Fiberoptic intubation is a standard procedure for both the unanticipated and especially for the anticipated difficult airway and part of many airway algorithms [1-3]. Our method of fibreoptic intubation which was shown to be safe and time-efficient , consists of several steps: intravenous (i.v.) fentanyl, instillation of cocaine into lower nasal canals, translaryngeal anaesthesia of the upper airway, introduction of the fibreoptic instrument into the trachea, bolus administration of etomidate and advancing the tracheal tube after loss of consciousness. This method was originally developed from Kleemann in Germany  and slightly modified in our department (application of local anaesthetic through the cricothyroid membrane). Since its introduction in 1995 we have performed more than 6000 nasotracheal fibreoptic intubations with this technique. It has become an integral part of the ‘St Galler Airway Algorithm’ [6,7].
The concept of ‘awake’ fibreoptic intubation is often not clearly defined and influenced by personal preferences [8-11]. Either the entire procedure takes place under conscious sedation or only the introduction of the fibreoptic scope is performed in the awake patient followed by advancing the tube after induction of anaesthesia [4,12]. There are advantages and disadvantages to both approaches. With the conscious sedation approach the sedatives must be carefully titrated and both over-sedation or inadequate sedation can be harmful. One of the advantages of our approach is that it is strictly standardized. Most importantly, successful advancement of the tube through the nose and the glottis is facilitated in the anaesthetized patient. If, for any reason, the tube cannot be advanced into the trachea, it is very important that spontaneous breathing recovers rapidly. Our previous investigation  and continuous monitoring of the method suggest that the method is safe and in the rare cases where the tube cannot be advanced oxygenation could still be preserved.
Due to its popularity, propofol is also frequently used for fibreoptic intubation [13,14]. Therefore, it is tempting to replace etomidate with propofol in our algorithm. Propofol seems to be associated with more profound respiratory depression compared to etomidate [15,16]. Whether propofol can be used with the same margin of safety and therefore might replace etomidate in our airway algorithm, has not been investigated yet. The hypothesis of this prospective, randomized, double-blind investigation was that the time to recovery of spontaneous breathing after fibreoptic intubation is shorter with 0.2 mg kg−1 etomidate than with 2 mg kg−1 propofol.
Following local ethics approval and individual patient informed consent, it was planned to enrol 80 patients scheduled for elective ear nose and throat (ENT) surgery, ASA I-II with an anticipated difficult airway and aged up to 50 yr into the study. Age, height, weight and body mass index (BMI) were documented. No premedication was given on the day of surgery. The patients were monitored by continuous electrocardiogram (ECG), non-invasive arterial blood pressure (BP) at intervals of 3 min, pulse oximetry and a bispectral index monitor (BIS®, Version 3.12; Aspect Medical Systems Inc., Natick, MA, USA). Each patient received 2 mL 1% lidocaine i.v. for prevention of pain on injection of the induction agent.
Our method of fibreoptic intubation as part of an established airway algorithm has been described in detail previously . For this investigation we did not modify the algorithm except for more frequent verbal assessment of consciousness after the study drug was given. The procedure consisted of the following six steps:
- Injection of 2 μg kg−1 fentanyl i.v.
- Instillation of 0.25 mL 10% cocaine nasal drops into each nostril.
- Transcricoid injection of 2 mL 1% lidocaine for local anaesthesia of the larynx and proximal trachea.
- Preoxygenation with a firmly applied mask until FEO2 of 90% (capnomac oximetry). The FECO2 values at the end of preoxygenation were documented.
- Introduction of the fibreoptic scope (3.7 mm; Karl Storz GmbH & Co. KG, Tuttlingen, Germany) via the lower nasal canal into the trachea. Continuous insufflation of oxygen (4L min−1) into the respiratory tract via the working channel of the fibreoptic instrument.
- Injection of the study drug according to randomization.
- After loss of consciousness, advance of an armoured tracheal tube (ID 6.0 mm, Rüschelit® tracheal tube, Kernen, Germany) and check of its position.
The recommended dose of etomidate (Etomidate Lipuro®) is between 0.15 and 0.3 mg kg−1 and for propofol between 1.5 and 2.5 mg kg−1 . Etomidate Lipuro® is a white liquid and not clear; so the study could be blinded. The goal of the study was to assess the respiratory-depressant properties (side-effect) of the two drugs at equipotent doses with regard to hypnosis (desired effect) at the time of peak effect . Since no information was available from the literature about equi-hypnotic doses of etomidate and propofol we used induction doses which are established in our institution that is 0.2 mg kg−1 of etomidate and 2 mg kg−1 of propofol. Using BIS we attempted to confirm that the two doses were adequate and equi-hypnotic. By using propofol 2% and etomidate 0.2% the volume of either drug in the syringe was identical. The drugs were injected over 10 s.
The following times were documented, all measured from the beginning of the injection of the hypnotic: time to loss of consciousness, time to recovery of spontaneous breathing, the lowest BIS value and the time of the lowest BIS value. The patients were continuously asked to open their eyes and close them after injection of the study drug. The time at which the patient no longer responded to this command was documented as the time to loss of consciousness. If the BIS value increased to >60 (possibility of explicit memories), the patients were asked to breathe and open their eyes. The time of recurrence of spontaneous breathing (first movement of the diaphragm or capnography signal (Capnomac®; Datex, Helsinki, Finland) was documented. Decreases in BP >20% of baseline were treated with i.v. administration of 5 mg ephedrine hydrochloride (Ephedrin®; Streuli & Co. AG, Uznach, Switzerland). If the SPO2 dropped below 90% during the apnoea phase, the patient was immediately ventilated with 100% oxygen. All patients were asked about their last recall.
Due to the pharmacodynamic properties of the two hypnotics, we assumed a time difference from beginning of injection of the hypnotic to return of spontaneous breathing of 90 s. The prospective power analysis based on this (β = 0.2; α = 0.05) resulted in a required sample size of 40 patients per group. The patients were assigned to one of the two hypnotics according to an ungrouped randomization table . During the study we recorded very varied times of return of spontaneous breathing. Since we were worried about very long apnoea times, we stopped the ongoing study and performed unplanned interim analyses after 20 and 40 patients. Recruitment was stopped after 40 patients, because we obtained significant interim results.
The statistical calculations were performed using Statistica® (Statsoft Europe GmbH, Hamburg, Germany). The median results were compared using the U-test. A Bonferroni's test correction was applied because of the interim analysis after 20 patients. Differences were regarded as statistically significant if P < 0.025 with the Bonferroni's test correction. To demonstrate the comparability of the two groups of patients, which were of very different sizes due to unexpectedly abandoning further recruitment, a Χ2-test between the expected and actual number of patients was conducted. This showed no significant difference between the group sizes.
Fourty patients were studied. One patient in the propofol group had to be excluded from the evaluation because he erroneously received premedication. Due to the method of randomization and the premature discontinuation of the study, the etomidate group consisted of 25 patients and the propofol group of 14. The etomidate group had eight males and seventeen females, and the propofol group nine males and five females. There were no significant differences between the two groups of patients with regard to age, height and weight (Table 1).
The time to loss of consciousness (interquartile range [range]) was 27 s (23-32 [18-40]) in the etomidate group and 30 s (26-36 [24-42]) in the propofol group; the difference was not significant. The time to recovery of spontaneous breathing differed significantly: for etomidate 81 s (62-102 [0-166]), and for propofol 146 s (95-260 [65-315]); P = 0.001 (Fig. 1). The lowest BIS values in the two groups were not different (Fig. 2): 46 (39-63 [21-82]) in the etomidate group and 45 (37-50 [28-63]) in the propofol group. Figure 3 shows the time at which the lowest BIS value was reached in each group: for etomidate 58 s (51-68 [38-100]), and for propofol 90 s (52-125 [38-172]); P = 0.015.
The last recall of all patients was the invitation to open and close their eyes. There was no difference between the FECO2 values at the end of preoxygenation: the median (interquartile range [range]) in the etomidate group was 4.9 vol.% (4.6-5.2 [3.2-6.1]) and 5.1 vol.% (4.5-5.2 [4.2-5.9]) in the propofol group. The results for the haemodynamic variables showed no significant differences (Table 2). The lowest SPO2 was 88% in one patient in each group, and one patient in each group had a once drop in BP of >20% of baseline.
This prospective, double-blind, randomized study showed a significant prolongation of the time to recovery of spontaneous breathing for propofol (induction dose 2 mg kg−1) in contrast to etomidate (induction dose 0.2 mg kg−1). Therefore, propofol, even though more often used for fibreoptic intubation, is not able to replace etomidate as a key element of our safe and time-efficient technique of fibreoptic intubation. The method of advancing the tube just after loss of consciousness permits an easy introduction of the tube through the nose and an easy advancement through the glottis. From our point of view, this is a step towards safety, because advancing a tube during deep (but only short-lasting) hypnosis provides optimal conditions. This was clearly demonstrated in our own study in which passing the tube through the nose and/or the glottis only failed in 9 out of 955 nasotracheal fibreoptic intubations (0.9%) . These intubations were performed by 18 anaesthetists with different levels of experience in this technique. More than 92% of these intubations were successfully achieved within 3 min.
For management of the anticipated difficult airway the maintenance or rapid restoration of spontaneous breathing to avoid hypoxia is crucial. Therefore, awake intubation is an integral part of almost all guidelines for management of the anticipated difficult airway [3,20,21].
There is only general agreement that patients with a severely compromised airway - which is in most cases a clinical diagnosis - should be intubated awake without any sedation, not even for verification of the trachea via the fibreoptic instrument . But, in daily practice, the concept of fibreoptic intubation in the awake patient is not clearly defined in most cases, and is subject to marked institutional and personal preferences [8-11]. This means, that the entire procedure often takes place either under conscious sedation  or only the introduction of the fibreoptic scope is performed in the awake patient, but the tube is advanced after induction of anaesthesia . Therefore most common techniques for ‘awake’ fibreoptic intubation are a compromise between safety and practicability (acceptance, respectively).
If sudden complications occur, such as difficulty in advancing the tracheal tube through the nose or the glottis [4,22] or dislocation of the tube, rapid recovery of spontaneous breathing is very important. The time to the recovery of spontaneous breathing should therefore be as short as possible. This means that the induction agent plays a key role in the whole procedure.
In order to compare drugs concerning their respiratory depression potential it is important that the drugs are equipotent with regard to their primary effect (i.e. their level of hypnosis). Equipotent doses should cause the same effects at the time to peak effect . In our study we used BIS and although the lowest BIS values were similar in the two groups the time to maximum effect was different. Since this was achieved significantly earlier with etomidate than with propofol there are better conditions (deeper levels of hypnosis) at the right time of advancement of the tube through the nose and/or the glottis.
A number of factors influence and enhance the respiratory-depressant effects of propofol. Sarton and colleagues  investigated the influence of anaesthetics on the control of respiration, especially the effects of hyperventilation and hypocapnia on spontaneous breathing. According to their investigations, propofol generally leads to apnoea, especially if the patient is hypocapnic. Drummond and colleagues  reported the same results in investigations into the influence of hypocapnia and anxiety on the effects of etomidate and propofol on the occurrence of apnoea. Bouillon and colleagues  showed that propofol in clinical concentrations is a potent ventilatory depressant. In our investigation, we documented the FECO2 value at the end of the preoxygenation. There were no significant differences and the values in the etomidate and propofol groups were in the normal range. We were therefore able to rule out hypocapnia as a cause for the markedly longer apnoea time in the propofol group.
The effects of etomidate and propofol on haemodynamics have been investigated in numerous studies. In our study we could maintain cardiovascular stability. However, we only enrolled patients in ASA Classes 1 and 2 and aged up to 50 yr. Many authors have reported haemodynamic instability using propofol [24,25]. Very unfavourable outcomes, particularly following bolus induction with propofol in patients in ASA Classes 3 and 4, have been reported . Etomidate is known for its cardiovascular stability and is also recommended for induction in patients with severe coronary heart disease [24,25,27].
Our study has limitations. We did not investigate the influence of fentanyl on respiratory depression itself. But, by measuring the FECO2 at the end of preoxygenation (there was no difference between groups) a major clinical impact could be ruled out. Further, we cannot rule out any synergy between propofol and fentanyl, which is different to that between etomidate and fentanyl.
In conclusion, bolus injections of propofol 2 mg kg−1 led to significantly longer times to recovery of spontaneous breathing compared to bolus injections of etomidate 0.2 mg kg−1, and consequently carries a higher risk of hypoxia. Therefore, we still consider that etomidate is the drug of choice for our technique of nasotracheal fibreoptic intubation.
The study was supported by Karl Storz company GmbH & Co. KG, Tuttlingen, Germany: Availability of the fibreoptic instrument for study period.
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