The use of propofol and short-acting opioids may provide adequate conditions for laryngoscopy and tracheal intubation without the use of neuromuscular blocking agents [1-3]. Such a technique is of value in particular situations in which these drugs need to be avoided (myopathies, known allergic reactions) or in cases where succinylcholine is contraindicated (hyperkalaemia, burns, plasma cholinesterase deficiency, penetrating eye injury). Moreover, avoiding muscle relaxants when they are not required for the planned procedure may also reduce the likelihood of awareness during general anaesthesia.
Tracheal intubation facilitated with alfentanil followed by propofol is not new. Scheller and colleagues  compared various doses of alfentanil in combination with propofol 2 mg kg−1 and found that at least 40 μg kg−1 alfentanil was needed to achieve adequate conditions. Higher doses of alfentanil were not associated with better intubating conditions. Others have also reported satisfactory conditions for tracheal intubation using various combinations of propofol, alfentanil and lidocaine [2,3]. However, large doses of alfentanil may delay recovery and the return of spontaneous respiration after short surgical procedures, especially in the ambulatory setting.
Remifentanil is a fentanyl derivative with an ester linkage (3[-4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine] propanoic acid, methyl ester). It is a pure μ-agonist and rapid breakdown of the ester linkage by non-specific tissue and plasma esterases is responsible for its unique characteristics . It has a short half-life, and in contrast to alfentanil the time to recovery is not greatly influenced by the dose; the onset of effect is similar to that of alfentanil, i.e. 1-2 min [5,6]. Those clinical properties make remifentanil ideal for circumstances in which an intense narcotic effect of short duration is required. Thus, remifentanil may be more useful for tracheal intubation in patients undergoing ambulatory surgery because the large doses likely to be required are less likely to compromise a rapid recovery or return of spontaneous respiration. We designed a randomized, double-blind study and compared the intubating conditions and cardiovascular responses to induction and endotracheal intubation in pre-medicated patients receiving either alfentanil 40 μg kg−1 or remifentanil 2, 3 or 4 μg kg−1, followed by propofol 2 mg kg−1.
Approval from the Ethics Committee of Ege University Hospital and informed written consent from the patients were obtained. We studied 80 ASA I-II patients, aged 15-60 yr, presenting for elective ambulatory urological surgery. Exclusion criteria included: a history of drug or alcohol abuse, a gastro-oesophageal reflux or hiatus hernia, cardiovascular disease, reactive airway disease, a body mass index ≥30 kg m−2, allergies to any of the study drugs, administration of sedative or narcotic drugs in the previous 24 h, renal or hepatic impairment, or a Mallampati classification of airway anatomy above Class II .
Midazolam 0.03 mg kg−1 intravenously (i.v.) was given as premedication approximately 5 min before induction of anaesthesia. All patients were given physiological saline 0.9% 7 mL kg−1 i.v. before anaesthesia was induced. Patients were randomized to one of four study groups of 20 patients each to receive one of the following drugs in a double-blind manner: alfentanil 40 μg kg−1 (Group A40); remifentanil 2 μg kg−1 (Group R2); remifentanil 3 μg kg−1 (Group R3); and remifentanil 4 μg kg−1 (Group R4). A nurse who did not take part in the study prepared the coded test syringes. The nurse drew the alfentanil or remifentanil into a 10 mL syringe and filled it with saline to a total volume of 10 mL. All the anaesthetists were blinded to the nature of the opioid and the dose of remifentanil. Baseline heart rates (HR) and mean arterial pressures (MAP) were recorded. After preoxygenation for 2 min, atropine 0.01 mg kg−1 i.v. was given to all patients. The study drug was then injected over 90 s. Sixty seconds later, an infusion of propofol 2.0 mg kg−1 was given over 10 s. When the patient became unconscious, judged by the loss of the response to command and the loss of the eyelash reflex, manual ventilation of the lungs by a facemask was started. Forty-five seconds after propofol, the patient's postinduction vital signs were recorded. Ninety seconds after the propofol administration, laryngoscopy and tracheal intubation were attempted - endotracheal tube 7.0 mm (women) or 8.0 mm (men) - using a Macintosh size 3 laryngoscope blade. The ease of mask ventilation (easy = 1, difficult = 2, impossible = 3), jaw relaxation (complete = 1, slight tone = 2, stiff = 3, rigid = 4), laryngoscopy (easy = 1, fair = 2, difficult = 3, impossible = 4), vocal cord position (open = 1, moving = 2, closing = 3, closed = 4), and patient response to tracheal intubation (coughing, limb movement) and slow (5 s) inflation of the endotracheal tube cuff (none = 1, slight = 2, moderate = 3, severe = 4) were assessed by the intubating anaesthetist (IA). These criteria were used to score overall conditions at intubation as excellent (all criteria scored as 1), good (mask ventilation scored as 1, and the other criteria as 1 or 2) or poor (one of the criteria scored as 3). Patients who could not be intubated at the first attempt were given atracurium 0.5 mg kg−1 i.v. and tracheal intubation was completed. Adverse events such as laryngospasm, bronchospasm or chest wall rigidity - indicated by the difficulty to ventilate the lungs - and the administration of further drugs were also recorded.
Monitors included an automated arterial pressure cuff, electrocardiogram, peripheral pulse oximeter and capnometer. Control values of arterial pressure, heart rate and peripheral oxygen saturation (SPO2) were obtained before atropine (preinduction). Then the measurements were performed 45 s after the bolus dose of propofol was given (postinduction) and immediately after tracheal intubation (postintubation), 3 and 5 min after intubation. Ephedrine 6 mg was administered if MAP was reduced to >30% of baseline, and atropine 500 μg was administered if HR was <50 beats min−1. Anaesthesia was maintained with 0.5-1% isoflurane and 66% nitrous oxide in oxygen, and the lungs were ventilated to normocapnia. No further stimulation was applied to the patient during the study period.
χ2 Fisher's exact test was used for nominal variables. One-way ANOVA, post-hoc test/Duncan test were used for numerical variables. Repeated measures of ANOVA was used to analyse haemodynamic variables according to the model of two-factor experiments (group and time) with a repeated measure on one factor (time). If there was interaction between two factors, then for each group, a one-factor (time) experiment model with a repeated measure ANOVA was used. When appropriate, Duncan's test was used as the post-hoc method.
There were no demographic differences between the groups (Table 1). The patients were all male since the relevant surgery was for varicocele. The lungs of all patients could be ventilated via a facemask after induction; no patient had clinically significant rigidity. Jaw relaxation was judged complete in 85% of patients in Group A40, in 75% in Group R2, in 95% in Group R3 and in 95% in Group R4. Laryngoscopy was easy in 95% of patients in Group A4, in 80% in Group R2, in 95% in Group R3 or in 100% in Group R4. Because of closed vocal cords, intubation was judged impossible in seven patients in the Group R2 and in one patient in Group R3 - intubation was completed in these patients using atracurium (Fig. 1). Patients' response (coughing or limb movement) after tracheal intubation and slow inflation of the endotracheal tube cuff were judged to be excellent with no coughing in 45% of patients in Group A40, in 20% in Group R2, in 75% in Group R3 and in 95% in Group R4 (Fig. 2). Overall intubating conditions were significantly better (P < 0.05), and the number of patients showing excellent conditions (jaw relaxed, vocal cords open, no movement or coughing) was significantly (P < 0.05) higher in Group R4 compared with Groups A40 and R2. There was also a difference between Groups R2 and R3 with respect to the overall conditions of intubation (P < 0.05) (Fig. 3).
There were no differences between groups with respect to changes in MAP. After the induction of anaesthesia, the decrease in MAP was significant (P < 0.05) in all groups. Compared with baseline values, MAP remained at a significantly lower level throughout the investigation in all groups (Fig. 4). There was a significant difference between groups with respect to changes in HR. A difference (Duncan test) was shown between Groups R2 and R3. There was a significant difference in time factor, and the time-group interaction was also significant, so the effect of time on each factor was evaluated separately. After induction of anaesthesia, HR decreased significantly from preinduction values (P < 0.05) in all groups. Compared with baseline values, HR remained significantly lower throughout the investigation in Groups A40, R3 and R4. The HR in Group R2 patients returned to baseline values 3 min after tracheal intubation (Fig. 4). No patient needed treatment for bradycardia or hypotension. Peripheral oxygen saturation remained at preinduction values (97-98%) in all groups throughout the investigation.
The results suggest that remifentanil 4 μg kg−1 - administered with propofol 2 mg kg−1 - provided good or excellent conditions in all premedicated patients with a favourable airway anatomy. Remifentanil 4 μg kg−1 offered a significant improvement in overall conditions for intubation compared with either alfentanil 40 μg kg−1 or remifentanil 2 μg kg−1. Seven patients (35%) could not be intubated with remifentanil 2 μg kg−1, but increasing the dose to 3 or 4 μg kg−1 led to excellent intubating conditions in 75 and 95% of patients, respectively. Alfentanil 40 μg kg−1 provided excellent conditions in 45% of the patients. Based on its analgesic efficacy and respiratory depressant effects, remifentanil has been estimated to be 20-30 times more potent than alfentanil after a single bolus dose . A larger dose of alfentanil might have provided as good a condition for intubation as remifentanil 4 μg kg−1. However, a higher dose might be quite unsuitable in the ambulatory setting. Remifentanil, with its very rapid elimination, has the advantage of a greater margin for dosing, since the time for recovery is not greatly influenced by the dose .
Stevens and Wheatley  compared different doses of remifentanil in combination with propofol 2 mg kg−1 and reported that remifentanil 3-4 μg kg−1 provided satisfactory intubating conditions more reliably than remifentanil 1-2 μg kg−1. We used the same study design and obtained similar results. In another study, which included a standard comparator group receiving alfentanil, Kleomola and colleagues  reported that administration of remifentanil 4 μg kg−1 in combination with propofol 2.5 mg kg−1 offered significant improvements in overall conditions compared with alfentanil 30 μg kg−1. They found that tracheal intubation was judged impossible in 20, 25 or 5% of patients receiving alfentanil 30 mg kg−1, remifentanil 3 mg kg−1 or remifentanil 4 μg kg−1, respectively. In contrast, tracheal intubation was possible in all patients given alfentanil 40 μg kg−1 in our study, in which the higher dose suggested by Scheller and colleagues  was used. We found that tracheal intubation was impossible in 35% of those receiving remifentanil 2 μg kg−1 and in 5% of those receiving remifentanil 3 μg kg−1. The study drug was injected over 30 s and tracheal intubation was attempted 60 s after propofol 2.5 mg kg−1 in Kleomola and colleagues . Despite the differences in the study design, our results are in accordance with those of Kleomola and colleagues, which showed that the best method was the combination of remifentanil 4 μg kg−1 with propofol.
In our study, good or excellent intubation conditions were obtained in 65% of the patients using remifentanil 2 μg kg−1, whereas the same incidence rate was 75% in Stevens and Wheatley . In contrast, satisfactory intubating conditions were demonstrated in 90% of patients after remifentanil 2 μg kg−1 - combined with propofol 2 mg kg−1 - by Woods and colleagues . In another study, they found that overall intubating conditions were acceptable in 80% of patients given remifentanil 2 μg kg−1. Overall, intubating conditions were assessed as either unacceptable or acceptable in those studies [10,11]. Considering laryngoscopy, intubation and skin incision, tracheal intubation was the strongest stimulus . On this basis, it is important to produce adequate conditions for laryngoscopy, but preventing subsequent coughing or responses after tracheal intubation is more important. Although not statistically significant, excellent intubation conditions were achieved with remifentanil in doses of 3 μg kg−1 and 4 μg kg−1 in 75 and 95% patients, respectively. This suggests that 4 μg kg−1 is the appropriate dose of remifentanil in this clinical setting.
Alexander and colleagues suggested a higher dose of remifentanil, 5 μg kg−1. The study design differed significantly from above-mentioned studies as well as our own, since remifentanil was given as a rapid bolus and tracheal intubation was performed 60 s after a bolus of remifentanil. Muscle rigidity may be associated with large doses of potent opioids . It is also recommended that the dose of remifentanil be given over not less than 30 s. In Stevens and Wheatley  and Woods and colleagues , tracheal intubation was performed 90-120 s after remifentanil, a timing that is crucial in order for peak plasma and effector site concentrations to be reached . We used the same study design as Stevens and Wheatley  and administered remifentanil as a slow infusion over 90 s. No patient exhibited signs of opioid-induced muscular rigidity in our study. Alfentanil 40 μg kg−1 i.v. followed by propofol 2 mg kg−1 i.v. did not cause clinically significant rigidity in our study and this finding is in accordance with the results of previous studies . A slow rate of administration and prior administration of a benzodiazepine are effective in preventing opioid-induced muscle rigidity.
The study design of previous investigations that compared various doses of alfentanil and remifentanil with respect to intubation conditions and haemodynamic response - without using neuromuscular blocking agents - differ from one another in several respects. Such differences were the actual doses of the short-acting opioid and propofol, duration of the infusion of the study drugs and timing of the tracheal intubation. Moreover, in some studies, patients were given i.v. infusions for hydration or anticholinergic drugs [8,9]. Mean arterial pressure and HR decreased after induction of anaesthesia in all groups; however, these decreases were tolerated in these healthy hydrated patients and no further intervention was needed in our study. In Grant and colleagues , two of 20 patients receiving remifentanil 2 μg kg−1 required ephedrine to support the circulation. In Stevens and Wheatley , patients were given physiological saline 0.9% 7 mL kg−1 before the induction of anaesthesia and no patient required treatment for bradycardia or hypotension. In Thompson and colleagues , in the absence of a concurrent vagolytic agent, remifentanil was associated with bradycardia or hypotension, or both, in five of 10 patients compared with one patient who received remifentanil and glycopyrrolate. Their results suggest pretreatment with a vagolytic agent may be required if the incidence rate of bradycardia and hypotension is to be minimized. Kleomola and colleagues  considered the administration of an anticholinergic agent necessary, which might have contributed to the observed stability of HR in their study. In our study, we also considered giving atropine since remifentanil is well known to cause bradycardia. In accordance with the results of two studies [8,9], concomitant administration of the anticholinergic drug, atropine, as well as intravenous fluids beforehand might have resulted a better haemodynamic outcome in our study.
Sebel and colleagues  observed that decreases in HR after remifentanil were independent of the given dose - escalating from 2 to 30 μg kg−1. The authors suggested that prior treatment with glycopyrrolate might have masked a dose-related effect. In accordance with the results of this study , HR was consistently reduced in the period before and after induction despite atropine and the varying doses of remifentanil in our study. However, this decrease did not necessitate any treatment. Note that the routine use of atropine to mask the side-effects of high-dose remifentanil also has its own side-effects because of the blockade of muscarinic cholinergic receptors in the periphery and in the central nervous system. Peripheral effects, e.g. a dry mouth, may be irritating, but atropine has a mild antisialagogue effect compared with glycopyrrolate and scopolamine . Central nervous system side-effects have been seen with relatively large doses of atropine, e.g. 1-2 mg . We did not observe tachycardia in our study, but older individuals may not tolerate the side-effects of muscarinic blockade.
This technique may be a useful alternative when the use of muscle relaxants is contraindicated. It is also advantageous in cases where tracheal intubation is necessary, but neuromuscular block is not required to facilitate surgical access. Avoiding muscle relaxants when they are not required for the planned procedure may prevent the potential complications of their use, misuse and antagonism. When compared with patients receiving no 'reversal' agents, patients receiving neostigmine have an increased frequency of postoperative nausea and vomiting . When succinylcholine is not used, the clinician may avoid its potential to cause associated myalgia, as well as the less common and more serious complications (masseter spasm, malignant hyperthermia and disturbances of cardiac rhythm). We believe this method of tracheal intubation is very important since excessive or unnecessary neuromuscular blockade is one of the factors contributing to awareness under general anaesthesia . The use and misuse of muscle relaxants is often thought to contribute to awareness. The administration of muscle relaxants during balanced anaesthesia is often routine, albeit often unnecessary, and it removes important motor signs of awareness. Limiting the use of muscle relaxants to appropriate indications and not using them as substitutes for anaesthesia, or to prevent movement in all patients, should help one to prevent awareness . Grant and colleagues  suggested that this technique could also be advantageous in the event of a prolonged difficult intubation that was predicted or unexpected, since it could allow assessment of the airway by laryngoscopy. The decision whether or not to awaken the patient or proceed could then be made.
However, this technique cannot be recommended for elderly, compromised patients, or in those with clinically significant cardiovascular or cerebrovascular disease. The decrease in arterial pressure might not be well tolerated in those less healthy patients. It should also be noted that tracheal intubation without neuromuscular block can be hazardous in some situations. If laryngoscopy and tracheal intubation are attempted under inadequate conditions, trauma to the airway or inadequate ventilation of the lungs can result. The advantages and disadvantages of this technique should be weighed for each individual patient.
We conclude that remifentanil 4 μg kg−1 in combination with propofol 2 mg kg−1 provide good-to-excellent conditions for endotracheal intubation and allow successful tracheal intubation in all patients so long as they have a favourable airway anatomy. This combination of drugs prevents the cardiovascular response to tracheal intubation without marked cardiovascular depression. Better hydration beforehand and concomitant administration of an anti-cholinergic drug, atropine, might have resulted in a better haemodynamic outcome in our study.
1. Scheller MS, Zornow MH, Saidman LJ. Tracheal intubation without the use of muscle relaxants: a technique using propofol and varying doses of alfentanil. Anesth Analg
2. Beck GN, Masterson GR, Richards J, Bunting P. Comparison of intubation following propofol and alfentanil with intubation following thiopentone and suxamethonium. Anaesthesia
3. Davidson JA, Gillespie JA. Tracheal intubation after induction of anaesthesia with propofol, alfentanil and IV lidocaine. Br J Anaesth
4. Thompson JP, Rowbotham DJ. Remifentanil - an opioid for the 21st century. Br J Anaesth
5. Glass PSA, Hardman D, Kamiyama Y, et al.
Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (G187084B). Anesth Analg
6. Egan TD, Minto CF, Hermann DJ, et al.
Remifentanil versus alfentanil: comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. Anesthesiology
7. Mallampati S, Gatt S, Gugino LD, et al.
A clinical sign to predict difficult tracheal intubation: a prospective study. Can J Anaesth
8. Stevens JB, Wheatley L. Tracheal intubation in ambulatory surgery patients: using remifentanil and propofol without muscle relaxants. Anesth Analg
9. Kleomola UM, Mennander S, Saarnivaara L. Tracheal intubation without the use of muscle relaxants: remifentanil or alfentanil in combination with propofol. Acta Anaesthesiol Scand
10. Woods AW, Grant S, Davidson JA. Duration of apnoea with two different intubating doses of remifentanil. Eur J Anaesthesiol
11. Grant S, Noble S, Woods A, Murdoch J, Davidson JAH. Assessment of intubating conditions in adults after induction with propofol and varying doses of remifentanil. Br J Anaesthesia
12. Kazama T, Ikeda K, Morita K. Reduction by fentanyl of the Cp50 values of propofol and hemodynamic responses to various noxious stimuli. Anesthesiology
13. Alexander R, Olufolabi A, Booth J, El Moalem H, Glass PS. Dosing study of remifentanil and propofol for tracheal intubation without the use of muscle relaxants. Anaesthesia
14. Woods AW, Grant S. Remifentanil and intubating conditions. Anaesthesia
15. Thompson JP, Hall AP, Russell J, Cagney B, Rowbotham DJ. Effect of remifentanil on the haemodynamic response to orotracheal intubation. Br J Anaesth
16. Sebel PS, Hoke JF, Westmoreland C, et al.
Histamine concentrations and hemodynamic responses after remifentanil. Anesth Analg
17. Moss J, Renz CL. The autonomic nervous system. In: Miller RD, ed. Anesthesia,
5th edn. Pennsylvania, USA: Churchill Livingstone, 2000: 564-565.
18. Ding Y, Fredman B, White PF. Use of mivacurium during laparoscopic surgery: effect of reversal drugs on postoperative recovery. Anesth Analg
19. Bailey PL, Egan TD, Stanley TH. Intravenous opioid anaesthetics. In: Miller RD, ed. Anesthesia,
5th edn. Pennsylvania, USA: Churchill Livingstone, 2000: 273-376.