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Original Article

Remifentanil provides better protection against noxious stimuli during cardiac surgery than alfentanil

Heijmans, J. H.*; Maessen, J. G.; Roekaerts, P. M. H. J.*

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European Journal of Anaesthesiology: August 2004 - Volume 21 - Issue 8 - p 612-618


The development of total intravenous (i.v.) anaesthesia and the widespread acceptance of propofol in cardiac anaesthesia have led to an increased interest in the combination of propofol with fentanyl, sufentanil or alfentanil [1-3]. The pharmacokinetic-based drug infusion systems, target-controlled infusion (TCI), can rapidly achieve and maintain a constant blood concentration of i.v. anaesthetic drugs [4,5] allowing more precise drug titration and, as a result, fast recovery [6]. Alfentanil has been considered a very suitable opioid to use in combination with propofol, because of its pharmacokinetics, rapid onset of action and short duration of action. However, its context-sensitive half-time increases with the duration of infusion and reaches a plateau after approximately 1 h [7]. Due to its potency and predictable pharmacokinetic characteristics, remifentanil, an ultra short-acting opioid agonist with a close concentration-effect relationship, may be the ideal opioid to use in combination with propofol for continuous i.v. administration [8]. Its brief and constant context-sensitive half-time, however, mandates a specific strategy for postoperative pain relief [9]. The administration of a morphine derivative just before stopping the remifentanil infusion may be a simple and effective strategy for achieving good postoperative pain control [10-12]. However, this technique could jeopardize early extubation after a remifentanil-based anaesthetic technique.

There are several reports about severe cardiovascular depression with remifentanil in patients undergoing cardiac surgery [13,14]; these cardiovascular effects could be, in part, attributed to the dose and method of administration of remifentanil.

We hypothesized that remifentanil-TCI propofol anaesthesia with the administration of the synthetic morphine derivative pirinitramide (piritramide) upon cessation of the remifentanil administration would produce a shorter time to tracheal extubation compared with an alfentanil-TCI propofol anaesthetic technique. To test this hypothesis, we compared two infusion regimens of remifentanil with an earlier described alfentanil infusion regimen [3] and included detailed haemodynamic assessments. Two remifentanil concentrations were studied since the optimal dose of remifentanil providing adequate anaesthesia without cardiovascular instability, has not yet been described.


The study was approved by our hospital's Ethics Committee and written informed consent was obtained from 75 patients who were randomized into a higher-dose remifentanil group (HDRG), a low-dose remifentanil group (LDRG) or an alfentanil group (AG), in combination with a propofol-TCI technique. The study was blinded for the opioid infusion. Exclusion criteria included left ventricular ejection fraction of less than 25%, hypothermic circulatory arrest, recent myocardial infarction, preoperative inotropic or intraaortic balloon pump support, emergency surgery and significant pulmonary, endocrine, metabolic, or neurological diseases. All patients were receiving chronic β-adrenoceptor blocking drugs. The distribution of other medications affecting cardiovascular variables (calcium antagonists, ACE inhibitors, nitrates) was the same in all groups. All these other medications were stopped the evening before surgery. Patients were premedicated with lorazepam, administered together with their individual β-adrenoceptor blocking drug. Upon arrival in the operation room, patients received 7.5 mL kg−1 of a glucose-salt containing infusion and baseline haemodynamic data (T1) were obtained: heart rate (HR), systolic, mean and diastolic arterial pressure (SAP, MAP, DAP). During the induction of anaesthesia, this solution was administered to maintain cardiac filling pressures at their normal values (central venous pressure (CVP) between 6 and 12 mmHg). After preoxygenation and baseline haemodynamic measurements, a precurarization dose of pancuronium 20 μg kg−1 was administered to the patient. Immediately after this, both the alfentanil (Rapifen®, Janssen Pharmaceutica, Beerse, Belgium) or remifentanil (Ultiva®, GlaxoSmithKline, Zeist, The Netherlands) and propofol infusions were administered with the BD Master Diprifusor® TCI system (software developed by the University of Glasgow, UK).

Three groups of patients were compared: Group 1 (HDRG): a loading dose of remifentanil 2.5 μg kg−1 was infused over 4 min; thereafter, remifentanil was infused at a maintenance rate of 0.5 μg kg−1 min−1 throughout surgery. Group 2 (LDRG): a loading dose of remifentanil 2.5 μg kg−1 was infused over 4 min; thereafter, remifentanil was infused at a maintenance rate of 0.25 μg kg−1 min−1 throughout surgery. Group 3 (AG): a loading dose of alfentanil 50 μg kg−1 was infused over 4 min; thereafter, alfentanil was infused at a maintenance rate of 1 μg kg−1 min−1 throughout surgery.

The initial infusion setting for propofol on the Diprifusor® was a plasma concentration of 2 μg mL−1 to be reached in 4 min, thereafter the propofol infusion was set at a plasma concentration of 1 μg mL−1. If the patient was still responsive after this 4 min period, the Diprifusor® setting remained at 2 μg mL−1 until the patient became unresponsive; thereafter, the Diprifusor® was set at 1 μg mL−1. When patients became unresponsive to verbal commands (failure to open the eyes on three consecutive requests), additional pancuronium was given to facilitate endotracheal intubation. Thereafter, patients' lungs were ventilated with oxygen-enriched air without the addition of volatile anaesthetics.

Blood pressure and HR were registered at the following time intervals: T1: baseline; 5 min after insertion of the venous cannulae and radial artery cannula; T2: 4 min after the start of induction; T3: 3 min after endotracheal intubation; T4: 3 min after incision; T5: immediately before sternotomy; T6: 3 min after sternotomy; T7: immediately after heparinization; at the time of an haemodynamic intervention (see below) and 2 min after this intervention.

At the time of an alteration in study drug administration (opioid bolus dose or propofol target-control adjustment) and 2 min after alterations in study drug administration, an additional remifentanil bolus dose 1 μg kg−1 was administered in Groups 1 and 2. An additional bolus dose of alfentanil 25 μg kg−1 was administered in Group 3 if there were responses indicating inadequate anaesthesia with this infusion regimen: (a) systolic blood pressure 25 mmHg above preinduction control; (b) a HR above 90 beats min−1 in the absence of hypovolaemia (CVP <6 mmHg); (c) other autonomic signs such as lachrymation, flushing or sweating, somatic responses including swallowing, coughing, eye opening, grimacing or bodily movements.

If the first dose of opioid was not fully effective within 2 min, a second dose was administered. If there was no effect within 2 min, the target plasma concentration of propofol was increased in 1 μg mL−1 steps until haemodynamic control was achieved. Once the patient's response was considered adequately controlled, the propofol infusion was decreased to the 1 μg mL−1 setting, which was the original maintenance period infusion rate.

Any hypotension, defined as a SAP below 80 mmHg for more than 1 min, occurring during induction or during the maintenance of anaesthesia period, was treated with i.v. fluids, and, when indicated, incremental doses of ephedrine 2.5 mg i.v. and/or dopamine infusion. Bradycardia, defined as a HR < 40 beats min−1 for more than 1 min, was treated with atropine i.v.

Haemodynamic interventions were defined as: (a) administration of an extra volume load (250 mL of a colloid solution (Haemohes 6®, B. Braun Medical, Oss, The Netherlands)); (b) administration of ephedrine; (c) administration of dopamine; (d) administration of atropine.

Standard institutional hypothermic (28°C) cardiopulmonary bypass (CPB) with cold cardioplegic solution cardiac arrest was performed in all patients. Before weaning from CPB, patients were rewarmed to a rectal temperature of 35°C. After the patient had arrived in the intensive care unit (ICU), the sedative-analgesic infusions were continued for 4 h and then stopped. In Groups 1 and 2, an infusion of remifentanil 0.025 μg kg−1 min−1 and in Group 3 an infusion of alfentanil 0.1 μg kg−1 min−1 was administered. Fifteen minutes before cessation of the sedative-analgesic infusion, pirinitramide - a synthetic morphine derivative (analgesic potency in comparison with morphine (= 1) is 0.7-0.3 mg kg−1 i.v. was administered to the HDRG and LDRG, and placebo was administered to the AG in a blinded fashion [15]. Acetaminophen (paracetamol) 1 g rectally four times daily was started when the patient arrived in the ICU.

Propofol was continued in the ICU at a rate of 0.5 mg kg−1 h−1 and, if necessary, increased to achieve the desired level of sedation (Ramsay sedation score 3, 4 or 5) [16].

The criteria for initiating the weaning process were haemodynamic stability, normothermia (core temperature >36.5°C), chest tube drainage <100 mL h−1, no important dysrhythmias, absence of shivering and acceptable ventilatory parameters during synchronous intermittent mandatory ventilation (FiO2 ≤40%, peak end-expiratory pressure ≤5 cmH2O, PO2 ≥12 kPa).

When the patient was awake, oriented and cooperative and had started triggering the ventilator, the ventilator setting was switched to the pressure-support mode. If the patient's triggering was adequate, the pressure support was gradually decreased, maintaining ventilatory parameters within acceptable limits (tidal volume >5 mL kg−1, vital capacity >10 mL kg−1, respiratory rate >10 breaths min−1, minute ventilation >90 mL kg−1 min−1, FiO2 ≥40%, peak end-expiratory pressure ≤5 cmH2O, PO2 ≥12 kPa). If the patient could maintain these ventilatory parameters during 30 min of spontaneous respiration with the peak end-expiratory pressure set at 5 cmH2O, tracheal extubation was performed. Arterial blood-gas values were assessed before tracheal extubation, and at 30 min and 4 h after extubation. After this initial 4 h period in the ICU, pirinitramide 0.3 mg kg−1 intramuscularly (i.m.) was administered upon demand.

The primary efficacy variable of this study was the time of extubation: time from arrival in the ICU to extubation, and time from stopping the sedative infusion to extubation.

The secondary efficacy variables were:

• The haemodynamic stability associated with the anaesthetic management as measured by the haemodynamic data at T1, T2, T3, T4, T5, T6 and T7 and by the number of haemodynamic interventions in the pre-bypass period.

• The suppression of intraoperative responses to noxious stimuli in the pre-bypass period as assessed by the number of extra bolus doses of the opioid and by the number of alterations in propofol plasma concentration settings.

• The quality of post-sedation pain management as measured by the number of opioid administrations in the ICU until discharge to a step-down unit.

The number of patients required for this study was based on an expected difference in the time of extubation; 75 patients (25 patients per treatment arm) were recruited to detect a difference of at least 1 standard deviation (SD) between both HDRG and LDRG, and the AG at α = 0.025 and β = 0.10 (power = 0.9).

Statistical analysis

Extubation times were compared among the three groups with the Kruskal-Wallis test. The number of haemodynamic interventions, of opioid-sedative interventions, and of postoperative pirinitramide administrations were compared among the groups using Fisher's exact test. For the haemodynamic data, baseline-adjusted means with their standard errors were estimated using a mixed-model ANOVA with one common baseline value. The explanatory variables are: time (a within-patient factor with six levels: T2-T7), treatment group (a between-patient factor with three levels) and with the baseline (T1) measurement of the outcome variable considered as a co-variate. Also, the time-by-treatment interaction was tested.


Patient characteristics and surgical data are shown in Table 1.

Table 1
Table 1:
Patients' characteristics and surgical data in patients undergoing propofol anaesthesia with either high-dose remifentanil, low-dose remifentanil or alfentanil for coronary artery surgery (n = 25 patients).

Extubation time

No differences were observed between extubation times in the three groups (Table 2). Median extubation time after stopping the i.v. administration of sedative-opioid drugs was 300 min in the HDRG, 270 min in the LDRG and 270 min in the AG (P = 0.606).

Table 2
Table 2:
Extubation times.

Haemodynamic stability

Arterial pressure and HR measured at T1, T2, T3, T4, T5, T6 and T7 are shown in Figure 1. Significant time-by-treatment interactions were seen for SAP (P = 0.015), for MAP (P = 0.009) and for DAP (P = 0.006). No significant interaction was seen for HR (P = 0.489). Also, no constant treatment effect was seen for HR (P = 0.288). Time effects were highly significant (P > 0.01) for all haemodynamic variables considered. Figure 1 shows that HR remained stable in all groups throughout the study period. The induction of anaesthesia resulted in similar decreases in arterial pressure in the three groups. After endotracheal intubation, there was a similar, slight increase in arterial pressure in the various groups. Thereafter, arterial pressure remained stable and below baseline throughout the study period in HDRG; however, in LDRG and in the AG, arterial pressures increased and were higher than in HDRG from the start of surgery until the pre-cannulation surgical period.

Figure 1
Figure 1:
Haemodynamic effects of three different anaesthetic regimens in the pre-bypass period. Time points: 1: baseline; 2: 4 min after the start of induction; 3: 3 min after intubation; 4: 3 min after incision; 5: immediately before sternotomy; 6: 3 min after sternotomy; 7: immediately after heparinization. Note that the scale for HR is from 50 to 80 beats min−1 and that the scale for arterial pressure is from 50 to 160 mmHg. Data are the mean ± SD. *At these time points arterial pressures were significantly different between the three groups (P < 0.01).

The number of haemodynamic interventions in the pre-bypass period are shown in Table 3. Extra fluid was administered once in nine patients in HDRG, in five patients in LDRG and in four patients in AG. In one of the nine patients in the HDRG, a second bolus dose of extra fluid was given. Ephedrine 2.5 mg intravenously was given in three patients in HDRG, in three patients in the LDRG and in four patients in AG. Atropine 0.5 mg intravenously was used in one patient in AG. No dopamine was needed in any patient.

Table 3
Table 3:
The number of haemodynamic interventions in the pre-bypass period.

Atropine was administered for bradycardia after induction but before endotracheal intubation; most of the extra fluid and ephedrine was given in the preincision period in the absence of surgical stimulation.

The suppression of intraoperative responses to noxious stimuli in the pre-bypass period

The number of bolus doses of the opioid and of alterations in propofol-TCI settings are shown in Table 4. In HDRG, five patients required an extra bolus dose of the opioid. In LDRG, 16 patients were given an extra bolus of the opioid and in AG 15 patients (P < 0.015). An increase in the dose of propofol was necessary in one patient in HDRG, in four patients in the LDRG and in two patients in AG.

Table 4
Table 4:
The suppression of intraoperative responses to noxious stimuli in the pre-bypass period.

Post-sedation analgesic requirements

All patients remained overnight in the ICU. According to standard hospital procedures, patients who had undergone surgery in the morning hours were discharged from the ICU the next morning, patients who had undergone surgery in the afternoon were discharged from the ICU the following afternoon. Length of stay in the ICU was therefore similar in the three groups.

During the patient's stay in the ICU pirinitramide i.m. was given to the patient when judged indicated by the nursing staff (VAS >40 mm). In HDRG, 11 patients received one dose of pirinitramide during their stay in the ICU. In LDRG, 12 patients received one dose of the opioid and one of these 12 patients received two doses. In AG, one dose of the opioid was given to 18 patients (Table 5).

Table 5
Table 5:
Post-sedation analgesic requirements.

There were no significant differences in the incidence of ischaemic injury in the three groups. None of the patients reported intraoperative recall.


In the present study, no differences in extubation time were observed among the three different anaesthetic techniques for coronary artery surgery. The administration of the long-acting opioid pirinitramide 15 min before stopping the propofol-remifentanil infusion did not prolong extubation time as compared to the propofol-AG and provided good postoperative analgesia. However, in the remifentanil 0.5 μg kg−1 min−1 patient group, the suppression of haemodynamic responses to noxious stimuli was superior, as indicated by the significantly less additional opioid bolus doses required in this group. Also, in the remifentanil 0.5 μg kg−1 min−1 patient group, haemodynamic stability was superior, as indicated by the significant differences in blood pressures between the groups at the fixed measurement time points during surgery.

Total i.v. anaesthesia with a TCI of low-dose propofol has been described in cardiac surgery [17]. The optimal target plasma propofol concentration is affected by the opioid with which propofol is combined and has not yet been defined [18]. A propofol plasma concentration of 1.5-2 μg mL−1 has been used in cardiac surgery, without intraoperative recall [19].

Due to their pharmacokinetic profile, both alfentanil and remifentanil are very suitable opioids to combine with propofol for cardiac anaesthesia when a fast postoperative recovery from surgery and anaesthesia is desired. An alfentanil infusion of 1 μg kg−1 min−1, supplemented with additional boluses as necessary to the individual patient's requirements and immediately before surgical events that are known to be particularly stressful, has been described as a good anaesthetic technique for cardiac surgery. This technique was described as being probably superior to a technique which attempts to blunt all stress responses by the continuous administration of high infusion rates of the opioid without the use of boluses [3,20].

The optimal dose of remifentanil infusion during cardiac surgery is still controversial [21]. Infusions between 0.25 and 4 μg kg−1 min−1 have been described. Severe cardiovascular depression with remifentanil has been reported. Perhaps infusion rates too high (1-4 μg kg−1 min−1) for the surgical stimulus present, or the administration of bolus doses of remifentanil in the absence of surgical intervention could explain, at least in part, this observed haemodynamic instability. In the present study, haemodynamic effects upon induction of anaesthesia were similar in the three groups, and during induction and surgery severe cardiovascular depression was not observed. The minor decreases in arterial pressure were similar in the three groups and could easily be treated with extra fluid and small doses of ephedrine. The need for additional bolus doses of the opioid or sedative was significantly less in the HDRG (P = 0.015). Therefore, in the present study, the haemodynamic response to stressful events was better controlled with remifentanil at an infusion rate of 0.5 μg kg−1 min−1.

A major drawback of remifentanil, in this clinical setting, is the minimal residual analgesia in the postoperative period. In the present study, remifentanil or alfentanil in combination with propofol were administered up until 4 h after the patient's arrival in the ICU. It has been reported that there is a lack of opioid tolerance during remifentanil and alfentanil infusions for postoperative pain [22,23]. Pirinitramide or placebo was administered in a blinded fashion i.v. 15 min before cessation of the remifentanil infusion or of the alfentanil infusion, respectively. This technique provided good analgesia during the awakening and weaning period. Our hypothesis is that the administration of pirinitramide could explain, at least in part, why the anticipated difference in extubation time between remifentanil and alfentanil was not observed in the present study. Only in 11 patients in the HDRG one dose of pirinitramide i.m. was given during the stay in the ICU vs. 18 patients in the AG. Patients were questioned about their pain sensations by the nursing staff at predetermined regular intervals on a scale from 'no pain' to 'slight pain' to 'moderate pain' to 'severe pain' to 'very severe pain'. Pirinitramide i.m. was administered 'on demand' whenever the patient's pain sensation was between slight and moderate.

In the present study, a delay of 4h was chosen in the ICU before the cessation of the sedative-analgesic infusion to ensure the absence of bleeding, haemodynamic instability and hypothermia. Systemic normothermia with a core temperature of approximately 36.5°C is a key requirement for readiness of weaning and extubation in post-cardiac surgical patients.

This study was not part of a fast-tracking protocol after cardiac surgery, as we believe that efforts in fast tracking are better focused on the perioperative care of high-risk patients rather than on methods to further reduce the already short duration of postoperative ventilatory support in low-risk patients [24].

In conclusion, in this study no differences were found in extubation times between remifentanil/pirinitramide- and alfentanil-based total i.v. anaesthetic techniques using a TCI of propofol. Remifentanil-based cardiac anaesthesia was associated with superior suppression of intraoperative responses to noxious stimuli and resulted in superior haemodynamic stability. Good postoperative analgesia could easily be obtained by the administration of a long-acting opioid before cessation of the infusion of remifentanil. Further investigations are warranted to compare the use of intraoperative remifentanil and different strategies of postoperative pain management on postoperative recovery characteristics.


We would like to thank the CTICU nurses and the nurse anaesthetists for their help and participation in this study.


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© 2004 European Academy of Anaesthesiology