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Anesth Analg 2005;101:371-376 © 2005 International Anesthesia Research Society doi: 10.1213/01.ANE.0000156950.21292.1A
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Abstract |
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We evaluated the effect of different combinations of fentanyl-isoflurane on early recovery from anesthesia in 80 adult patients undergoing laparoscopic cholecystectomy. Anesthesia was induced with fentanyl 2 µg/kg and thiopental 5 mg/kg. Nitrous oxide was not used and patients were randomly assigned to one of four groups: Group 1 (n = 20) received 0.6% end-tidal isoflurane plus fentanyl, Group 2 (n = 20) received 1.2% end-tidal isoflurane plus fentanyl, Group 3 (n = 20) received 1.8% end-tidal isoflurane plus fentanyl, and Group 4 (n = 20) received only isoflurane. In Groups 1, 2 and 3 isoflurane concentration was kept constant and fentanyl was given as necessary to maintain the mean arterial blood pressure within ± 10% of the minimum mean arterial blood pressure measured in the ward. In Group 4, isoflurane concentration was adjusted to maintain mean arterial blood pressure as above. At the end of skin closure isoflurane was discontinued and the time to spontaneous breathing (TSB), time to extubation (TE) and time to eye opening (TEO) were recorded. In the postanesthesia care unit, the degree of sedation, respiratory rate, Spo2, emesis, pain, and morphine consumption were evaluated every 15 min for 1 h, and thereafter every 30 min until discharge. Fentanyl requirements were 8.3 ± 4.5 µg/kg (mean ± sd) in Group 1, 3.8 ± 1.3 µg/kg in Group 2, and 3.0 ± 0.7 µg/kg in Group 3 (P < 0.001), whereas in Group 4 the mean end-tidal concentration of isoflurane was 2.0% ± 0.4%. Although the mean TSB was <5.5 min in all groups, TE increased from 7.3 ± 5.1 min in Group 1 to 20.6 ± 10.7 min in Group 4 (P < 0.001), and TEO increased from 7.4 ± 5.1 min in Group 1 to 25.8 ± 9.4 min in Group 4 (P < 0.001). There were no differences among the groups in any of the variables measured in the postanesthesia care unit. This study shows that the combination of a small concentration of isoflurane and a relatively larger dose of fentanyl results in a faster recovery from anesthesia than the inverse combination of doses.
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Introduction |
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Several studies have sought to define the interaction between propofol and opioids in terms of their optimal concentrations or the infusion rates necessary to obtain adequate anesthesia and fast recovery (1–3). Although a number of studies show a dose-related reduction of minimum alveolar concentration (MAC) by opioids, (4–7) there are few studies concerning the effect that different dose combinations of inhaled anesthetics and opioids might have on clinical end-points, such as early recovery from anesthesia and adverse effects. Two studies with sevoflurane and remifentanil found that the combination of a small concentration of sevoflurane and rapid infusion rates of remifentanil resulted in faster recovery compared with the use of larger concentrations of sevoflurane and smaller doses of the opioid (8,9). In the case of propofol, however, its optimal concentration for faster recovery varies depending on the opioid that is being coadministered. Thus with remifentanil the recommended plasma levels of propofol are 40% to 50% less than when it is administered along with fentanyl (1). As remifentanil and sevoflurane have a more rapid context-sensitive decrement time than any other opioid or volatile anesthetic (10), it is likely that the ideal combination of a longer lasting opiate (e.g., fentanyl) with a slower volatile anesthetic (e.g., isoflurane) is different than that demonstrated with remifentanil and sevoflurane. However, this possibility has not been studied. In addition, although a given combination of an opioid and a volatile anesthetic can be optimal for early recovery and awakening from anesthesia, different combinations of doses can be associated with different incidences of adverse effects (11). Thus, the aim of this study was to determine a dose combination of isoflurane and fentanyl that produces adequate anesthesia and results in faster recovery and less incidence of early adverse effects.
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Methods |
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After obtaining institutional ethics committee approval and informed consent, 80 unpremedicated ASA physical status I–II patients, aged 20–60 yr, scheduled for elective laparoscopic cholecystectomy under general anesthesia were studied. Exclusion criteria included chronic or acute intake of any sedative and analgesic drug (within the previous 48 h) and any known adverse effect to the study drugs. In the operating room, noninvasive arterial blood pressure measurements every 2.5 min, electrocardiogram, and pulse oximetry were initiated. Induction of anesthesia was with fentanyl 2 µg/kg and thiopental 5 mg/kg. Tracheal intubation was facilitated with rocuronium 0.4–0.6 mg/kg. For maintenance, nitrous oxide was not used and patients were randomly assigned by means of a table of random numbers generated by a computer to 1 of 4 groups of 20 patients each: Group 1 received 0.6% end-tidal (ET) isoflurane plus fentanyl, Group 2 received 1.2% ET isoflurane plus fentanyl, Group 3 received 1.8% ET isoflurane plus fentanyl, and Group 4 received only isoflurane. In Groups 1, 2, and 3 the predetermined isoflurane concentration was kept unchanged during surgery and 25–50 µg bolus doses of fentanyl were given as necessary to maintain the mean arterial blood pressure (MAP) within 10% of the minimum MAP measured in the ward. In Group 4, only isoflurane (i.e., no additional fentanyl) was given to maintain intraoperative MAP within the same range as the other groups. Although MAP was the main and the only objective end-point to administer fentanyl (or isoflurane in Group 4), the anesthesiologist was allowed to give more fentanyl (Groups 1 to 3) or more isoflurane (Group 4) if the patient presented signs of inadequate anesthesia, such as tachycardia, sweating, lacrimation, or movements.
All patients received ketorolac 60 mg IV after induction of anesthesia. Mechanical ventilation was adjusted to an ETco2 of 33–35 mm Hg during surgery and increased to 40 mm Hg at skin closure. By the end of surgery, patients having an asymmetrical response to double burst stimulation were given neostigmine and atropine. At the end of skin closure, isoflurane was discontinued (T0) and after a further 2 min under mechanical ventilation with the same ventilatory variables and 100% oxygen (>5 L/min), patients were left in apnea until spontaneous breathing. Tracheal extubation was accomplished when patients no longer tolerated the endotracheal tube. No stimulation was applied to patients during the first 10 min after T0, from the 11th minute to the 20th minute patients were called by their name every minute, and from the 21st minute the name and a tactile stimulation were applied every minute if the patient was not awake. Intraoperatively, ET isoflurane concentration was recorded every 5 min and the mean value of these recordings was obtained for each patient. The mean isoflurane concentration from all patients in a group was used to calculate the mean concentration for the entire group. All patients were classified according to a risk score for postoperative nausea and vomiting (12), and no prophylactic antiemetic drugs were given.
Starting at T0, evaluation of early recovery from anesthesia was by the time to spontaneous breathing (TSB), time to tracheal extubation (TE), and time to eye opening (TEO). In the postanesthesia care unit (PACU) patients breathed room air and evaluations included respiratory rate, continuous Spo2, degree of sedation (0 = awake, 1 = drowsy, 2 = asleep, but could be wakened, 3 = deep sleep, difficult to wake up), pain scores both at rest and on coughing using a visual analog scale (0 mm = no pain to 100 mm = unbearable pain), and emetic episodes. All measurements were recorded on arrival and every 15 min for 60 min and thereafter every 30 min until discharge to the ward. Morphine 2–3 mg IV was given if the pain score at rest was 
50 mm. Hypoxemia (Spo2 
90%) was treated with 40% oxygen by mask. Discharge of patients from PACU was left to the discretion of the anesthesiologist, and no attempt was made to speed this process. All measurements in the operating room and PACU were made by investigators blinded as to the study drugs.
Sample size calculated to find as statistically significant a difference of 10 min in the time to tracheal extubation between any 2 groups, with ß = 0.20 and 
= 0.05, resulted in a sample size of 18 patients per group. Statistical analysis was with Kolmogorov-Smirnov's as a test of normality. This was followed by one-way and two-way analysis of variance and Friedman's test for data with and without normal distribution, respectively. Proportions were analyzed with 
2 testing and Bonferroni's correction was used for multiple comparisons. A value of P < 0.05 was considered significant. Values are reported as mean ± sd unless otherwise stated.
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Results |
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There were no significant differences in patient characteristics, duration of surgery, or anesthesia among the groups (Table 1). Fentanyl requirements and isoflurane concentration are shown in Table 1.
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Indices of early recovery from anesthesia are shown in Figure 1. Whereas mean TSB was <5.5 min in all groups (not significant), TE increased linearly from 7.3 ± 5.1 min in Group 1 to 20.6 ± 10.7 min in Group 4 (P < 0.001), and TEO increased linearly from 7.4 ± 5.1 min in Group 1 to 25.8 ± 9.4 min in Group 4 (P < 0.001). TE and TEO were significantly faster in Group 1 compared with each of the other groups (P < 0.01). Group 2 had a faster TE than Group 3 (P < 0.05) and a faster TEO than Groups 3 and 4 (P < 0.01). No significant differences were found between Groups 3 and 4. No patient arrived at the PACU with sedation grade 3 and median time (range) to reach grade 0 was: 0 (0–60) min in Group 1, 30 (0–150) min in Group 2, 0 (0–120) min in Group 3, and 0 (0–120) in Group 4 (not significant).
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In the PACU, 1 patient in Groups 1 and 2, and 2 patients in Group 4 did not have a complete follow-up; these patients were excluded from this part of the analysis. No significant differences were found in pain scores either at rest (Fig. 2) or on coughing. Morphine was required in 42% of patients in Group 1, 53% of patients in Group 2, 60% of patients in Group 3, and in 72% of patients in Group 4 (not significant). The median (range) requirements of morphine were 0 (0–13) mg in Group 1, 3 (0–12) mg in Group 2, 3 (0–15) mg in Group 3, and 6 (0–12) mg in Group 4 (not significant).
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Episodes of hypoxemia occurred in 2 patients in Groups 1, 2, and 3, and none in Group 4 (not significant) and all were successfully treated with 40% oxygen by mask. No patient had a respiratory rate <12 breaths/min.
The median Apfels' risk score for postoperative nausea and vomiting was 2 in the 4 groups (not significant). The incidence of postoperative nausea and vomiting was 26% in Group 1, 21% in Group 2, 15% in Group 3, and 39% in Group 4 (not significant).
Times to discharge to the ward were 128 ± 28 min in Group 1, 116 ± 25 min in Group 2, 121 ± 34 min in Group 3, and 130 ± 22 in Group 4 (not significant).
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Discussion |
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The main finding of this study is that the administration of large concentrations of isoflurane plus small doses of fentanyl is associated with significantly longer early recovery times from anesthesia than smaller concentrations of isoflurane plus larger doses of fentanyl. These different dose combinations of fentanyl and isoflurane, however, result in a similar incidence of early side effects in the PACU.
Fast and predictable recovery from anesthesia is a necessary condition to improve both patient safety and efficiency of the operating room and PACU. Simulations with IV anesthetics have shown that this is best accomplished by the use of short-acting drugs (1). The combination of propofol and remifentanil results in significantly faster times to awakening compared with other opioids, and this difference becomes larger as the duration of anesthesia increases (1). In addition, for any combination of an opioid and hypnotic to provide anesthesia there is an optimal concentration of each drug that will provide the most rapid recovery, and any deviation from this optimum will result in longer recovery times (1,13,14). Although these general principles have been determined for IV drugs, similar studies with inhaled anesthetics have been done only for the combination of sevoflurane and remifentanil (8,9). Breslin et al. (8) found faster times to spontaneous respiration, to eye opening, to laryngeal mask airway removal, and to orientation in adults receiving 0.5 MAC sevoflurane plus remifentanil compared with 1.0 and 1.5 MAC sevoflurane plus remifentanil or sevoflurane alone (8). Similarly, van Delden et al. (9) also found that recovery, assessed with similar variables, was faster after anesthesia with 0.4 MAC sevoflurane plus remifentanil than with either 0.8 or 1.2 MAC and remifentanil.
Recovery from general anesthesia based on the combination of a hypnotic, either an IV or inhaled anesthetic, and an opioid depends on two factors. One is the "return of consciousness," determined by the decrement time of the hypnotic, and the other, in case the patient is not breathing, is the "return to spontaneous ventilation," determined by the opioid concentration. The general rule to provide an adequate anesthesia and faster recovery is that the optimal dosing of a given hypnotic and opioid combination is the one for which the plasma concentration of the drug with the shorter context-sensitive decrement time is maximized, while the plasma concentration of the slower one is maintained at just the level producing the desired effect (15).
Remifentanil has the shortest context-sensitive decrement time among opioids and, with the possible exception of sevoflurane and desflurane (10), this is also true compared with the context-sensitive decrement time of the currently available hypnotics. All the other opioids have a longer context-sensitive decrement time than all the presently used hypnotics (i.e., volatile or IV drugs). Thus, although the optimal dosing of remifentanil plus hypnotic is one in which remifentanil concentration is maximized and the hypnotic is maintained at a concentration just sufficient to ensure loss of consciousness, the situation changes with a different opioid. Fentanyl has a significantly longer half-life (and context-sensitive half-time when given as infusion) than remifentanil, and when combined with propofol the optimal dose of this hypnotic for adequate anesthesia and faster recovery is different than when given along with remifentanil. Although for an anesthesia lasting 60 minutes the recommended effect-site concentration (EC95%) of propofol is 2.70 µg/mL when given with remifentanil, it should be increased by 66%, to 4.48 µg/mL, with fentanyl (1). If the optimal dose combination of inhaled anesthetics and opioids also varies depending on the drugs used, the findings for sevoflurane and remifentanil might not be applicable to isoflurane and fentanyl. Nevertheless, with the combination of these 2 drugs we found essentially the same qualitative results as the previous studies: the early recovery was significantly faster with 0.5 MAC isoflurane plus fentanyl than in the groups with larger isoflurane concentrations and less opioid. However, although early recovery is equally fast with 0.5 MAC isoflurane plus fentanyl and 0.4–0.5 MAC sevoflurane plus remifentanil (e.g., mean TEO of 7.4 minutes in our study compared with 6.5 minutes and 8.3 minutes with sevoflurane) (8,9), at larger concentrations, isoflurane resulted in a significantly prolonged recovery compared with sevoflurane (e.g., at 1.5 MAC, mean TEO was 24.4 minutes in our study compared with 12.7 minutes with sevoflurane) (8). This suggests that, at least at the doses of opioids used in this and the other studies (8,9), the limiting factor for a fast recovery is not the plasma concentration of opioid but the inhaled anesthetic given and its ET concentration. However, the administration of larger doses of opioids, particularly the longer-lasting opiates, can result in a significantly delayed recovery from anesthesia.
The much slower recovery with isoflurane compared with sevoflurane at larger concentrations can be explained by pharmacokinetic differences between the two anesthetics. The context-sensitive half-times of isoflurane and sevoflurane are small (<5 minutes) and do not increase significantly with increasing duration of anesthesia (10). This explains the fast recovery with the 2 gases when administered in small concentrations (e.g., 0.5 MAC). However, at larger concentrations, such as 1.5 MAC, approximately 80% reduction of this concentration is needed to approach 1 MAC awake and the 80% decrement times of both anesthetics are very different. Although in the case of sevoflurane the 80% decrement time is also small (<8 minutes) and does not increase significantly with duration of anesthesia, the 80% decrement time of isoflurane increases significantly to approximately 20 minutes after 70–75 minutes of anesthesia (10). This time is close to the 24 minutes to eye opening in the group given 1.8% ET isoflurane in our study.
For the combination of propofol and fentanyl, their optimal effect-site concentrations vary depending on the duration of anesthesia and, despite this modification, the time to awakening increases as anesthesia prolongs (1). If something similar occurs for volatile anesthetics and opioids, the optimal combination of isoflurane and fentanyl (and the times to recovery) found in our study for anesthesia lasting 70 to 80 minutes could be no longer valid for those of different duration. This can be particularly relevant for anesthesia of longer duration with the potential accumulation of fentanyl.
The adverse effects of any technique are eventually more important than the speed of recovery. We found a similar incidence of side effects among the four groups. There were no significant differences in the degree of sedation or in the incidence of postoperative emesis. No patient had a respiratory rate less than 12 breaths per minute, and the few patients with hypoxemia when breathing room air were all easily managed with oxygen by mask. Although there were no differences in the intensity of pain, morphine requirements showed a clear tendency to be inversely related to the dose of fentanyl administered. Although this was not statistically significant, it might be an additional advantage of a technique based on larger doses of fentanyl.
An important adverse effect in the study by van Delden et al. (9) is the patient in the 0.8 MAC group who reported a recall of surgery. In this study, however, maintenance ET concentrations of sevoflurane decreased to 0.68% in the 0.8 MAC group and even to 0.38% in the group assigned to receive 0.4 MAC (9). These concentrations are less than 1 MAC awake of sevoflurane (16), and this can explain this finding. In the case of isoflurane, the concentration for 50% probability of loss of recall is 0.19% (17) and the MAC awake ranges from 0.23 to 0.3 MAC (18–20). Because in our study no patient had an ET concentration less than 0.5 MAC at any moment during surgery, the risk of awareness was conceivably much less. This is supported by the fact that among hundreds of patients receiving 0.5 MAC of volatile anesthetics plus remifentanil no patient presented recall of intraoperative events (21). In addition, when a hemodynamic variable such as MAP is used to titrate the administration of anesthetics, the basal value chosen and the maximal change allowed can influence the risk of awareness and, therefore, its incidence. We chose as baseline the minimal MAP measured at the ward and only allowed an increase of 10% before giving more fentanyl. In the study by van Delden et al. (9) an increase in systolic blood pressure of more than 15 mm Hg above baseline was allowed before increasing the remifentanil infusion rate; however, baseline was not defined. Considering as baseline the MAP measured when the patient arrives in the operating room—sometimes much higher than the minimum in the ward—may lead to a lighter anesthesia and increased risk of awareness. However, given the infrequently reported incidence of intraoperative awareness (22), the occurrence of a type ß error for this adverse effect in our study cannot be excluded.
In conclusion, the concentration of isoflurane 0.6% ET plus fentanyl administered in doses necessary to maintain stable intraoperative hemodynamics results in recovery from anesthesia being significantly faster than techniques based on larger isoflurane concentrations.
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Footnotes |
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Presented, in part, as a poster presentation at the Euroanaesthesia 2003 Meeting, May, 31–June 3, 2003, Glasgow, Scotland.
Accepted for publication January 5, 2005.
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References |
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- Vuyk J, Mertens MJ, Olofsen E, et al. Propofol anesthesia and rational opioid selection: determination of optimal EC50-EC95 propofol-opioid concentrations that assure adequate anesthesia and a rapid return of consciousness. Anesthesiology 1997;87:1549–62.[Web of Science][Medline]
- O'Hare RA, Mirakhur RK, Reid JE, et al. Recovery from propofol anaesthesia supplemented with remifentanil. Br J Anaesth 2001;86:361–5.
[Abstract/Free Full Text] - Lentschener C, Ghimouz A, Bonnichon P, et al. Remifentanil-propofol vs. sufentanil-propofol: optimal combinations in clinical anesthesia. Acta Anaesthesiol Scand 2003;47:84–9.[Web of Science][Medline]
- Sebel PS, Glass PS, Fletcher JE, et al. Reduction of the MAC of desflurane with fentanyl. Anesthesiology 1992;76:52–9.[Web of Science][Medline]
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[Abstract/Free Full Text] - Lang E, Kapila A, Shlugman D, et al. Reduction of isoflurane minimal alveolar concentration by remifentanil. Anesthesiology 1996;85:721–8.[Web of Science][Medline]
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- van Delden PG, Houweling PL, Bencini AF, et al. Remifentanil-sevoflurane anaesthesia for laparoscopic cholecystectomy: comparison of three dose regimens. Anaesthesia 2002;57:212–7.[Web of Science][Medline]
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