Awake nasotracheal fiberoptic intubation is an established method of securing a difficult airway. Awake fiberoptic intubation requires a safe sedation scheme that blunts airway reflexes, maintains spontaneous ventilation, and provides conscious sedation. Short-acting and therefore easily titratable analgesics are excellent choices for the intensely stimulating, but usually brief airway manipulation during fiberoptic nasotracheal intubation. Remifentanil, an ultra-short-acting opioid, undergoes a rapid metabolism by blood and tissue nonspecific esterases, which results in lack of drug accumulation and easily titratable analgesia (1). Previous studies have shown the safety and efficacy of remifentanil as an IV adjunct to local anesthesia for treating pain and patient discomfort during many surgical procedures (2,3). Only one recently published investigation compared remifentanil with the commonly used combination of fentanyl and midazolam for awake fiberoptic intubation (4). Two further case reports reported successful management of fiberoptic tracheal intubation with remifentanil-induced analgesia (5,6). Different remifentanil dosage regimens used for awake fiberoptic intubation were not compared until now.
In this study, our aim was to determine an appropriate remifentanil dosage regimen required for awake nasotracheal fiberoptic intubation that provides adequate analgesia and airway reflex suppression under sufficient spontaneous ventilation. The effects of two different dosage regimens of remifentanil on patient comfort and sedation, hemodynamic stability, intubating conditions, and recall of the procedure were compared.
After institutional ethics committee approval and written, informed consent, we studied 24 patients, aged 19–70 yrs, ASA physical status I–II, in a prospective, randomized, double-blinded manner. All patients underwent elective nontumor surgery of the cervical spine, where hyperextension is considered a risk. Exclusion criteria were obesity >30% above ideal body weight, gastroesophageal reflux, uncontrolled hypertension, ischemic heart disease, reactive airway disease, hepatic or renal disorders, a history of drug abuse and a long term use of benzodiazepines or tricyclic antidepressants. Patients were also excluded if they had apparent airway abnormalities [Mallampati score III–IV (7), thyromental distance under 6 cm], or a history of laryngopharyngeal surgery. All patients fasted for at least 6 h before surgery. Each patient received at least 500 mL of Ringer’s solution IV 1 h before surgery. Usual monitoring was used. Cannulation of the radial artery of the nondominant arm was performed under local anesthesia for blood pressure monitoring and for blood collection during the study period. Arterial blood samples for blood gas analysis were drawn before and after every 2 min throughout airway manipulation.
All patients were premedicated with midazolam 0.05 mg/kg IV and glycopyrrolate 0.2 mg IV 15 min before start of the study.
Before airway manipulation, every patient received topical anesthesia of the airway structures: the nasal mucosa of both nostrils was prepared with a vasoconstrictor (oxymetazoline) and lidocaine 2% spray.
Patients were randomly assigned to the following study groups using a sealed envelope technique: remifentanil 0.75 μg/kg administered over 30 s, followed by a continuous infusion of remifentanil 0.075 μg · kg−1 · min−1 (Group L), or remifentanil 1.5 μg/kg administered over 30 s, followed by a continuous infusion of remifentanil 0.15 μg · kg−1 · min−1 (Group H). The bolus dose of remifentanil as well as the continuous infusion were administered via a continuous infusion pump. Solutions of remifentanil hydrochloride (reconstituted to a concentration of 100 μg/mL) were prepared and administered by a co-investigator imperceptibly for the endoscopist.
Airway manipulation was started 60 s after administration of the bolus dose: Both nostrils were probed with nasopharyngeal tubes (covered with lidocaine jelly 2%) of increasing sizes and the more patent nostril was chosen for intubation, the other nostril was used for oxygen insufflation (3–4 L/min).
The largest tube was left in place for at least 1 min. After removal of the nasopharyngeal tube, a nasotracheal spiral tube (7- to 7.5-mm diameter in men, 6- to 6.5-mm diameter in women; Mallinckrodt Medical, Athlone, Ireland) was guided into place with the bronchoscope. After orientation and localization of the laryngo-epiglotteal region, 5 mL of lidocaine 2% was sprayed on the supraglottic region through the working channel of the bronchoscope. Additionally, 2 mL of lidocaine 2% was administered on the vocal cords immediately before passage.
After successful passage of the tube through the vocal cords and after identification of the carina, the tube was positioned approximately 3 cm above the carina and the cuff inflated. Propofol 1–2 mg/kg IV was administered to induce general anesthesia and establish mechanical ventilation.
The Observer’s Assessment of Alertness/Sedation Scale (OAA/S) (8) was used to assess sedation by measuring four component categories, and the summed score was assigned (Table 1). OAA/S was determined before start of study medication and every 2 min during airway manipulation.
On the first postoperative day, an investigator blinded to the protocol evaluated the patients on their recall and level of discomfort during fiberoptic intubation. The visual analog scale (VAS) score from 0 to 100 described “no recall” to “perfect recall” and “no discomfort” to “extreme discomfort.”
Jaw relaxation, vocal cord movement, coughing, and limb movement were judged by the intubating investigator, using a modified version of the intubating conditions score described by Woods et al. (9) and Grant et al. (10). According to the study protocol, “laryngoscopy” was excluded.
Normally distributed metric variables (test of normality: Shapiro-Wilk) were tested with the t-test for independent samples with correction for heteroscedasticity. Ordinal variables or not normally distributed metric variables were analyzed with the Mann-Whitney U-test. Fisher’s exact test for 2 × 2 tables was used. All tests are two-tailed with a confidence level of 95% (P < 0.05). No adjustments for the P values (such as Bonferroni corrections) were made, therefore all P values are only descriptive. Consequently, significances of P < 0.05 reflect the probability of differences that can at best be used for generating hypotheses, but do not prove them.
Awake nasotracheal fiberoptic intubation could be performed in 22 of 24 patients. Transnasal passage of the tube was not possible in two patients because of anatomic variations. From the remaining 22 patients, 10 were assigned to Group L and 12 to Group H. Both study groups were similar with respect to demographic and baseline physiologic characteristics (Table 2). Sedation was sufficient in all patients: OAA/S sum score decreased from 20 (baseline) to a minimum of 11 (after 8 and 10 min of continuous remifentanil infusion) in both groups. All patients were able to cooperate during airway manipulation (OAA/S sum score >10). Administration time and dosage of remifentanil led to increasing differences of the OAA/S values between groups. Consequently, patients in Group H were sedated more profoundly 8 and 10 min after start of study medication (P = 0.032 and P = 0.021, respectively) (Fig. 1).
Three patients (30%) in Group L had no recall (VAS 0) 24 h after intubation; slight memories (VAS 1–20) were described by 4 patients (40%). Clear but not unpleasant memories (VAS 20–50) were described by the remaining 3 patients (30%).
Seven patients (58.3%) in Group H had no recall and the remaining patients described only slight memories. Patients in Group H had less recall on airway manipulation (P = 0.032).
Four patients (40%) in Group L and 3 patients (25%) in Group H described little discomfort (VAS 10–40) during fiberoptic intubation. No significant difference was observed between groups. No patient recalled pain in either group.
Jaw relaxation, vocal cord movement, and limb movement did not differ between groups. Coughing was observed more often in Group L patients (P = 0.044) (Fig. 2).
There was no difference in systolic, diastolic, and mean arterial blood pressure, as well as heart rate between groups. These variables did not differ significantly from baseline values.
A dose-dependent potentiation of remifentanil’s depressant effect on respiratory rate was observed in our patients. Paco2 was significantly higher in patients in Group H, but did not exceed 61 mm Hg (Fig. 3). Oxygenation was sufficient in all patients throughout the whole study period (Spo2 >95%). No bradypnea (respiratory rate <8 breaths/min) or apnea was observed in our patients.
Several medications have been used for sedation and analgesia during awake nasotracheal fiberoptic intubation. The combination of fentanyl (11) and alfentanil (12) supplemented with diazepam, as well as fentanyl supplemented with propofol (13), have been investigated. The most widely used sedation-analgesia technique seems to be fentanyl and midazolam carefully titrated in small bolus doses (14).
A short-acting and therefore easily titratable opioid such as remifentanil is an excellent choice for the intensely stimulating, but usually brief, airway manipulation during fiberoptic nasotracheal intubation. Remifentanil’s short context-sensitive half-life and its rapid plasma-effect site equilibration make the degree of analgesia precisely controllable. Three publications described the use of remifentanil for awake fiberoptic intubation: two case reports described successful awake, fiberoptic tracheal intubation with remifentanil analgesia in patients in whom orotracheal intubation was not feasible because of severe inflammation of the head and neck (5,6). In one case, remifentanil was administered at a continuous rate; in the other case, the remifentanil dose was adjusted according to patient needs. In both cases, the remifentanil doses were larger than in our study. A remifentanil bolus was not administered in either case.
Furthermore, remifentanil was recently compared with fentanyl supplemented with midazolam for awake fiberoptic intubation (4). In this study, remifentanil was increased during airway manipulation: 0.1 μg · kg−1 · min−1 was administered during the painful and uncomfortable insertion of nasopharyngeal tubes. Only then was remifentanil further increased to 0.25 and 0.5 μg · kg−1 · min−1 during fiberoptic instrumentation. The mean total dose of remifentanil was 3.6 ± 1.4 μg/kg administered over 4.4 ± 1.4 minutes. The authors found that remifentanil seemed to improve intubating conditions and quality of fiberoptic intubation in comparison to the conventional fentanyl/midazolam regimen. In view of these results, we did not include a control group treated with a commonly used sedative medication. In our study, the mean total dose of remifentanil was 1.46 μg/kg in patients receiving small-dose remifentanil and 2.92 μg/kg in patients receiving large-dose remifentanil administered over approximately 10 minutes. Therefore, when compared with the study by Puchner et al. (4), our recommended remifentanil dosage regimen required less than half the amount of remifentanil administered over double the time.
To rapidly achieve optimal analgesia, continuous infusion of remifentanil is often initiated by a bolus dose. However, ventilatory control is impaired even after the administration of remifentanil 0.5 μg/kg IV over 5 seconds (15). To avoid this situation, the manufacturer recommends that a bolus dose should be administered over 30 seconds. In contrast to previous works dealing with awake nasotracheal intubation, we decided to administer a bolus of remifentanil to our patients, because the nasopharyngeal airway insertion seems be the most painful part of the procedure. The largest effect-site concentration after a bolus dose of remifentanil correlates certainly with the most intense analgesia, but also with the highest possibility of respiratory depression.
In our study, the highest Pco2 was 61 mm Hg measured in patients receiving large-dose remifentanil. Although respiratory impairment did not result in a critical condition and sufficient spontaneous ventilation was maintained in these patients, we recommend the use of a small-dose remifentanil regimen, which did not impair ventilation for routine clinical use.
The use of remifentanil alone without the addition of midazolam fails to provide sufficient sedation (2). For this reason, we decided to add midazolam to improve the quality of sedation in our patients. It was beyond the aim of our study to elucidate the effects of midazolam on remifentanil. However, we used the same dose of midazolam in both study groups. Furthermore, we administered glycopyrrolate 0.2 mg IV to our patients to reduce secretions during fiberoptic intubation and to avoid bradycardia and hypotension. These effects of remifentanil are often seen after a bolus dose in the absence of a vagolytic drug (16,17).
The aim of our study was, contrary to all previous studies, to determine an appropriate remifentanil dosage regimen required for awake nasotracheal fiberoptic intubation. Ideally, the adequate dosage regimen should provide patient comfort and sedation as well as prevention from negative recall of the procedure. Furthermore, it should ensure good airway reflex suppression under sufficient spontaneous ventilation, hemodynamic stability, and adequate intubating conditions. Our data suggest that both dosage regimens ensured patient comfort and sedation, although patients receiving large-dose remifentanil were sedated more profoundly and had less recall than patients receiving small-dose remifentanil. Despite the fact that coughing was observed more often in patients receiving small-dose remifentanil, both dosage regimens blunted airway reflexes sufficiently and ensured adequate intubating conditions. Hemodynamics remained stable in all patients during airway instrumentation. Nevertheless, we found that the small dose of remifentanil fulfills all desired criteria and that the double amount of remifentanil, as administered to Group H patients, did not result in any additional benefit. We therefore recommend remifentanil 0.75 μg/kg administered over 30 seconds followed by continuous infusion of 0.075 μg · kg−1 · min−1, supplemented with midazolam 0.05 mg/kg for awake nasotracheal fiberoptic intubation.
The authors thank Wolfgang Schimetta, PhD, Institute of Systems Sciences, University of Linz, Austria, for his technical support with statistical analysis.
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