen and Kissin (7) proposed that decreased afferent input to the brain could lessen excitatory descending modulation of spinal cord motor neurons and suppress motor function. Thus, the combination of decreased inputs from sensory and motor afferents seen with epidural anesthesia would be a reasonable mechanism for general anesthetic effects and for decreased requirements of anesthetics. Second, local anesthetics bind to the sodium channel in the inactivated state and prevent subsequent channel activation and large transient sodium influx associated with membrane depolarization (18). Third, it has been observed that propofol, as well as local anesthetics, enhance γ-aminobutyric acid-mediated chloride currents, which facilitate inhibitory neurotransmission in neurons (19). In addition, reduction in the requirement of fentanyl could result from the direct epidural sensory block of the noxious stimulus.
Local anesthetics in small doses depress posttetanic potentiation (20). They have a direct effect on presynaptic, postsynaptic, and muscle membrane, which may result in enhancement of neuromuscular block of both depolarizing and nondepolarizing muscle relaxants (21–23), the mechanism that perhaps is responsible for the reduction in requirement of vecuronium observed in our study. Telivuo and Katz (23) found an additional decrease in the twitch height and tidal volume with lidocaine, mepivacaine, prilocaine, and bupivacaine in patients partially paralyzed with alcuronium.
Although there are synergistic interactions between hypnotics, opioids, and muscle relaxants, the results of the present study confirm that requirements for these drugs are reduced by epidural bupivacaine during general anesthesia. These findings may have clinical implications for the practice of anesthesia, where it is common to combine epidural with general anesthesia. Perhaps the findings will prompt us to plan the optimal dosing guidelines so as to avoid overdosing, and thus delayed recovery.
1. Iselin-chaves IA, Flaishon R, Sebel PS, et al. The effect of the interaction of propofol and alfentanil on recall, loss of consciousness, and the bispectral index. Anesth Analg 1998;87:949–55.
2. Ben Shlomo I, Tverskoy M, Fleyshman G, Cherniavsky G. Hypnotic effect of i.v. propofol is enhanced by i.m. administration of either lignocaine or bupivacaine. Br J Anaesth 1997;78:375–7.
3. Tverskoy M, Ben Shlomo I, Vainshtein M, et al. Hypnotic effect of i.v. thiopentone is enhanced by i.m. administration of either lignocaine or bupivacaine. Br J Anaesth 1997;79:798–800.
4. Senturk M, Pembeci K, Menda F, et al. Effects of intramuscular administration of lidocaine or bupivacaine on induction and maintenance doses of propofol evaluated by bispectral index. Br J Anaesth 2002;89:849–52.
5. Hodgson P, Liu S, Gras T. Does epidural anesthesia have general anesthetic effects? A prospective, randomized, double blind, placebo-controlled trial. Anesthesiology 1999;91:1687–92.
6. Tverskoy M, Fleyshman G, Bachrak L, Ben Shlomo I. Effect of bupivacaine induced spinal block on the hypnotic requirement of propofol. Anaesthesia 1996;51:652–3.
7. Eappen S, Kissin I. Effect of subarachnoid bupivacaine block on anesthetic requirements for thiopental in rats. Anesthesiology 1998;88:1036–42.
8. Himes RS Jr, DiFazio CA, Burney RG. Effects of lidocaine on the anesthetic requirements for nitrous oxide and halothane. Anesthesiology 1977;47:437–40.
9. Reves JG, Glass PSA, Lubarsky DA. Nonbarbiturate intravenous anesthetics. In: Miller RD, ed. Anesthesia. Philadelphia: Churchill Livingstone, 2000:228–72.
10. Bailey PL, Egan TD, Stanley TH. Intravenous opioid anesthetics. In: Miller RD, ed. Anesthesia. Philadelphia: Churchill Livingstone, 2000:273–376.
11. Smith C, McEwan AI, Jhaveri R, et al. The interaction of fentanyl on the Cp 50 of propofol for loss of consciousness and skin incision. Anesthesiology 1994;81:820–8.
12. Glass PSA, Gan TJ, Howell S, Ginsberg B. Drug interactions: volatile anesthetics and opioids. J Clin Anesth 1997;9:185–225.
13. Vuyk J, Lim T, Englbers FH, et al. The pharmacodynamic interaction of propofol and alfentanil during lower abdominal surgery in women. Anesthesiology 1995;83:8–22.
14. Katoh T, Ikeda K. The effects of fentanyl on sevoflurane requirements for loss of consciousness and skin incision. Anesthesiology 1998;88:18–24.
15. Tverskoy M, Shifrin V, Finger J, et al. Effect of epidural bupivacaine block on midazolam requirements. Reg Anesth 1996;21:209–13.
16. Ben-David B, Vaida S, Gaitni L. The influence of high spinal anesthesia on sensitivity to midazolam sedation. Anesth Analg 1995;81:525–8.
17. Lanier WL, Iaizzo PA, Milde JH, Sharbrough FW. The cerebral and systemic effects of movement in response to noxious stimulus in lightly anesthetized dogs: possible modulation of cerebral function by muscle afferents. Anesthesiology 1994;80:392–401.
18. Morgan RGE Jr, Mikhail MS. Local anesthetics. In: Morgan GE, ed. Clinical Anesthesiology. 2nd ed. Stamford, CT: Appleton & Lange, 1996;193–200.
19. Nordmark J, Rydqvist B. Local anesthetics potentiate GABA mediated C2 currents by inhibiting GABA uptake. Neuroreport 1997;8:465–8.
20. Usubiaga JE, Standaert F. The effects of local anesthetics on motor nerve terminals. J Pharmacol Exp Ther 1968;159:353–61.
21. Kordas M. The effect of procaine on neuromuscular transmission. J Physiol (Lond) 1970;209:689–99.
22. Nonaka A, Sugawara T, Suzuki S, et al. Pretreatment with lidocaine accelerates onset of vecuronium-induced neuromuscular blockade. Masui 2002;51:880–3.
© 2004 International Anesthesia Research Society
23. Telivuo LL, Katz RL. The effects of modern intravenous local analgesics on respiration during partial neuromuscular block in man. Anaesthesia 1970;25:30–5.