Carotid endarterectomy (CEA) is regaining popularity in the treatment of patients with transient ischaemic attacks (TIA) and reversible ischaemic neurological deficits. There is evidence to suggest that the procedure provides greater benefit than medical treatment in symptomatic patients presenting with severe carotid stenosis (70–90% diameter reduction) [1–4]. Recent surveys indicate that CEA is associated with a perioperative mortality between 0.5% and 2% and morbidity between 2% and 4% . The primary causes of this morbidity and mortality are new neurological deficits and myocardial infarction . The anaesthetic management should therefore aim to combine haemodynamic stability with rapid emergence. This will enable early neurological assessment during the recovery period and perhaps reduce the risk of these significant complications.
Remifentanil is a fentanyl derivative with an ester linkage. It is a pure µ-receptor agonist and the rapid breakdown of the ester linkage by non-specific tissue and plasma esterases is responsible for its unique characteristics . The pharmacodynamic and pharmacokinetic properties of remifentanil suggest that it may be useful for neurovascular procedures where haemodynamic stability, rapid emergence and early postoperative neurological examination are essential.
The aim of this study was to compare the effects of remifentanil and fentanyl on the haemodynamic changes and emergence characteristics in patients undergoing CEA under general anaesthesia.
After Local Research Ethics Committee approval and written informed consent, 33 patients admitted for CEA were recruited to this prospective randomized double-blind study. Exclusion criteria included patients with chronic use of opioids, opioid use within 12 h of surgery or a hypersensitivity to opioids and/or propofol/lipid emulsions.
On the morning of surgery, patients received their routine medications, but were not given any other premedication. Patients were randomized to receive either remifentanil or fentanyl via a blind-envelope method. All opioid infusions were diluted such that infusions could be given on a ml kg−1 h−1 basis and separate syringes prepared for the induction, maintenance and emergence periods. This ensured that the investigators and attending anaesthetists were blinded to the identity of the opioid received by each patient.
On arrival in the anaesthetic room, routine monitoring was instituted including direct invasive arterial pressure measurement. Prior to induction patients were preloaded with 500 mL of Hartmann's solution and preinduction heart rate (HR) and mean arterial pressure (MAP) were recorded as baseline. All patients were preoxygenated, followed by a slow bolus injection of the study drug (remifentanil 0.5 µg kg−1 or fentanyl 1µg kg−1) which was continued as an infusion (remifentanil 0.2 µg kg−1 min−1 or fentanyl 2 µg kg−1 h−1). Propofol was titrated (1–2 mg kg−1) until loss of consciousness was observed and atracurium (0.5 mg kg−1) was used to facilitate intubation. Anaesthesia was maintained with isoflurane (ETISO% – end-tidal concentration of 0.5%), and the lungs mechanically ventilated with a nitrous oxide/oxygen mixture (66:34%) to an end-tidal CO2 (ETCO2) of 4.5 kPa.
Haemodynamic variables (HR, MAP) were recorded at induction, intubation, skin incision, pre- and postextubation and at 10-min intervals throughout the procedure. If a change greater than 20% of baseline occurred in MAP or HR the opioid infusions were adjusted in the first instance, as clinically appropriate (remifentanil 0.05–2 µg kg−1 min−1, fentanyl 1–3 µg kg−1 h−1), until their preset ranges were reached. We chose these doses according to previous clinical experience. If the haemodynamic variables were still outside the preset limits then ETISO% was adjusted (0.4–0.6%). After this either ephedrine or antihypertensive agents were used as clinically appropriate.
Prior to surgical skin preparation a transcranial Doppler (TCD) was placed over the ipsilateral temporal area to insonate the middle cerebral artery (MCA) and a cerebral function monitor (CFM) was attached. At the time of internal carotid artery cross-clamping a shunt was inserted if the percentage drop in flow velocity was greater than 60% of baseline, accompanied by a sustained fall (> 1 min) in the CFM . The skin incision line was infiltrated with 0.5% bupivacaine immediately before commencement of surgery.
After carotid artery closure, the fentanyl infusion was replaced by a 0.9% NaCl infusion whereas the remifentanil infusion was replaced by another remifentanil infusion at the same rate. After skin closure all infusions were stopped, the anaesthetic discontinued and the patients' lungs ventilated with 100% oxygen. The time to spontaneous respiration, extubation, eye opening and the incidence of coughing during emergence were recorded. The patient was then transferred to the recovery area where haemodynamic monitoring was continued. Analgesic, antiemetic and antihypertensive medication requirements were recorded.
All data were analysed using StatView5 software (SAS institute Inc., SAS Campus Drive, Cary, USA) and are presented as mean values ± one standard deviation (SD) unless otherwise stated. Continuous data were compared using factorial and repeated measures analysis of variance (ANOVA) with Bonferroni correction for multiple comparisons as appropriate. P < 0.05 was considered statistically significant.
We studied 33 patients who had no neurological deficit before surgery. Demographic variables were similar between the two groups (Table 1.) One patient in the fentanyl group was excluded from the analysis after surgical complications requiring major blood transfusion and admission to the intensive care unit after surgery.
There was no difference in the length of procedure, internal carotid artery cross-clamp time or the number of shunts used between the groups. In both drug groups some patients required bolus doses of ephedrine to maintain a stable MAP. This was given prior to surgical stimulus, while the patient was being prepared for surgery in 11 of the 13 patients (Table 2.)
The haemodynamic data during induction, maintenance and emergence (Figures 1–3 respectively) and the TCD middle cerebral artery flow velocity (MCAFx) data (Figure 4) were similar between the groups. At induction both groups had a significant decrease in MAP (P < 0.001), and the remifentanil group had a significant decrease in HR (P = 0.001). After endotracheal intubation both MAP and HR increased significantly from preintubation levels (P < 0.01), but not above the preoperative values. For the period between intubation and skin incision, MAP and HR for both groups were significantly lower than preoperative baseline (P < 0.01), and there were no haemodynamic changes at the time of incision. During the maintenance period of anaesthesia HR and MAP were significantly lower than baseline (P < 0.05) in both the fentanyl and remifentanil groups. At extubation there was a significant rise in HR and MAP in the remifentanil group. However, this was not in excess of the preoperative baseline values.
The time to eye opening after discontinuation of anaesthesia was significantly shorter in the remifentanil compared with the fentanyl group (6.62 min ± 3.89 vs. 18 min ± 15.18, P = 0.015).
The incidence of coughing at extubation appeared to be less in the remifentanil group although the figures were too small to analyse. In the surgical recovery area there were no differences between the groups in the analgesic, antihypertensive and antiemetic medications required. The Glasgow Coma Scores (GCS) at 15 min after admission to the recovery area were the same (Table 3.)
The principle aims of the anaesthetic management for patients undergoing CEA are the control of MAP and the maintenance of cerebral perfusion to minimize myocardial and cerebral ischaemia. These aims are more difficult to achieve in the patient population which present for CEA because of pre-existing factors such as peripheral vascular and ischaemic heart disease causing a higher relative risk after surgery . There is renewed interest in many centres for use of a regional technique for this operation , although there is little evidence of the overall benefit in outcome of regional techniques compared with a general anaesthetic technique.
In this pilot study, remifentanil was found to have similar effects compared with fentanyl on MAP and HR during induction and maintenance of anaesthesia when used to supplement an isoflurane/nitrous oxide anaesthetic technique. The reduction in these parameters supports other data demonstrating significant reductions in MAP and HR with remifentanil . The decreases in MAP and HR may have been minimized if an infusion of the anaesthetic agents were given at induction rather than a bolus. In addition, more vigorous fluid preloading prior to induction could have reduced MAP changes, or prior administration of glycopyrollate may have reduced the bradycardic effect.
Although the response to intubation was not completely obtunded with either drug, neither MAP nor HR increased above baseline measurements. The rise in HR and MAP was less in the remifentanil group compared with the fentanyl group despite a low induction dose of remifentanil. Although this might indicate that a higher dose of opioid could be used to reduce this response to intubation, there was no response to the initial surgical stimulus in either group. Further, there was no difference in the haemodynamic changes during maintenance of anaesthesia. Indeed, a higher induction dose of remifentanil may have reduced the MAP and HR to an unacceptable level and a higher dose of fentanyl may have had longer lasting effects on the recovery period.
Both MAP and HR were significantly lower than baseline throughout the maintenance period in both groups, which potentially could increase the risk of myocardial and cerebral ischaemia. However, perioperative strokes are more probably to be embolic rather than a result of low flow states [12,13] and in this study adequate cerebral blow flow was demonstrated using continuous MCAFx and CFM monitoring which contributed to the lack of adverse neurological sequelae. In our methodology, we intended to use vasoconstrictors if patients were considered to be at risk from hypotension. Thus no intervention was made if MAP decreased by up to 20% providing there was no significant change in MCA flow velocity.
The period of highest risk for myocardial ischaemia is during emergence [14,15] and haemodynamic changes need to be particularly well controlled during this period. In this study, MAP and HR increased significantly at extubation in the remifentanil group, which although sustained in recovery, was not in excess of baseline. There was no change in the fentanyl group at extubation and MAP and HR remained significantly lower than preoperative levels in the recovery period. Although this would infer greater stability in the fentanyl group, establishing MAP to preoperative levels would ensure adequate flow through the endarterectomy vessel and improved cerebral perfusion. Postoperative hypertension (defined as systolic arterial pressure > 200 mmHg) increases the risk of developing neurological deficits (10.2%) compared with normotension (3.4%) , and also increases the risk of stress or rupture of the anastomosis or haematoma formation at the operative site. This must be avoided, and was not a problem in either group in our study.
The MCAFx changed very little in either group prior to ICA clamping. This implies that autoregulation was maintained in both groups, supporting other reports with remifentanil  and fentanyl.
The most significant difference between the two groups in this study was the mean time taken for eye opening and extubation, 6.6 min in the remifentanil group compared with 18 min in the fentanyl group. Emergence was equally smooth in both groups. The difference in time to eye opening occurred even after stopping the fentanyl infusions at the beginning of wound closure. The shorter awakening time with remifentanil is due to its pharmacodynamic and pharmacokinetic properties. It has a rapid onset of action (half-time equilibration between blood and effect compartment of 1.3 min , and a measured context-sensitive half-life of 3.2 min after a 3-h infusion) . Fentanyl is relatively fast acting (half-time equilibration between blood and effect compartment of 4.7 min ), but after a 3-h infusion one would expect to wait over 120 min for a 50% reduction in the effect site concentration . However, this study was a clinical comparison and not a pharmacological one. In our study, anaesthesia lasted approximately 3 h and emergence was fastest in the remifentanil group. This shorter time to eye opening has the advantage of a quicker neurological assessment after operationy.
Published potency ranges of these opioids are wide and we chose the initial bolus and subsequent maintenance ranges from previous clinical experience . Remifentanil is said to be 1.2 times more potent than fentanyl and this was reflected in our choice of initial induction dose.
Although seven patients in the remifentanil group required postoperative analgesia compared with three in the fentanyl group, this was not statistically significant. Although difficult to take inference from a small trial such as this one, this trend of increased analgesic requirement in the remifentanil group could be expected due to its rapid metabolism and may have become significant with more subjects in each group. All other recovery characteristics were similar for both groups.
One of the recognized advantages of remifentanil is that it is easy to titrate its effect thus making it a more versatile opioid to use in high-risk cases. When combined with a target-controlled infusion of propofol, remifentanil may well provide the ideal conditions for a total intravenous technique. Indeed, this has been found to be a suitable technique for neurosurgical procedures . Other studies have used remifentanil in a nitrous oxide/opioid anaesthetic but the incidence of rescue anaesthesia with isoflurane was high , and we believe it should be combined with another anaesthetic agent.
In conclusion, this study has demonstrated that in patients undergoing CEA under general anaesthesia, there appears to be no difference in haemodynamic stability when isoflurane/nitrous oxide anaesthesia is supplemented with fentanyl or low-dose remifentanil. Recovery characteristics are similar, with the exception that remifentanil does enable a more rapid time to eye opening and extubation. Although this may be an advantage, there was no obvious difference in immediate outcome between the two groups.
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