Awake intubation is the technique most commonly chosen in patients with a difficult airway,1 but gag, cough, and laryngospasm in response to intubation can be troublesome during the procedure. Rarely will awake patients allow the airway to be instrumented without adequate airway topical anesthesia. Thus, effective airway topical anesthesia is mandatory for the comfort of the awake patient and subsequent successful instrumentation.2 As a cornerstone in managing difficult airways,3 the fiberoptic bronchoscope (FOB) is often used to apply local anesthetics to the airway in a “spray-as-you-go” fashion. This method can provide flexibility in selectively anesthetizing the airway, and is a suitable choice for most awake intubations.4 Adequate airway topical anesthesia generally determines the ease and comfort of awake fiberoptic intubation.3
When the spray-as-you-go technique is used for airway topical anesthesia, 2%5,6 and 4%7,8 solutions of lidocaine are commonly selected. Although adequate airway topical anesthesia with minimum concentration and dosage of local anesthetics is important for patient safety,9 no report in the literature has objectively compared the safety and efficacy of 2% and 4% lidocaine during airway topical anesthesia with the spray-as-you-go technique. Therefore, this randomized, double-blind, clinical study was designed to determine whether there were clinically relevant differences in the safety and efficacy of airway topical anesthesia between 2% and 4% lidocaine used by a spray-as-you-go technique in patients with a difficult airway.
After local research ethics committee approval, ASA physical status I-III adult patients scheduled to undergo surgery with general anesthesia between October 2007 and January 2008 were recruited. Patient characteristics such as age, gender, weight, and height were noted. Before surgery, all patients received a full-scale airway evaluation. Patients were included in this study if a staff anesthesiologist not involved with the study determined that they would require an awake fiberoptic orotracheal intubation (FOI) based on clinical predictors or history of difficult intubation. These predictors included a history of multiple or failed laryngoscopy, Mallampati class 3 or 4 with a history of severe snoring on sleeping in the supine position, thyromental distance <60 mm (corresponding to an average distance of 3 finger breadths), limited mouth opening with interincisor distance <30 mm and head and neck movement <80°.10 The exclusion criteria were patient refusal, inability to cooperate with adequate airway assessment, history of hepatic, renal and coagulation diseases, respiratory tract pathology, pregnancy, patients receiving long-term opioids or sedatives, and risk of regurgitation-aspiration.
Fifty-two patients were enrolled into the study over a 4-mo period. During the preoperative visit, the details of the fiberoptic techniques for airway topical anesthesia and awake intubation were explained, and informed patient consent was obtained. Patients did not receive any premedication and were fasting for at least 6 h. Perioperative monitoring included a 3-lead electrocardiogram, pulse oxymetry and noninvasive arterial blood pressure (BP) and capnography after tracheal intubation. In the preoperative holding area, a 20-gauge IV cannula was inserted, and atropine 10 μg/kg was administered IV for its antisialogogue effect.2 An 18-gauge indwelling IV cannula was also inserted into the antebrachial or antecubital vein on the contralateral arm for serial plasma lidocaine level sampling. In all patients, the posterior pharynx was anesthetized with 5 intraoral sprays using 10% lidocaine (Xylocaine® 10% oral spray, Astra® Pharmaceutical Products, Inc, Westborough, MA); each depression of the release button delivered 0.1 mL (10 mg). In the operating room, patients received fentanyl 1.5 μg/kg IV and midazolam to achieve anxiolysis as defined by an Observer’s Assessment of Alertness/Sedation Scale (OAA/S) of 14–16.11 After initiation of sedation, patients breathed 100% oxygen via a facemask at any interval of airway manipulations. If the OAA/S was <14, or the patient was not cooperative due to excessive sedation, the patient was excluded from this study.
A 1.1 mm single-orifice epidural catheter was threaded through the suction channel of a FOB with an outer diameter of 3.1 mm (Olympus LF-DP, Tokyo, Japan).2,4 An anesthesiologist who had prepared the treatments and was not involved in data recording attached a Luer-locked syringe prefilled with the study drugs to the proximal sleeve of the epidural catheter. Both airway topical anesthesia and awake orotracheal intubation using the FOB were performed by the staff anesthesiologists experienced in the two techniques and highly trained in difficult airway management. They had performed awake FOI in more than 100 patients with difficult airways before this study.
After the desired level of sedation was achieved, patients were randomly assigned to 1 of 2 study groups (n = 26 per group) to receive 2% lidocaine (Group 1) or 4% lidocaine (Group 2) by a spray-as-you-go technique with the FOB, in a double-blind manner. Randomization was performed using computer-generated random numbers in sealed envelopes. The FOB operators and the investigators were blinded to the lidocaine concentration. Before airway topical anesthesia, the patient was positioned supine with the head and neck in a neutral position. An oral airway was inserted into the oropharynx and the jaw was lifted by an assistant. Airway topical anesthesia was achieved with the spray-as-you-go technique previously described.2–4 The FOB was inserted through the oral airway into the hypopharynx and its tip was first positioned at the epiglottic vallecula and then in the vicinity of the piriform recess. Three milliliters of the study drug were slowly sprayed in 3 aliquots of 1-mL onto these supraglottic areas and the FOB was then removed. After 5 min, this procedure was repeated. After another 5-min waiting period, the FOB was reinserted to expose the glottis and 0.5 mL of the study drug was sprayed into the laryngeal area. This procedure was repeated at 3-min intervals until adequate anesthesia of the vocal cords, as evidenced by cessation of the laryngeal response to further lidocaine administration.4 The FOB was then advanced into the trachea and its tip was positioned 2 cm below the vocal cords. During inspiration, 3 mL of the study drug was sprayed into the trachea.
The time for each airway spray, namely the period from initial insertion of the FOB to its withdrawal from the patient’s mouth after completion of airway topicalization, was recorded using a digital stopwatch. The total times for airway sprays were measured as the times from first insertion of the FOB to its withdrawal from the patient’s mouth after the endotracheal spray (including the waiting time between repeated sprays). During each airway spray, an independent investigator unaware of the patient’s group assignment, observed and scored a patient’s comfort using a 4-point scale: no response = 1; slight gagging = 2; moderate gagging = 3; severe gagging or patient’s inability to tolerate = 4. Gagging was considered slight if only one episode of gagging occurred, moderate if 2–3 gagging episodes occurred, and severe if more than 3 episodes occurred. After completion of airway topical anesthesia, total dosages of lidocaine (including 50 mg used for intraoral sprays) were noted. Patients were also asked whether they had experienced any local anesthetic side effects, such as dysphoria, dizziness, nausea, and shivering, visual auditory disturbances, involuntary movements, etc.9
Five minutes after endotracheal spray, a suitable Murphy-type cuffed polyvinyl chloride endotracheal tube (ETT) (Hudson Respiratory Care Inc, Temecula, CA) that was preselected for the patient was threaded over the FOB. The awake FOI was performed according to the techniques previously described.3 After the glottis was exposed, the FOB was passed between the vocal cords into the mid-trachea. Carinal stimulation was avoided by advancing the tip of the FOB a maximum of 4 cm below the glottis. Then the ETT was inserted over the FOB into the trachea and was secured 3–4 cm above the carina. During awake FOI, supplementary airway topical anesthesia was provided with a single lidocaine injection through the FOB as required for patient comfort. After insertion of the ETT into the trachea, an independent blinded investigator scored patient’s reaction using a modified 6-point scale (no reaction = 1; no change or a single change in the facial expression: slight reaction = 2; grimacing facial expressions: moderate reaction = 3; severe facial grimace but retained ability to follow verbal command and no reflex head movements: severe reaction = 4; severe facial grimace associated with head movements, but still able to obey verbal command: very severe reaction = 5; and severe facial grimace associated with protective head and limb movements hindering the procedure, and inability to obey any verbal command: uncooperative = 6).12 Cough severity was rated on a 4-point scale (no cough = 1; slight coughing = 2; moderate coughing = 3; severe coughing = 4). Coughing was considered slight if no more than 2 coughs in sequence occurred, moderate if 3–5 coughs in sequence occurred and severe if more than 5 coughs in sequence occurred.13 Tracheal intubating conditions were assessed using a 3-point scale (excellent = no response and cough; adequate = both patient’s coughing and reaction scores were ≤3; unacceptable = both patient’s coughing and reaction scores were ≥4). The intubation times, defined as the period from initial insertion of the FOB to start of ventilation through the ETT, were measured with a stopwatch. The number of intubation attempts, the difficulties encountered, and the additional maneuvers needed during awake FOI were noted. The independent investigator also recorded BP and heart rate (HR) before airway sprays with the FOB (baseline), immediately after completion of airway sprays at different targeted areas, at intubation and 1 min after intubation. After confirmation of correct ETT placement by chest auscultation and capnography, general anesthesia was induced with IV propofol and maintained with IV fentanyl, 1%–2% end-tidal isoflurane plus 60% nitrous oxide in oxygen and vecuronium for muscle relaxation.
A baseline blood sample (5 mL) was obtained from the indwelling IV cannula before any lidocaine was administered (T0). Further blood samples were obtained after supraglottic and laryngeal sprays, and at 10-min intervals until 60 min had elapsed from the final endotracheal spray. After centrifugation, plasma was collected and kept frozen at −20°C for later analysis. Assays were performed using high-performance liquid chromatography with ultraviolet detection accurate to 0.02 μg/mL.14
Statistical analysis of data was performed with SPSS (Version 11.5, SPSS Inc., Chicago, IL). Nonparametric data from the 2 study groups were compared using a χ2 test. Parametric data from the 2 study groups were compared using two tailed t-tests. The intragroup comparisons of hemodynamic data at different observed points were done using repeated measures analysis of variance. Where significance was determined, Fisher’s protected least significant difference post hoc test was applied. Sample size was selected to detect a projected difference of 30% between groups with respect to patients’ reaction scores and coughing severity during awake FOI for a type I error of 0.05 (one-tailed) and a power of 0.8. Power calculation indicated that 26 patients per group would be required. The quantitative data were expressed as mean ± sd. A P value of <0.05 was considered statistically significant for all tests.
Fifty-two patients were studied. No patient was excluded due to excess sedation. Patient demographics were similar. The 2 patient groups were also comparable with respect to the dosages of midazolam administered for the desired level of sedation and patients’ OAA/S before and after airway topical anesthesia (Table 1).
There were no significant differences in the times for each airway spray in different targeted areas and total times for airway sprays between groups. Third and fourth sprays for adequate laryngeal anesthesia were required in 11 (42%) and 7 (27%) patients, respectively, in Group 1, in 8 (31%) and 5 (19%) patients, respectively, in Group 2 (P = NS between groups). The total dosages of lidocaine for airway sprays were significantly smaller in Group 1 (range of 3.2–4 mg/kg) than in Group 2 (range, 6.1–8.1 mg/kg) (Table 2).
All patients tolerated insertion of the FOB and airway sprays without severe gagging. During airway sprays, patients’ tolerance scores did not differ between groups. In both groups, however, patient comfort scores to first supraglottic and laryngeal sprays were significantly better than those to the endotracheal spray (Table 3).
In 51 of the 52 patients, awake FOI was accomplished successfully on the first attempt. In Group 2, 1 patient was not successfully intubated on the first attempt due to obscured vision with the FOB. During advancement of the ETT over the FOB, the ETT was impinged at the level of the glottis in 5 patients in Group 1, and in 7 patients in Group 2. It was effectively corrected by a 90° counterclockwise rotation of the ETT. When the ETT was inserted into the trachea, 7 patients in Group 1 and 9 patients in Group 2 showed no response in facial expression. All of the remaining patients exhibited mild or moderate reaction. The incidences of slight and moderate coughing were 54% and 15%, respectively, in Group 1, and 50% and 12%, respectively, in Group 2. No patient required supplemental lidocaine during awake FOI. After intubation, all patients were cooperative and were able to obey verbal commands without defensive movement and episodes of severe coughing and breath-holding. There were no significant differences in the intubation times, patients’ reaction and coughing scores, or incidences of coughing or intubating conditions between groups (Table 4).
Before the start of airway topical anesthesia, plasma levels of lidocaine were zero in all patients. The plasma lidocaine concentrations at all observed times after supraglottic sprays were larger in Group 2 than in Group 1 (Fig. 1). Peak plasma concentrations were observed at 20, 30, and 40 min after termination of lidocaine spray in 15, 8 and 3 patients, respectively, in Group 1, and in 19, 5 and 2 patients, respectively, in Group 2. Peak plasma lidocaine concentrations assayed in all patients were below 5 μg/mL. In Group 2, 1 patient who received 7.5 mg/kg of lidocaine reported dizziness, shivering, and tinnitus without evidence of hypotension 3 min after endotracheal spray. The plasma lidocaine concentration after endotracheal spray in this patient was 2.8 μg/mL. The remaining patients did not experience any side effect from lidocaine. Throughout the study, continuous oximetry and electrocardiogram monitoring revealed no abnormalities.
In both groups, systolic BP and HR increased gradually with each stage in the airway manipulation process and were significantly above baseline values during endotracheal spray and intubation. However, they recovered to baseline values at 1 min after intubation. Systolic BP and HR at all observed time points did not differ between groups (Figs. 2 and 3).
The primary aims of this study were to determine whether there were clinically relevant differences in the safety and efficacy of airway topical anesthesia between 2% and 4% lidocaine used in a spray-as-you-go technique with the FOB. When this airway topical anesthesia technique is used, local anesthetics are usually sprayed in the airway via either the suction channel of the FOB or through an epidural catheter passed through the FOB.2,4 The latter technique has been shown to be superior, by allowing more accurate delivery of local anesthetic and thus decreasing the dose needed for airway topical anesthesia.4 Thus, an epidural catheter technique was thus used in this study.
Our results clearly showed that, except for the total dosages and plasma concentrations of lidocaine, the 2 groups were comparable with regard to reaction scores, coughing severity, intubating conditions and hemodynamic changes during awake FOI. Also, symptoms of toxicity occurred in 1 patient who received 4% lidocaine. These results suggest that 2% and 4% lidocaine administered by a spray-as-you-go technique with the FOB have similar efficacy of airway topical anesthesia for awake FOI. As compared with 4% lidocaine, however, 2% lidocaine may provide a greater margin of safety, as it results in lower plasma concentrations of lidocaine.
In our study, 61.5%–73.1% of patients displayed grimacing and coughing responses during awake FOI, but most of these responses were slight and did not significantly impede fiberoscopy or tracheal intubation. The range of patient reaction and coughing scores were only 1.9–2.0 and 1.7–1.9, respectively. Furthermore, all patients exhibited excellent or acceptable intubating conditions. Therefore, we consider that under adequate sedation with fentanyl and midazolam, both 2% and 4% lidocaine administered to the airway by a spray-as-you-go technique can provide clinically acceptable intubating conditions for awake FOI.
The lack of complete airway topical anesthesia in either group may be explained by several factors. First, the lidocaine solution cannot be aerosolized when delivered via the epidural catheter technique, as needed for penetration of the airway mucosa.9 Our previous work showed that a modified spray-as-you-go technique using a combination of the FOB and the MADgic® atomizer could produce adequate airway topical anesthesia for awake FOI.15 This is probably because the MADgic® atomizer delivers atomized lidocaine solution directly to the airway mucosa.4 Second, because of the flexibility of the FOB and the active airway reflexes of awake patients, the stream of lidocaine injected via an epidural catheter can often be misdirected away from the targeted supraglottic and glottic areas.2 Third, each spray only covers a small airway area due to the fine but nonatomized stream of lidocaine. Moreover, airway secretions can also impede effective topical anesthesia by diluting lidocaine applied to the airway mucosa and forming a mechanical barrier between lidocaine and the mucosa.9 Therefore, variable efficacy of airway topical anesthesia is inevitable. Fourth, when the endotracheal spray is performed, the tip of the FOB must be advanced into the site below the glottis to prevent its slipping out of the trachea as the result of coughing or head movement. A nonatomized lidocaine solution is actually injected in the upper trachea and the spreading of lidocaine is achieved mainly by patient’s coughing immediately after injection. Thus, it is impossible to ensure that lidocaine is well distributed along the infraglottic area and tracheal wall. It has been demonstrated that compared with the spray-as-you-go technique, the translaryngeal injection of lidocaine at a more proximal site in the airway can produce more effective airway topical anesthesia for fiberoscopy.16 Fifth, topical local anesthetics are less effective because of the diminished buffering capacity of the airway mucosa, which limits release of the anesthetic base.9 Also, the stretch receptors at the root of the tongue, which cause the gag reflex, are submucosal and not easily blocked after topical application of local anesthetics.4,9 It is generally believed that even the most thorough airway topical anesthesia may also be inadequate for awake intubation in some patients.17
There are relatively large differences in the time required for lidocaine sprays to provide satisfactory airway topical anesthesia (11–70 min) reported in different studies.5–7,18 The total times for airway sprays in our study are in agreement with previously reported results. Our study showed that, in most patients, peak plasma lidocaine concentrations were observed 20 to 30 min after lidocaine administration. This also corresponds with the findings of previous studies in which peak plasma lidocaine levels usually occur at 10–15 min (range, 5–30 min) in adult patients after administration of lidocaine (doses of 3.2–8.5 mg/kg) by the spray-as-you-go technique.5,7,18–20
The maximum safe dosage of lidocaine for airway topical anesthesia has generally been considered to be 4 mg/kg.2,4,9 In our study, the total dosages of lidocaine approximated this maximum safe dosage in Group 1, but the maximum was exceeded in Group 2. However, the plasma lidocaine concentration assay showed that the highest drug levels were only 2 and 3.6 μg/mL in Groups 1 and 2, respectively, which were within normal therapeutic plasma concentrations (2–5 μg/mL).9 In addition, only 3 patients (11.5%) in Group 2 had peak plasma lidocaine levels of >3 μg/mL. This discrepancy between the large dose of lidocaine used in the airway by the spray-as-you-go technique and the low plasma concentration has also been confirmed in previous comparable studies.5,7,18–20 This phenomenon may be due mainly to drug losses during airway sprays.3,9 In our study, 73%–76% of the total lidocaine dose was administered to the oropharynx, supraglottic sites, and vocal cords. Thus, most of the lidocaine may have been swallowed by awake patients as it pooled in the posterior oropharynx during airway sprays. After endotracheal spray, some lidocaine is also likely to be coughed into the pharynx and subsequently swallowed, thus undergoing “first-pass metabolism” in the liver, which removes almost 70% of lidocaine.18
Some researchers have suggested dosages of up to 7–9 mg/kg for topically applied lidocaine during fiberoscopy or awake FOI without complications.6–8,19,21 However, we do not agree that such large doses of lidocaine are safe in routine clinical practice. First, lidocaine pharmacokinetics are complex and may be affected by many factors.7 This means that the plasma lidocaine level achieved in a particular patient is often unpredictable, even though a safe dosage has been used. In our and previous studies,5,7,18–20 the relatively large standard deviations of plasma lidocaine concentrations underscore the significant individual variation in lidocaine absorption. Previous studies have also shown that even when recommended doses are used, patients still sometimes achieve an unexpectedly high plasma level.19,22,23 In a report of anesthetists attending a training course in airway topical anesthesia, Martin et al.6 noted that after administration of 2% lidocaine (7.1–14.8 mg/kg) by a spray-as-you-go technique, 92% (36 of 39) of subjects reported subjective central nervous system side effects, and 3 subjects experienced tremors, usually considered a sign of early toxicity. When airway topical anesthesia was produced with up to 9 mg/kg of lidocaine in 200 healthy anesthesiologists who underwent fiberoscopy and intubation without sedation as part of a training course, 71 subjects (36%) reported symptoms that could be attributed to lidocaine toxicity.24 In addition, a healthy volunteer died from lidocaine toxicity after fiberoptic bronchoscopy for research purposes.25 Second, lidocaine toxicity can occur even when the plasma lidocaine levels are in the safe range. In the study by Williams et al.,7 4 subjects with peak plasma lidocaine concentrations of <5 μg/mL experienced the presymptoms of toxicity. In our current study, 1 patient with plasma lidocaine concentration of 2.8 μg/mL reported early signs of toxicity. Based on these reports, we recommended that 2% lidocaine be used for airway topical anesthesia with the spray-as-you-go technique. This increases the safety margin, and allows additional lidocaine to be administered when airway topical anesthesia is inadequate.
In the present study, we also found that, in both groups, patients’ comfort scores to first supraglottic and laryngeal sprays were significantly better than those to endotracheal spray, suggesting that tracheal stimulus caused by the endotracheal spray may cause patients more discomfort. This is in agreement with previous studies that have shown that cough was one of the most distressing symptoms associated with awake FOI.3,12
BP and HR changes during a procedure may give an indirect indication of the distress or discomfort produced.7 In our study, systolic BP and HR increased gradually with each stage in the airway manipulation process and significantly exceeded baseline values at endotracheal spray and intubation. In both groups, however, mean maximum increases in systolic BP and HR observed during airway manipulation were <20% of baseline values. Also, they recovered rapidly to baseline values at 1 min after intubation, consistent with previous studies.7,8 These slight cardiovascular responses may be attributed to tracheal stimulation caused by the insertion of the FOB and ETT. There is increasing evidence to suggest that tracheal stimulation is the primary cause of the cardiovascular response26 and effective airway topical anesthesia can completely block these adverse responses.5,12 The lack of significant differences in the cardiovascular intubation responses between groups suggests that 2% and 4% lidocaine administered by the spray-as-you-go technique are equally effective for awake FOI.
In an unblinded, comparative study in morbidly obese patients, Wieczorek et al.27 claimed that using 40 mL of atomized lidocaine 2% or 4% can provide equally rapid and effective airway topical anesthesia. In fact, ideal intubating conditions are reached only in patients receiving 4% lidocaine with doses of 11 mg/kg. Six of 14 patients (42%) receiving 2% lidocaine experienced a gagging response on positioning the ETT, and 1 patient did not tolerate airway manipulation, despite administration of 6 mg/kg of lidocaine. We feel that this high incidence (42%) of gagging on intubation is clinically significant, despite the lack of statistical significance. In this randomized, double-blind, comparative study with a larger patient sample, we demonstrated that both 2% and 4% lidocaine administered in the airway by the spray-as-you-go technique provided clinically acceptable intubating conditions for awake FOI, though total dosages of lidocaine were significantly lower in our study compared with those in Wieczorek et al.’s study.27
Wieczorek et al. ’s study points out several patient safety issues.28,29 The first is the use of relatively large doses of lidocaine (800–1600 mg) in a short time (5 min).27 This practice may, in fact, ignore the potential for significant morbidity, especially since the patients in the study received general anesthesia immediately after awake intubation, such that any possible clinical signs of toxicity were masked. This limitation may be even more significant in patients with a normal Body Mass Index compared with the morbidly obese patients, because the lower total dose of lidocaine in these patients will likely limit the efficacy of airway topical anesthesia due to local anesthetic wasting.30 It has been estimated that only 8%–12% of lidocaine given by a nebulizer reaches the airway.31 The second more serious limitation relates to the “art” of airway topicalization using the atomizer technique, which will invariably influence the amount of drug administered. This includes the success of achieving continuous deep inspiratory efforts for several minutes, maintaining clamping of the nares, and the “painting” of the oropharyngeal structures with lidocaine spray throughout the respiratory cycle.27
Although 2%–4% lidocaine applied to the airway mucosa begins to produce topical anesthesia in about 1 min, 3–5 min of contact time is usually required to provide adequate penetration of lidocaine into the airway mucosa for maximal effect.32 For this reason, we repeated the airway sprays at 3–5 min intervals, such that the protocol required 21–24 min from the first application of lidocaine to intubation of the trachea. One may argue that this delay is not practical because most anesthesiologists prefer a faster onset of airway topical anesthesia. However, we feel that as with other local anesthesia methods, “tincture of time” should be one of the most useful supplements to airway topical anesthesia.3 Inadequate airway topical anesthesia due to slow onset of maximal effect often results in repeated drug use in a short time, leading to overdoses of lidocaine. In contrast, fractional doses of lidocaine sprayed into the airway over a longer period result in a lower plasma drug level.9 Because adequate airway topical anesthesia with minimum dosage of lidocaine is of paramount importance for patient safety, a reasonable waiting period after each airway spray is preferred.5,7,15
In conclusion, our study demonstrates that both 2% and 4% lidocaine, administered to the airway by a spray-as-you-go technique with the FOB, can provide clinically acceptable intubating conditions for awake FOI in sedated patients with a difficult airway. As compared with 4% lidocaine, however, 2% lidocaine requires a smaller total dose and results in lower plasma concentrations. We recommend that 2% lidocaine be used during airway topical anesthesia with the spray-as-you-go technique.
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