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Recovery from propofol anaesthesia supplemented with remifentanil

2001; Elsevier BV; Volume: 86; Issue: 3 Linguagem: Inglês

10.1093/bja/86.3.361

1471-6771

R OʼHare, R. K. Mirakhur, J. E. Reid, Dara S. Breslin, A. Hayes,

Intensive Care Unit Cognitive Disorders

We have examined the effects on recovery end-points of supplementation of a propofol-based anaesthetic with remifentanil. After induction of anaesthesia with propofol and remifentanil 1.0 μg kg−1, 15 patients each were randomly allocated to target plasma propofol concentrations of 2, 3, 4 or 5 μg ml−1for maintenance of anaesthesia. Remifentanil was administered by infusion for supplementation in doses required for maintenance of adequate anaesthesia. All patients received 50% nitrous oxide in oxygen and ventilation was controlled. The total amount of drugs used and times to different recovery end-points were recorded. Cognitive function was also assessed using a Mini-Mental State questionnaire. The median dose of remifentanil for maintenance of adequate anaesthesia (excluding the initial bolus dose) in the four groups was 0.21, 0.15, 0.11 and 0.13 μg kg−1 min−1 respectively (P=0.0026). The median times to eye opening and orientation were shortest in the 2 μg ml−1 group [6.0 and 6.5 min, 8.5 and 10.8 min, 13.4 and 15.8 min, and 14.2 and 19.5 min respectively in the propofol 2, 3, 4, and 5 μg ml−1 groups respectively (P<0.001)]. The times to discharge from the recovery ward and the Mini-Mental State scores were not significantly different. We have examined the effects on recovery end-points of supplementation of a propofol-based anaesthetic with remifentanil. After induction of anaesthesia with propofol and remifentanil 1.0 μg kg−1, 15 patients each were randomly allocated to target plasma propofol concentrations of 2, 3, 4 or 5 μg ml−1for maintenance of anaesthesia. Remifentanil was administered by infusion for supplementation in doses required for maintenance of adequate anaesthesia. All patients received 50% nitrous oxide in oxygen and ventilation was controlled. The total amount of drugs used and times to different recovery end-points were recorded. Cognitive function was also assessed using a Mini-Mental State questionnaire. The median dose of remifentanil for maintenance of adequate anaesthesia (excluding the initial bolus dose) in the four groups was 0.21, 0.15, 0.11 and 0.13 μg kg−1 min−1 respectively (P=0.0026). The median times to eye opening and orientation were shortest in the 2 μg ml−1 group [6.0 and 6.5 min, 8.5 and 10.8 min, 13.4 and 15.8 min, and 14.2 and 19.5 min respectively in the propofol 2, 3, 4, and 5 μg ml−1 groups respectively (P<0.001)]. The times to discharge from the recovery ward and the Mini-Mental State scores were not significantly different. The use of opioids to supplement anaesthesia is a common practice. Remifentanil is a recently introduced opioid analgesic with characteristics of rapid onset and rapid recovery even after prolonged use. The rapid onset results mainly from the short equilibration time between the blood and effect compartments, and the rapid recovery results from the specific kinetic characteristics of this opioid.1Egan TD Minto CF Hermann DJ et al.Remifentanil versus alfentanil: comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers.Anesthesiology. 1996; 84: 821-823Crossref PubMed Scopus (356) Google Scholar 2Kaplia A Glass PSA Jacobs JR et al.Measured context-sensitive half-times for remifentanil and alfentanil.Anesthesiology. 1995; 83: 968-975Crossref PubMed Scopus (367) Google Scholar It is metabolized by non-specific esterases and has a high rate of clearance.3Glass PSA Hardmann D Kamiyama Y et al.Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (G187084B).Anesth Analg. 1993; 77: 1031-1040Crossref PubMed Google Scholar 4Selinger K Natin RL Smith GA Enzymatic and chemical hydrolysis of remifentanil.Anesthesiology. 1995; 83: A834Google Scholar Its other unique feature is a short, unchanging context-sensitive half-time even after prolonged infusion.2Kaplia A Glass PSA Jacobs JR et al.Measured context-sensitive half-times for remifentanil and alfentanil.Anesthesiology. 1995; 83: 968-975Crossref PubMed Scopus (367) Google Scholar It has been shown that the use of higher doses of remifentanil can result in the use of lower doses of propofol to prevent responses to tracheal intubation and surgery.5Fragen RJ Randel GI Librojo ES et al.The interaction of remifentanil and propofol to prevent response to tracheal intubation and the start of surgery for outpatient knee arthroscopy.Anesthesiology. 1994; 81: A376Crossref PubMed Scopus (256) Google Scholar However, it is not known if this has any influence on recovery. The aim of this study was to examine recovery with the use of remifentanil to supplement anaesthesia maintained with different preselected target plasma concentrations of propofol. Sixty adult patients aged 18–65 years and conforming to ASA grades I or II were recruited into the study with their written informed consent and approval from the Research Ethics Committee. They were to undergo elective surgery of at least 30 min duration. Patients on regular sedative or opioid medication were excluded. No premedication was administered. Anaesthesia was induced and maintained with propofol using a target controlled infusion system (Diprifusor, Zeneca Ltd, Macclesfield, UK).6White M Kenny GNC Intravenous propofol anaesthesia using a computerised infusion system.Anaesthesia. 1990; 45: 204-209Crossref PubMed Scopus (175) Google Scholar 7Swinhoe CF Peacock JE Glen JB Reilly CS Evaluation of the predictive performance of a ‘Diprifusor' TCI system.Anaesthesia. 1998; 53: 61-67Crossref PubMed Scopus (130) Google Scholar The target plasma concentration for induction was set at 4–6 μg ml−1. After loss of the eyelash reflex and verbal response, a bolus dose of remifentanil 1 μg kg−1was administered over 30–60 s and infusion was started at an initial rate of 0.5 μg kg−1 min−1. Muscle relaxation, if required, was provided with rocuronium 0.5 mg kg−1. The airway was maintained using a laryngeal mask airway (LMA †LMA® is the property of Intavent Limited. ) or a tracheal tube. Patients were allocated randomly, using a computer-generated randomization scheme, to target plasma concentrations of propofol (CT) of 2, 3, 4 or 5 μg ml−1 for maintenance of anaesthesia. The infusion rate of remifentanil was adjusted to provide adequate anaesthesia while maintaining the preselected CT constant. The patients' lungs were ventilated with a mixture of 50% nitrous oxide in oxygen to maintain normocapnia. Anaesthesia was deemed to be adequate if heart rate and/or arterial pressure remained within 20% of baseline values and there was no movement, lachrymation or sweating in response to surgery. All patients received tenoxicam 20 mg and morphine 10 mg i.v. 15–20 min before the expected end of surgery. The wound was infiltrated with bupivacaine. Neuromuscular block, when instituted, was monitored using a peripheral nerve stimulator and antagonized with neostigmine 50 μg kg−1 in a mixture with glycopyrrolate 10 μg kg−1. Propofol, nitrous oxide and remifentanil were stopped when the last skin suture was applied and recovery from neuromuscular block had been ascertained. The times to resumption of spontaneous respiration and extubation and/or LMA removal were recorded, as were times to opening the eyes on command, giving the correct date of birth, and orientation for date and time after cessation of all anaesthesia. The doses of remifentanil and propofol administered during the maintenance were recorded. Pain on arrival in the recovery ward was assessed using a 10 cm visual analogue scale (VAS; 0=no pain, 10=worst pain). A Mini-Mental State (MMS) assessment questionnaire8Chung F Lavelle PA McDonald S Chung A McDonald NG Cognitive impairment after neuroleptanalgesia in cataract surgery.Anesth Analg. 1988; 64: 614-618Google Scholar was administered before anaesthesia and 2 h after operation. An assessment was carried out at 4 h if the score had not returned to baseline at 2 h. The assessments of all recovery end-points and MMS assessments were carried out by an observer who was blinded to the group allocation of the patients. The time when patients were ready for discharge from the recovery ward was recorded by the nursing staff (based on observation of control of pain, absence of emetic sequelae, and satisfactory cardiovascular and respiratory observations). The nursing staff were also unaware of the identity of the groups. The incidence of nausea or vomiting was recorded over the first 24 h period. The patients' sense of well-being was scored the next day during the post-operative visit or by a telephone call (if already discharged) using a 10 cm VAS (0=‘feels lousy', 10=‘feels great'). On the next day, patients were also asked three non-leading questions to look for evidence of recall. These were: ‘What was the last thing you remember before going to sleep?'; ‘Did you have any dreams whilst you were under the anaesthetic?'; and ‘What was the first thing you remember when you woke up?' The continuous data were subjected to one-way analysis of variance, or the Kruskal–Wallis tests, depending on the distributions or significant differences in variances, followed by post-tests if indicated [Bonferroni tests for ANOVA (analysis of variance) and Dunn tests for Kruskal–Wallis tests]. The frequency distributions were subjected to χ2 tests and differences were considered significant if P was <0.05. The statistical analysis was performed on a desktop computer using the Prism version 3.0 statistical software (Graph Pad, San Diego, CA, USA). The groups did not differ significantly with respect to age, weight, height and duration of anaesthesia (Table 1). A total of 13 patients (five in the 2 μg ml−1group, one in the 3 μg ml−1group, three in the 4 μg ml−1and four in the 5 μg ml−1 group) received muscle relaxation to facilitate surgery and were intubated, the airway being maintained in all other patients using an LMA. The patients were undergoing orthopaedic or general surgery, the distribution being similar within the groups.Table 1Patient characteristics and duration of anaesthesia. Mean (sd)Target plasma concentration of propofol (μg ml−1)2345Age (yr)32 (12)32 (9)29 (13)34 (10) (range)(18–57)(19–51)(18–64)(19–50)Weight (kg)67 (8)75 (14)72 (17)79 (17)Height (cm)172 (8)171 (11)174 (11)172 (11)M:F11:47:810:510:5Duration of anaesthesia (min)87 (41.1)79 (38.6)73 (29.1)82 (45.1) Open table in a new tab The median CT of propofol for induction of anaesthesia was 6 (range 5–6) μg ml−1, with a mean induction dose of 1.9 (sd 0.37) mg kg−1. The mean time to loss of consciousness was 1.7 (0.5) min. The doses of remifentanil and propofol used during the maintenance period (excluding the bolus doses given at induction) are given in Table 2. There was a significant difference between the groups in the dose of remifentanil administered [median 0.21, 0.15, 0.11 and 0.13 μg kg−1min−1 in the 2, 3, 4 and 5 μg ml−1propofol groups respectively (P<0.01)]. The dose of propofol administered was also significantly different; as expected, it increased with increasing target concentration of propofol [0.08, 0.12, 0.16 and 0.20 mg kg −1min−1 (median values) in the four groups respectively (P<0.001)]. The doses of both remifentanil and propofol in the 13 patients receiving muscle relaxants were similar (remifentanil 0.12–0.30 μg kg−1min−1 and propofol 0.08–0.09 mg kg−1min−1 in the five patients in the 2 μg ml−1 group; remifentanil 0.15 μg kg−1min−1 and propofol 0.11 mg kg−1min−1 in the one patient in the 3 μg ml−1 group; remifentanil 0.08–0.16 μg kg−1min−1 and propofol 0.15 mg kg−1min−1 in the three patients in the 4 μg ml−1 group; and remifentanil 0.05–0.25 μg kg−1min−1 and propofol 0.19–0.23 mg kg−1min−1 in the four patients in the 5 μg ml−1 group).Table 2Doses of remifentanil and propofol (μg kg −1 min−1; median and range) administered during the maintenance phase (excluding the induction doses of propofol and remifentanil). aP<0.05 compared with 4 and 5 μg ml−1 CT groups; bP<0.001 compared with 4 and 5 μg ml−1 CT groups; cP<0.001 compared with 5 μg ml−1 CT group. n=15 except where indicatedTarget plasma concentration of propofol (μg ml−1)2345Remifentanil0.2a (0.08–0.38)0.15 (0.08–0.32)0.11 (0.07–0.21)0.13 (0.05–0.25)Propofol0.08b (0.07–0.08)0.12c (0.08–0.15)0.16 (0.15–0.18)0.20 (0.15–0.28)(n=13)(n=13)(n=14) Open table in a new tab The times to various recovery end-points are given in Table 3. In the propofol 2 μg ml−1 CT group (who received the highest dose of remifentanil), the LMA was removed or extubation was carried out significantly earlier (median time 6.0, 8.3, 9.7 and 11.1 min respectively in the 2.0, 3.0, 4.0 and 5.0 μg ml−1propofol groups; P=0.01). The corresponding median times to eye opening and orientation were 6.0 and 6.5, 8.5 and 10.8, 13.4 and 15.8, and 14.2 and 19.5 min respectively (P<0.001 for both end-points). MMS scores were not significantly different either between the groups or between the pre-operative and post-operative assessments within each group. One patient in the 5 μg ml−1 CT group had an MMS score of 21 at 2 h which returned to the pre-operative baseline value of 26 by 4 h.Table 3Times to attainment of different recovery endpoints, and Mini-Mental State (MMS) scores. Median (range). aP<0.05 compared with 4 and 5 μg ml−1 CT groups; bP<0.001 compared with 4 and 5 μg ml−1 CT groups; cP<0.05 compared with 4 and 5 μg ml−1 CT groups. n=15 except where indicatedTarget plasma concentration of propofol (μg ml−1)2345Spontaneous respiration (min)5.0 (2.6–9.2)6.7 (3.0–10.0)6.8 (1.0–14.8)7.3 (0.8–15.3)Removal of LMA/extubation (min)6.0a (3.4–9.7)8.3 (3.0–12.0)9.7 (5.0–18.0)11.1 (0.8–18.5)Eye opening (min)6.0b (4.4–10.8)8.5c (5.0–13.5)13.4 (6.0–23.5)14.2 (2.9–25.8)Orientation (min)6.5b (4.4–13.5)10.8c(7.2–25.6)15.8 (12.5–28.5)19.5 (8.9–35.6)MMS Pre-operative29.5 (26–30)29 (27–30)29 (26–30)30 (26–30) Post-operative29 (26–30)29 (28–30)29 (26–30)30 (21–30)(n=14) Open table in a new tab There was no significant difference between the groups in the VAS pain scores on arrival in the recovery ward (Table 4). In the first 4 h after anaesthesia, only two of the 60 patients complained of nausea or vomiting, although the number increased to 19 in the first 24 h. There was no significant difference between the groups. There was no significant difference between the groups in the time for readiness to discharge from the recovery ward (median time 100, 108, 95 and 110 min in the 2, 3, 4 and 5 μg ml−1 CT groups respectively). There was also no significant difference between the groups in the patients' sense of well-being on the day after surgery.Table 4Post-operative visual analogue score (VAS; median and range) for pain, incidence of post-operative nausea or vomiting (PONV), discharge time from the recovery ward (median and range), and patients' sense of well-being on the VAS (median and range). No significant differencesTarget plasma concentration of propofol (μg ml−1)2345Pain (VAS score, cm)3 (1–6)3 (1–6)4 (1–7)3.5 (1–5)PONV Within 4 h (n)1/151/150/150/15 Within 24 h (n)5/153/158/153/15Time to discharge from recovery ward (min)100 (36–185)108 (52–186)95 (70–160)110 (34–215)Feeling of well-being (VAS score, cm)9 (4–10)8 (5–10)8 (1–10)9.5 (6–10) Open table in a new tab Four patients developed heart rates of 40–45 beats min−1, but this was not associated with any changes in arterial pressure and did not require treatment. One patient each in the propofol 2 and 3 μg ml−1 CT groups developed chest wall rigidity requiring administration of succinylcholine and tracheal intubation; anaesthesia and surgery were otherwise uneventful. No patient had recall of any intra-operative events when asked the next day. The results of this study show that adequate anaesthesia can be maintained by using different proportions of the hypnotic and the opioid. It is also evident that the use of a short-acting opioid, such as remifentanil, when given at a higher dose in association with a lower dose of the hypnotic (propofol) results in a more rapid, early recovery. It has been shown previously that opioids such as fentanyl and alfentanil exert a propofol-sparing effect, reducing its dose for maintenance of anaesthesia.9Thomas VL Sutton DN Saunders DA The effect of fentanyl on propofol requirements for day case anaesthesia.Anaesthesia. 1988; 43: 73-75Crossref PubMed Scopus (26) Google Scholar 10Vuyk J Lim T Engbers FH et al.The pharmacodynamic interaction of propofol and alfentanil during lower abdominal surgery in women.Anesthesiology. 1995; 83: 8-22Crossref PubMed Scopus (202) Google Scholar We have demonstrated a propofol-sparing effect of remifentanil that allows a lower propofol CT to be used for maintenance of anaesthesia. However, the propofol-sparing effect of fentanyl was not associated with an improvement in recovery time.9Thomas VL Sutton DN Saunders DA The effect of fentanyl on propofol requirements for day case anaesthesia.Anaesthesia. 1988; 43: 73-75Crossref PubMed Scopus (26) Google Scholar While propofol and alfentanil can be administered at different plasma concentrations to give an ideal ratio that could be used to give the most rapid return of consciousness, it requires a complicated step-down regime for both agents.10Vuyk J Lim T Engbers FH et al.The pharmacodynamic interaction of propofol and alfentanil during lower abdominal surgery in women.Anesthesiology. 1995; 83: 8-22Crossref PubMed Scopus (202) Google Scholar Vuyket al., using a computer simulation program, have also suggested that the propofol concentrations that allow the most rapid return of consciousness are lower when it is administered with remifentanil than when combined with alfentanil or fentanyl.11Vuyk J Mertens MJ Olofsen E Burm AGL Bovill JG 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: 1549-1562Crossref PubMed Scopus (255) Google Scholar Remifentanil is a unique drug, with rapid onset that allows rapid intraoperative titration dependent upon clinical needs, and rapid and predictable offset. It also has a short and constant context-sensitive half-life.2Kaplia A Glass PSA Jacobs JR et al.Measured context-sensitive half-times for remifentanil and alfentanil.Anesthesiology. 1995; 83: 968-975Crossref PubMed Scopus (367) Google Scholar 12Westmoreland CL Hoke JF Sebel PS Pharmacokinetics of remifentanil (GI87084) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery.Anesthesiology. 1993; 79: 893-903Crossref PubMed Scopus (343) Google Scholar Regardless of the duration of infusion, the decrease in plasma concentration to 50% has a time of 3.6 min.12Westmoreland CL Hoke JF Sebel PS Pharmacokinetics of remifentanil (GI87084) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery.Anesthesiology. 1993; 79: 893-903Crossref PubMed Scopus (343) Google Scholar These characteristics allow uncomplicated changes in infusion rates with rapid effect, making remifentanil an ideal adjunctive agent for i.v. anaesthesia. The present study has clearly shown the influence of its use on early recovery. As expected, patients in the groups receiving the higher CTs of propofol received significantly more propofol and those receiving the lower concentrations received significantly more remifentanil. By changing the balance of the anaesthetic agents and maintaining the same qualitative anaesthetic, patients in the 2 and 3 μg ml−1 CT groups had more rapid recovery and return of orientation. This was obviously because of the unique characteristics of remifentanil. However, in spite of early post-operative recovery in patients given the higher supplementation doses of remifentanil, there were no significant differences in the times when patients were ready for discharge from the recovery ward (although there was a trend towards a shorter time in the 2 μg ml−1 group) or in the patients' perception of well-being. This has been shown in another study recently, in which the use of remifentanil was associated with faster, early recovery but with no difference in discharge from the recovery ward and patient satisfaction.13Loop T Priebe H-J Recovery after anesthesia with remifentanil combined with propofol, desflurane or sevoflurane for otorhinolaryngeal surgery.Anesth Analg. 2000; 91: 123-129PubMed Google Scholar This indicates a useful effect of remifentanil supplementation only in the early post-operative period. This is perhaps what would be expected from a drug with a short duration of action. The actual discharge from the recovery ward may be influenced by other factors, such as post-operative pain or nausea and vomiting. The nurses' preconception of a minimal period of stay in the recovery ward may also play a role. It is our impression that, despite the availability of more rapidly-acting anaesthetic agents and faster recovery times, the actual time of discharge of patients from the recovery ward may be delayed by paperwork and logistic difficulties such as portering and the availability of surgical ward nursing staff to accept patients, factors over which anaesthetists may have little control. This has also been noted by others14Seago JA Weitz S Walczak S Factors influencing stay in the postanesthesia care unit: a prospective analysis.J Clin Anesth. 1998; 10: 579-587Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar 15Pavlin DD Rapp SE Polissar NL Malmgren JA Koerschgen M Keyes H Factors affecting discharge in adult outpatients.Anesth Analg. 1998; 87: 816-826PubMed Google Scholar and needs to be examined if full use is to be made of the advantages of new drugs and techniques. Nevertheless, an advantage in terms of early recovery is also useful, and would result in less need for intensive nursing supervision. The MMS assessment has been used previously by Chung in assessing the return of higher mental function in the elderly after neuroleptanaesthesia.8Chung F Lavelle PA McDonald S Chung A McDonald NG Cognitive impairment after neuroleptanalgesia in cataract surgery.Anesth Analg. 1988; 64: 614-618Google Scholar We, however, found little difference in these scores between the groups pre-operatively, and little difference between pre- and postoperative scores within each group. The MMS score may be an insensitive measure of recovery after administration of short-acting agents, or it may be more useful when applied at an earlier time. No patient had recall of any intra-operative events, although most could recall waking up in the operating theatre after surgery. A possible disadvantage of the use of remifentanil as the intra-operative opioid is the absence of immediate postoperative analgesia. This was taken into consideration in the present study by administration of morphine and tenoxicam, and infiltration of the wound with bupivacaine before termination of anaesthesia. This resulted in most patients being comfortable in all groups (no significant difference in VAS scores) but did not affect post-anaesthetic recovery, and may be of advantage in moderately painful procedures performed on day-case surgical patients. In conclusion, the results of our study show shorter recovery times when maintenance of anaesthesia is changed from using a higher dose of propofol with a lower dose of remifentanil to a regime with a lower dose propofol and a higher dose of remifentanil. However, the advantages are limited to early recovery. This study was supported by a grant from Glaxo Wellcome.