Central Manchester and Manchester Children's University Hospitals NHS Trust, Department of Anaesthesia, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK
* Corresponding author. E-mail: avohra{at}f2s.com
Accepted for publication August 1, 2005.
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Abstract |
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Methods. Twenty patients undergoing off-pump coronary artery bypass surgery, receiving standardized propofolfentanyl-based anaesthesia, randomly received infusions of either remifentanil 0.1 µg kg1 min1 (Group R, n=10) or saline (Group S, n=10), each infused at 0.12 ml kg1 h1. Propofol and trial drug infusion were continued into the postoperative period until the patients were ready to be woken up. Postoperative analgesia was provided with morphine infusion commenced immediately after operation, and was additionally nurse controlled on the basis of a visual analogue scale (VAS) score (010). Agitation score was recorded using a VAS of 03.
Results. In the first hour after discontinuing propofol and trial infusion, morphine requirements were significantly higher in the remifentanil group (8.15 (SD 3.59) mg) compared with the saline group (3.29 (2.36) mg) (P<0.01). There was no difference in the total morphine given during the period after stopping propofol or in the total requirement in the first 12 h postoperatively. There was no significant difference in either pain scores or agitation scores between the two groups.
Conclusion. Use of remifentanil is associated with increased opioid requirement in the first hour after it has been discontinued.
Keywords: analgesia, postoperative ; analgesics opioid, remifentanil ; surgery, cardiac
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Introduction |
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Remifentanil is an ultra-short-acting esterase-metabolized opioid (terminal half-life of 3.88.3 min and context-sensitive half-time of 35 min). It is structurally related to fentanyl and alfentanil and has selective µ-opioid agonist activity. In vitro and in vivo studies demonstrate rapid and extensive metabolism of this compound by ester hydrolysis.1 3 6 7 Use of remifentanil during anaesthesia provides intense analgesia and decreased sympathetic response to surgical stimulation. It has been used to provide sedation in intensive care units. Addition of remifentanil to the perioperative regime may be beneficial with greater cardiovascular stability intraoperatively and during sedation immediately postoperatively.8
Remifentanil is now used in cardiac surgery because of its effect on haemodynamic stability. It has been proposed as potentially suitable for fast-tracking patients after off-pump coronary artery (OPCAB) surgery as its short intense action allows early extubation. However, there is concern about its antanalgesic effect, leading to unfavourable emergence from anaesthesia, which is characterized by a suspected increased opioid requirement9 10 and agitation. The evidence for this effect is equivocal. Studies of volunteers and non-cardiac surgery patients have concluded that there is no tolerance to remifentanil.1113 However, it is notable that previous studies have focused on the period 1224 h postoperatively and not on the first hour.
The purpose of this prospective randomized double-blind controlled study was to determine the effects of remifentanil on postoperative analgesia requirement in patients undergoing OPCAB surgery. The main aim of the study was to assess the analgesic requirement in the first hour after stopping remifentanil infusion as well as for the 12 h after the end of surgery.
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Methods |
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Inclusion criteria were elective OPCAB and age 1875 years. Patients were excluded preoperatively if they gave a history of severely impaired cardiac function, severe pulmonary disease, diabetes mellitus, renal failure, drug dependence or uncontrolled hypertension. Those requiring emergency surgery were also excluded. Postoperative exclusions included reoperation, excessive bleeding and prolonged ventilation (>12 h).
The patients continued their usual medications including all cardiac drugs. All patients received standardized premedication with temazepam 2030 mg, metoclopramide 10 mg and sucralfate 2 g, given 90 min before operation. All patients were monitored according to standard guidelines. In addition, direct arterial and central venous pressure monitoring was established. Anaesthesia was induced using target-controlled infusion (TCI) of propofol with the target at 2.54 µg ml1 (AstraZeneca, Macclesfield, UK), fentanyl 15 µg kg1 and rocuronium 1.5 mg kg1. The trachea was intubated 3 min after induction. The patients were ventilated with oxygen-enriched air (50% oxygen). Anaesthesia was maintained with TCI propofol with the target between 1.8 and 4 µg ml1, guided by haemodynamic parameters. Muscle relaxation was maintained with boluses of rocuronium 1020 mg as required.
On the morning of surgery patients were randomly allocated to one of the two groups using a closed-envelope system. An anaesthetist, not directly involved in the study, prepared the infusion which consisted of four 50 ml syringes. The infusion was started 5 min after induction of anaesthesia as follows: Group R (remifentanil, n=10), remifentanil 50 µg ml1 at an infusion rate of 0.12 ml kg1 h1 (equivalent to 0.1 µg kg1 min1); Group S (control, n=10), normal saline 0.9% given at an infusion rate of 0.12 ml kg1 h1.
The anaesthetist(s) in charge, the nurses on the postoperative unit and the investigator were blinded to the nature of infusion. Blood pressure and heart rate were maintained within 20% of the preoperative measurements using cardiovascular drugs at the anaesthetist's discretion. Interventions used for raising or lowering the blood pressure or heart rate were recorded. Heart rate (HR), systolic arterial blood pressure (SAP) and mean arterial pressure (MAP) were recorded from 5 min before induction of anaesthesia to 1 h after commencement of surgery, and 5 min before and every 5 min for 90 min after the end of surgery.
At the end of surgery, patients were kept sedated with propofol 100200 mg h1, infusion of the study drug was continued and morphine 12 mg h1 was started. Patients were transferred to the cardiac intensive care unit (CICU). Tracheal extubation was performed when the patients were cardiovascularly stable, were normothermic (central temperature >36.5°C), were not bleeding (<50 ml h1) and had adequate spontaneous ventilation (tidal volume >7 ml kg1, and
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Patient age, gender, body weight, height and BMI were recorded. Duration of surgery, total duration of postoperative sedation, duration of postoperative intubation (intubation time) and total propofol infused were also recorded.
Morphine boluses were titrated by nursing staff according to VAS pain scores (if >5) or agitation (score of 2 or 3) and morphine infusion rate was continuously recorded. If pain was not controlled by morphine boluses, additional (non-opioid) analgesics were permitted. Morphine doses were noted as follows: total dose (mg) given before stopping propofol (Morphine pre-); total dose given 1 h after stopping propofol (Morphine 1 h); total dose given in first 12 h postoperatively (morphine 12 h). In addition, Morphine 1 h was subdivided into 15-min periods of morphine consumption.
Pain scores were evaluated as visual analogue scale (VAS) scores of 010 and recorded by the nurses at 5, 15, 30, 45, 60 min after stopping propofol and at the same intervals after extubation. Sedation scores (03) were recorded at 15-min intervals from the time of discontinuing propofol. An agitation score [0, patient is calm, comfortable and does not require any intervention; 1, patient is agitated and distressed, but settles with reassurance and verbal command; 2, patient is agitated and needs analgesics, mild sedation or both (one nurse could manage); 3, patient is agitated, cannot be managed by one nurse and requires heavy sedation or re-sedation or both (e.g. propofol infusion)] was recorded every 15 min for 12 h after propofol was stopped.
Data were analysed using the unpaired Student's t-test for parametric data, the MannWhitney U-test for non-parametric data and the 2-test as appropriate using SPSS version 9 software. A P-value <0.05 was considered statistically significant. Results are presented as mean (SD) or median (range).
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Results |
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There was no difference in morphine given to the two groups before stopping sedation (Table 3). Morphine requirement 1 h after stopping sedation was significantly higher in Group R (8.15 (3.59) mg) than in Group S (3.29 (2.36) mg) (P<0.01). The morphine required in the first hour was also analysed at 15-min intervals (Table 3). This showed that the maximum morphine consumption occurred in the first 30 min and was greater in Group R than in Group S (Fig. 1). There was no significant difference in total dose of morphine given to each group in the postoperative 12 h.
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Discussion |
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In our study, infusion of remifentanil 0.1 µg kg1 min1 for >8 h was associated with an increase in morphine requirement during the first hour but not at 12 h. This occurred despite use of fentanyl 15 µg kg1 at induction of anaesthesia and morphine infusion for 4 h prior to termination of remifentanil. The first hour, comparing remifentanil with placebo, has not previously been evaluated in patients receiving infusion for >2 h. This could explain why some previous studies have failed to show any difference in pain or morphine requirements. It appears that dose and duration of remifentanil are important factors in this hyperalgesia phenomenon. It may also be that the nature of surgery may affect the findings of different studies. Whether it is the duration of remifentanil infusion or the total dose that is more important in the development of hyperalgesia remains unclear. Future studies aimed at elucidating this would be useful.
Fletcher and colleagues14 have suggested that either acute tolerance occurs during infusion or the rapid offset of the drug from the opioid receptor with the slower attachment of opioids with less affinity is the cause of the pain and agitation seen following cessation of remifentanil. In our study, a significant difference in morphine requirement was seen in the first hour but not at 12 h. Unfortunately, we did not look at times between and do not know when the effect ceased to be significant. However, it is clear from our results that most of the difference in the absolute dosages of morphine occurred between 15 and 30 min. This fits well with the relative pharmacokinetics of remifentanil and morphine (remifentanil has a context-sensitive half-life of 8 min, and onset time for i.v. morphine is about 20 min) and would provide evidence for this theory. The observation that morphine prior to cessation of remifentanil has made no difference may be due to the relative affinities of the two drugs for the µ-opioid receptor or perhaps the small doses of morphine used (8 mg over 4 h). The effect of the induction dose of fentanyl is probably minimal. Furthermore, postulated mechanisms for acute tolerance, including alterations of N-methyl-D-aspartate (NMDA) receptors15 or downregulation of opioid receptors and decoupling from the transduction system,16 17 seem unlikely to have reversed within 1 h as would be suggested by our findings. Other studies have provided evidence to support the concept of tolerance. Vinik and Kissin10 measured pain tolerance in volunteers given remifentanil 0.1 µg kg1 min1 for 4 h. They observed that after reaching maximum analgesia in 6090 min, the analgesic effect of remifentanil began to decline. Guignard and colleagues9 demonstrated that increased morphine requirements persisted for 24 h after infusion of remifentanil 0.3 µg kg1 min1. Neither of these observations can be explained by a simple difference in the pharmacokinetics of different opioid receptor agonists. If acute tolerance was occurring during our study we might have expected to see some difference in the remifentanil group and the placebo group before cessation of remifentanil. There was no difference in morphine dosage as a result of study design, nor were the doses of propofol between the groups different. Furthermore, the haemodynamic variables measured (HR, SAP and MAP) were not different between the two groups until after the trial infusion was stopped. It is possible that increased sympathetic activity was masked by propofol infusion. Our study has not produced any evidence to support the concept of acute tolerance.
HR and MAP were significantly higher in Group R during the first hour after stopping sedation. The increase in MAP and HR could be explained on the basis of rapid reversal of the effect of remifentanil on factors affecting the cardiovascular system. We may assume that this is due to increased sympathetic outflow in response to pain.
There was no difference in agitation score between the two groups. Although not significantly different, patients who received remifentanil had higher pain scores, despite receiving more morphine, than those in the placebo group.
Prolongation of tracheal extubation time has been previously noted.5 18 In our study, although it took longer to extubate patients in the remifentanil group, the difference was not statistically significant (P=0.06). Significantly greater amounts of morphine given to the remifentanil group might be expected to contribute to a longer extubation time. Our results concur with those in other studies assessing fast-tracking patients after various surgical procedures,1921 and may have clinical relevance for fast-tracking patients after cardiac surgery.
We conclude that remifentanil is associated with increased analgesic requirements during the first 30 min to 1 h after cessation following prolonged use (>8 h). This may have clinical relevance to cardiac and non-cardiac surgery patients. Therefore we suggest that studies involving analgesic requirement following prolonged remifentanil infusion should focus on this earlier period. Our study appears to provide evidence to support a pharmacokinetic explanation for the observed increased requirement for morphine. Whilst we have not demonstrated acute tolerance to remifentanil, we have not been able to reject it. The aetiology of hyperalgesia following remifentanil requires further study.
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References |
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2 Egan TD. Pharmacokinetics and pharmacodynamics of remifentanil: an update in the year 2000. Curr Opin Anaesthesiol 2000; 13: 44955[CrossRef]
3 Thompson JP, Rowbotham DJ. Remifentanilan opioid for the 21st century. Br J Anaesth 1996; 76: 3413
4 Hall AP, Thompson JP, Leslie NA, Fox AJ, Kumar N, Rowbotham DJ. Comparison of different doses of remifentanil on the cardiovascular response to laryngoscopy and tracheal intubation. Br J Anaesth 2000; 84: 1002[Abstract]
5 Myles PS, Hunt JO, Fletcher H, Watts J, Bain D, Silvers A. Remifentanil, fentanyl, and cardiac surgery: a double-blinded, randomized, controlled trial of costs and outcomes. Anesth Analg 2002; 95: 80512
6 Kapila A, Glass PS, Muir JR et al. Measured context sensitive half-times of remifentanil and alfentanil. Anesthesiology 1995; 83: 96875[CrossRef][ISI][Medline]
7 Michelsen LG, Hug CC Jr. The pharmacokinetics of remifentanil. J Clin Anesth 1996; 8: 67982[CrossRef][ISI][Medline]
8 Lehmann A, Zeitler C, Thaler E, Isgro F, Boldt J. Comparison of two different anaesthesia regimens in patients undergoing aortocoronary bypass grafting surgery: sufentanil-midazolam versus remifentanil-propofol. J Cardiothoracic Vasc Anesth 2000; 14: 41620[CrossRef][ISI][Medline]
9 Guignard B, Bossard AE, Coste C et al. Intraoperative remifentaninil increases postoperative pain and morphine requirement. Anesthesiology 2000; 93: 40917[CrossRef][ISI][Medline]
10 Vinik HR, Kissin I. Rapid development of tolerance to analgesia to remifentanil infusion in humans. Anesth Analg 1998; 86: 130711[Abstract]
11 Cortínez LI, Brandes V, Muñoz HR, Guerrero ME, Mur M. No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. Br J Anaesth 2001; 87: 8669
12 Gustorff B, Nahlik G, Hoerauf K. No early tolerance during remifentanil infusion in volunteers. Eur J Anaesth 2001; 18: 138
13 Schraag S, Checketts M, Kenny G. Lack of rapid development of opioid tolerance during alfentanil and remifentanil infusions for postoperative pain. Anesth Analg 1999; 89: 7537
14 Fletcher D, Pinaud M, Scherpereel P, Clytis N, Chauvin M. The efficacy of intravenous 0.15 versus 0.25 mg/kg intraoperative morphine for immediate postoperative analgesia after remifentanil-based anesthesia for major surgery. Anesth Analg 2000; 90: 66671
15 Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995; 62: 25974[CrossRef][ISI][Medline]
16 Jordan B, Devi LA. Molecular mechanisms of opioid receptor signal transduction. Br J Anaesth 1998; 81: 1219
17 Albrecht S, Schuttler J, Yarmush J. Postoperative pain management after intraoperative remifentanil. Anesth Analg 1999; 89: S405[CrossRef][ISI][Medline]
18 Cheng DCH, Newman MF, Duke P et al. The efficacy and resource utilization of remifentanil and fentanyl in fast-track coronary artery bypass graft surgery: A prospective randomized, double-blinded controlled, multi-center trial. Anesth Analg 2001; 92: 10941102
19 Howie MB, Cheng D, Newman MF, et al. A randomized double-blinded multicenter comparison of remifentanil versus fentanyl when combined with isoflurane/propofol for early extubation in coronary artery bypass graft surgery. Anesth Analg 2001; 92: 108493
20 Engoren M, Glenn L, Fenn-Buderer N. A comparison of fentanyl, sufentanil, and remifentanil for fast-track cardiac anesthesia. Anesth Analg 2001; 93: 85964
21 Coriat P, Beaussier M. Fast-tracking after coronary artery bypass graft surgery. Anesth Analg 2001; 92: 10813
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